2023 The Emerging Roles of Long Non-Coding RNA in Host Immune Response and Intracellular Bacterial Infections

TYPE Review
PUBLISHED 21 April 2023

DOI 10.3389/fcimb.2023.1160198
The emerging roles of long non-

OPEN ACCESS coding RNA in host immune
EDITED BY
Jianfeng Wang,
Jilin University, China
response and intracellular
REVIEWED BY
Duc-Cuong Bui,
bacterial infections
University of Texas Medical Branch at
Galveston, United States
Li Xing, Aryashree Arunima, Erin J. van Schaik and James E. Samuel*
Shanxi University, China
Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University,
*CORRESPONDENCE Bryan, TX, United States
James E. Samuel
[email protected]
SPECIALTY SECTION
This article was submitted to The long non-coding RNAs (lncRNAs) are evolutionarily conserved classes of
Bacteria and Host,
a section of the journal non-coding regulatory transcripts of > 200 nucleotides in length. They modulate
Frontiers in Cellular and several transcriptional and post-transcriptional events in the organism.
Infection Microbiology
Depending on their cellular localization and interactions, they regulate
RECEIVED 06 February 2023 chromatin function and assembly; and alter the stability and translation of
ACCEPTED 07 April 2023
cytoplasmic mRNAs. Although their proposed range of functionality remains
PUBLISHED 21 April 2023
controversial, there is increasing research evidence that lncRNAs play a
CITATION
Arunima A, van Schaik EJ and Samuel JE
regulatory role in the activation, differentiation and development of immune
(2023) The emerging roles of long non- signaling cascades; microbiome development; and in diseases such as neuronal
coding RNA in host immune response and and cardiovascular disorders; cancer; and pathogenic infections. This review
intracellular bacterial infections.
Front. Cell. Infect. Microbiol. 13:1160198. discusses the functional roles of different lncRNAs in regulation of host immune
doi: 10.3389/fcimb.2023.1160198 responses, signaling pathways during host-microbe interaction and infection
COPYRIGHT caused by obligate intracellular bacterial pathogens. The study of lncRNAs is
© 2023 Arunima, van Schaik and Samuel. assuming significance as it could be exploited for development of alternative
This is an open-access article distributed
under the terms of the Creative Commons therapeutic strategies for the treatment of severe and chronic pathogenic
Attribution License (CC BY). The use, infections caused by Mycobacterium, Chlamydia and Rickettsia infections, as
distribution or reproduction in other
forums is permitted, provided the original
well as commensal colonization. Finally, this review summarizes the translational
author(s) and the copyright owner(s) are potential of lncRNA research in development of diagnostic and prognostic tools
credited and that the original publication in for human diseases.
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted KEYWORDS
which does not comply with these terms.
long non-coding RNAs (lncRNAs), host-pathogen interaction, obligate intracellular
pathogens, microbiota, inflammation, phagocytes, biomarker
1 Introduction
The genomes of simplest micro-organisms to complex genome of humans encode a
vast repertoire of biological information that needs to be unraveled at the molecular level.
Next-generation sequencing and recent developments in computational programming and
annotation methods have expanded our understanding of DNA beyond the protein-coding
regions of the genome (Liu et al., 2013; Uszczynska-Ratajczak et al., 2018). A comparison
Frontiers in Cellular and Infection Microbiology 01 frontiersin.org

Arunima et al. 10.3389/fcimb.2023.1160198
between the genomes of different species showed functional, sequence. The most widely used classification of lncRNAs is
evolutionary, and genomic similarities in their protein-coding based on their positioning in the genome which could be sub-
regions. This prompted a paradigm shift from mRNA-centric divided into five classes of lncRNA (Ma et al., 2013; St.Laurent
view of host gene regulation to the non-coding regions of the et al., 2015).
genome. Recent studies and consortiums like ENCODE (The
Encyclopedia of DNA Elements) and FANTOM (The Functional
Annotation of the Mammalian Genome) have characterized a 2.1 Based on genome location
section of the non-coding regions of the genome and identifies
their regulatory role in host transcriptome (Chen et al., 2017). 2.1.1 Intergenic and intronic lncRNAs
Among such loci are the long non-coding RNAs (lncRNAs) LncRNAs that are located and transcribed from different
(Uszczynska-Ratajczak et al., 2018). intergenic regions are designated intergenic lncRNAs (Figure 1A).
LncRNAs are classically defined as transcripts of at least > 200 LncRNAs transcribed from introns of protein-coding genes are
nucleotides in length (Uszczynska-Ratajczak et al., 2018). The designated intronic lncRNAs (Figure 1B). Long-intergenic non-
recent GENCODE v. 42 release shows out of 252,416 annotated coding RNAs (lincRNAs) are the most widely studied type of
transcripts, 89,305 are mRNA, while 57,936 are annotated lncRNAs lncRNAs. They are transcriptionally activated in a mechanism
in the human genome (Frankish et al., 2021). New tools like single similar to mRNA and are more conserved across species than
cell sequencing, rapid amplification of cDNA ends sequencing intronic lncRNA (Khalil et al., 2009; Guttman et al., 2010; Ma et al.,
(RACE-seq), capture long sequencing (CLS) method, 2013) and antisense transcripts (Guttman et al., 2010; Ma et al., 2013).
photoactivatable ribonucleotide-enhanced cross-linking and Their expression is more tissue-specific and stable as compared to
immunoprecipitation (PAR-CLIP), capture hybridization analysis other types of lncRNAs (Guttman et al., 2010; Cabili et al., 2011).
of RNA targets (CHART) and in vitro RNA antisense purification
(RAP) have expanded our understanding of lncRNA transcriptome 2.1.2 Bidirectional lncRNAs
and interactome (Agliano et al., 2019). The tools have validated Bidirectional lncRNAs are located head-to-head within 1kb of
these transcripts and annotated their genomic location and protein-coding genes, are transcribed under a bidirectional
structure (Chen et al., 2017). Studies have shown lncRNAs promoter (Figure 1C). This results in similar expression pattern
modulate diverse biological pathways at transcriptional, post- between the lncRNA transcripts and its protein-coding gene
transcriptional and epigenetic levels by acting as decoys, scaffold, (Carpenter et al., 2013; Atianand et al., 2017). LincRNAs and
guides, sponges or enhancers (Wang and Chang, 2011; St.Laurent bidirectional lncRNAs do not overlap with other genes, and are
et al., 2015). As a result, they play a critical role in diverse cellular therefore called as non-overlapping lncRNAs (Statello et al., 2021).
processes like embryonic development, stem cell pluripotency, Bi-directional or divergent promoters of lncRNAs are predicted as
neuronal and cardiac differentiation (DiStefano, 2018). They have sites for evolutionary divergence to new genes or for cis-regulation
also been linked to several cancer, immune response regulation, of protein-coding genes.
host-pathogen interaction and microbiota interaction (DiStefano,
2018; Agliano et al., 2019).
The current review has two main objectives. The first objective 2.1.3 Sense lncRNAs
is to understand the organization of lncRNAs in human genome Sense lncRNAs are a type of overlapping lncRNAs that are
and how they are functionally classified and regulated. Often, the transcribed from the sense strand of protein-coding genes
lncRNAs are spatio-temporally regulated and their genome location containing exons (Figure 1D). Interestingly, some sense lncRNAs
is biologically linked with the cellular pathways they are likely to can function as both RNA and protein-coding gene. For instance,
influence in the host (Herriges et al., 2014; Dempsey et al., 2018). steroid receptor RNA activator (SRA) gene can translate into
The second objective is to shed light on the role of several annotated protein, and the transcript can also function as scaffold for co-
and discovered lncRNAs that regulate the immune responses and activators and repressors to form complexes regulating
pathogenesis during host-pathogen interaction with a special focus transcription (Hubé et al., 2011).
on the obligate intracellular pathogens. The review also identifies
gap in lncRNA research and discusses lncRNA based therapeutic 2.1.4 Antisense lncRNAs or Natural antisense
approaches in diagnosis and treatment of infectious diseases. lncRNAs (NATs)
Antisense or NAT lncRNAs are transcribed from the antisense
strand of protein-coding genes. They are the most abundant type of
2 Classification of LncRNA lncRNAs found in the mouse and human genome (Agliano et al.,
2019). NATs are further classified into cis-NATs and trans-NATs
The classification of lncRNAs is mostly empirical and so far, (Figure 1E). cis-NATs are complementary to its overlapping
there are no standard parameters to classify them. However, protein-coding gene, while trans-NATs are located in different
lncRNAs can be classified according to different features as positions of the genome and are complementary to a protein-
follows: (A) genome location; (B) mode of action on DNA coding gene (Ohhata et al., 2022).

FIGURE 1
Classification of long non-coding RNA (lncRNA) based on genomic location. Protein-coding genes are represented in green and their exons are
represented in black-bordered, arrow-shaped box. Introns are denoted by solid black lines. LncRNAs are represented in blue and their exons are
represented in pink-arrow-shaped box. Direction of transcription is noted by the direction of the arrows. (A) Intergenic lncRNAs are transcribed from
the intergenic regions of both the strands. (B) Intronic lncRNAs are transcribed from introns of protein-coding genes. (C) Bidirectional lncRNAs are
located head-to-head with a protein-coding gene within 1 kb under a common bidirectional promoter. (D) Sense lncRNAs are transcribed from the
sense strand of the protein-coding genes and contain exons from protein-coding genes. The lncRNA may partially overlap with the protein coding
genes or may entirely overlap with the protein-coding gene through introns. (E) Antisense lncRNAs or naturally antisense transcripts (NATs) are
transcribed from the antisense strand of protein-coding genes. NATs comprises of cis-NATs and trans-NATs. cis-NATs can overlap with exons or
introns or may entirely overlap with the protein-coding sequence. trans-NATs is complementary to a target protein-coding gene and it is located in
distal part of the genome.
2.2 Based on mode of action on to regulate neighboring gene Ptgs2 (Elling et al., 2018). Cis-lncRNAs
DNA sequences because of their co-occurrence with neighboring gene are ideal
candidates for investigation of their biological role in host. This is
2.2.1 cis-lncRNA usually based on the hypothesis that, cis-lncRNAs could be
cis-lncRNAs are lncRNAs that can regulate expression of genes regulating the same biological pathways as their neighboring
located in the neighboring region (Ohhata et al., 2022). Most of the protein-coding gene (Robinson et al., 2020).
lncRNA from the global transcriptome exert cis-regulatory effects cis-lncRNA regulates neighboring gene either at transcriptional
on neighboring protein-coding gene (Engreitz et al., 2016). For or epigenetic level. It represses transcription either by binding to the
instance, AS-IL1a (AS- interleukin-1 a-subunit) (Chan et al., promoter of target gene and blocking the formation of pre-initiation
2015), lnc-IL7R (lnc-interleukin-7 receptor a-subunit) complex, or by interacting with the transcription factors (TFs)
(Hadjicharalambous et al., 2018), and IL-1b-enhancer RNA are (St.Laurent et al., 2015). For instance, lncRNA of DHFR (di-
examples of cis-acting lncRNA (Engreitz et al., 2016; Robinson hydrofolate reductase) can form a stable triplex structure with the
et al., 2020). LincRNA-Cox2 act as an enhancer RNA (eRNA) in cis promoter region (0.8-7.3Kb region upstream) of DHFR and TFIIb

to displace the pre-initiation complex for transcriptional inhibition mechanism similar to that required for mRNA maturation. The
(Martianov et al., 2007; Ma et al., 2013). SRG1 is ~0.4-1.9Kb of size matured lncRNA transcripts often comprise of 7-methyl guanosine
transcript that spans the promoter region of SER3 (m7G) cap at their 5’ ends and polyadenylation (poly-A tail) at 3’ ends.
(phosphoglycerate dehydrogenase gene in Saccharomyces At the chromatin level, lncRNA and mRNA show H3K4me3
cervisiae). The resultant SRG1-RNA prevents the TF binding to (trimethylation of histone 3 at Lys4) at the promoters. However,
SER3 promoter to inhibit transcription (Martens et al., 2004; Ma lncRNA that shows chromatin enrichment of H3K27ac (acetylation
et al., 2013). Interaction of cis-lncRNA with chromatin modifying of histone 3 Lys27) are repressed by CME complexes; Swr1, Rsc,
enzyme (CME) complex to regulate protein-coding gene expression Ino80 and Isw2 (van Attikum et al., 2007). The initiation sites of
can be negative or positive regulatory event. Xist is a 19 Kb lncRNA lncRNA for transcription are divergent like most of the eukaryotic
which interacts with polycomb repressive complex 2 (PRC2) to promoters. Most of the cis-lncRNA are transcribed antisense to the
trimethylate H3K27 that transcriptionally represses genes encoded protein-coding gene by RNA polymerase II. Usually, these mRNA-
on X-chromosome (Froberg et al., 2013; Maclary et al., 2017). lncRNA pair has coordinated expression, however transcription
GAL10-ncRNA (Gal10p-noncoding RNA) is ~4Kb lncRNA that elongation is productive only in sense direction (Core et al., 2008).
recruits Rpd3S HDAC (Rpd3 small histone deacetylase complex) to Asymmetric distribution of polyA- and splicing signals also
reduce acetylation of H3 histone and transcriptionally represses determine elongation and stability of mRNA-lncRNA pairs. For
GAL1 expression (Houseley et al., 2008; Leng et al., 2021). HOTTIP instance, polyadenylation signals in U1 snRNP are enriched in the
(HOXA transcript at the distal tip) is ~3.8 kb lncRNA in human cis antisense direction, while the splicing signals are enriched in the
that recruits MLL chromatin modifying complex to maintain a sense direction (Almada et al., 2013).
domain of active chromatin over the 5’ end of HOXA (homeobox A
cluster) (Wang et al., 2011; Ghafouri-Fard et al., 2020)
3.2 Post-transcriptional processing
2.2.2 trans-lncRNA of lncRNA
LncRNAs that can regulate expression of genes located in
different region are called trans-lncRNAs. For instance, lincRNA- Besides, 5’-capping, 3’-polyadenylation, splicing and chemical
Cox2 is upregulated (Carpenter et al., 2013) and lincRNA-erythroid base modification, lncRNAs undergo alternative types of processing
prosurvival (lincRNA-EPS) is downregulated (Robinson et al., to form mature lncRNAs. For instance, RNaseP-mediated cleavage
2020) in response to Toll-like receptor (TLR)-4 and TLR-2 is an alternative method of canonical cleavage and polyadenylation
stimulation in murine dendritic cells (DCs) and bone marrow to process 3’ ends of most lncRNAs. MALAT1 (metastasis
derived macrophages (BMDM). These lncRNAs regulate large associated lung adenocarcinoma) and NEAT1 (nuclear enriched
number of distally located interferon stimulated genes (ISGs) and abundant transcript 1) are highly abundant types of nuclear
NF-kB regulated genes (Carpenter et al., 2013). HOTAIR (HOX lncRNA, that localizes to the nuclear speckles and paraspeckles
antisense intergenic RNA) is a lncRNA transcribed from the HOXC respectively (Quinn and Chang, 2016). They have a tRNA-like-
(homeobox C cluster) gene locus in chromosome 12. It is exported cloverleaf structure in the 3’end and A/U-rich sequence which form
by Suz-Twelve protein to regulate the homologous target sites at a stable triple helix. RNaseP cleaves tRNA-like-cloverleaf structure
HOXD (homeobox D cluster) gene located in chromosome 2 (Rinn from the immature MALAT1 and NEAT1 to produce mature
et al., 2007). transcripts. The mature MALAT1 transcript is known as
MALAT1−associated small cytoplasmic RNAs (mascRNAs) which
structurally mimics tRNA and is exported to the cytoplasm (Wilusz
3 Biogenesis and regulation et al., 2008). mascRNA subunit is cleaved, the U–A•U RNA triple
of LncRNA helix at the 3′ end of mature MALAT1 increases the stability of the
transcript that enables it to regulate alternative splicing (Tripathi
The biogenesis of LncRNAs is similar to that of mRNAs and et al., 2010; Brown et al., 2012; Zong et al., 2016). A NAT of
regulated by several transcriptional and epigenetic regulators. The MALAT1 was recently discovered and annotated as TALAM1. It
study of the differences in biogenesis, processing and turnover of contributes to the stability of MALAT1 by promoting the 3′ end
lncRNAs is important as it influences their cellular fates cleavage and maturation of MALAT1. MALAT1 regulates the
and functions. transcription and stability of TALAM1 through a feed-forward
positive regulatory loop at the MALAT1 locus, that leads to high
cellular levels of MALAT1 (Zong et al., 2016). On the other hand,
3.1 Transcriptional processing of LncRNA NEAT1 is transcribed into two isoforms: a short form with a
canonical poly (A)-tail (NEAT1_1) and a long unspliced form
LncRNAs in comparison to mRNA contain fewer but longer that lacks polyadenylation (NEAT1_2). NEAT1_2 is 22.7
exons. Their cellular expression levels are low and exhibit low kilobases (kb) and is processed by RNase P (Wilusz et al., 2012;
primary sequence conservation. They are mainly transcribed by Cornelis et al., 2016). Post cleavage by RNAseP, NEAT1_2 is
RNA polymerase II, but also can be transcribed by other RNA processed into an RNA-stabilizing triple helix at its 3′ end and an
polymerases. Following transcription, they undergo splicing in a unstable tRNA-like by-product (Statello et al., 2021).

4 Localization of LncRNA such as for ZFAS1 regulates mRNAs encoding proteins from the
ribosomal complex. LncRNA UCA1 act as decoy of hnRNP1 to
Cellular localization of lncRNA can determine molecular prevent it’s binding to p27-mRNA and restrict translation.
contacts and hence its biological functions such as modulation of Cytoplasmic lncRNAs like LINK-A, lnc-DC, NKILA and Lethe
mRNA stability, signaling pathways, regulatory site of action and regulates different cellular signaling response. LINK-A activates
transcriptional expression of target gens. It can therefore be argued BRK kinase and promote HIF1a stabilization. Lnc-DC promotes
as a fundamental feature for understanding of lncRNA molecular STAT3 phosphorylation, while NKILA inhibit NF-kB signaling and
mechanisms. Based on their localization, lncRNAs can be classified Lethe reduces RelA transcriptional turnover (Noh et al., 2018).
into the classes described below.
4.3 Mitochondria associated lncRNAs

4.1 Nuclear lncRNAs
Mitochondrial associated lncRNAs often function in
Nuclear localization of lncRNAs is governed by several factors regulation of mitochondrial metabolism, apoptosis and the
such as splicing signals (Melé et al., 2017), polyadenylation signal at crosstalk of mitochondria with nuclei (Zhao et al., 2018). For
3’ end (Rosenberg et al., 2015), nuclear retention elements and instance, survival associated mitochondrial melanoma specific
repeats (Zuckerman and Ulitsky, 2019; Guo et al., 2020). For oncogenic non-coding RNA (SAMMSON) is a lncRNA that
example, in mouse embryonic stem cells (mESCs), splicing maintains mitochondrial homeostasis, mitochondrial 16S rRNA
inhibitor peptidylprolyl isomerase E suppresses splicing of a maturation and e xpression of mitochondria-encod ed
subset of lncRNAs, leading to significant nuclear retention of polypeptides (Leucci et al., 2016). The mitochondria-encoded
many lncRNAs in mESCs (Guo et al., 2020). LncRNA CCAT1 lncRNAs; lncND5, lncND6 and lncCytB form intermolecular
(colon cancer-associated transcript 1) produces two isoforms: the duplexes with mRNAs and regulate their stability and
long isoform (CCAT1-L) is nuclear and contains an internal expression (Statello et al., 2021). The RNA component of
polyadenylation site corresponding with the 3′ end of the short mitochondrial RNA-processing endoribonuclease (RMRP) is
isoform (CCAT1-S), which is cytoplasmic (Xiang et al., 2014). In exported to the cytoplasm through its association with RBP
addition, lncRNAs can often contain nuclear retention signals or HuR by exportin 1. RMRP is then exported to mitochondria,
motifs that recruit nuclear factors, which promote the nuclear where it stabilized by G-rich RNA sequence-binding factor 1
localization of the lncRNA. For example, the lncRNA maternally (GRSF1), which allows its enrichment in the mitochondrial
expressed gene 3 (MEG3) contains a 356-nucleotide nuclear matrix (Quinn and Chang, 2016).
retention element that associates with U1 snRNP (Azam et al.,
2019). Repeat elements also drive lncRNA nuclear retention
(Lubelsky and Ulitsky, 2018; Shukla et al., 2018). For instance, the 4.4 Exosome associated lncRNAs
lncRNA functional intergenic repeating RNA element (FIRRE)
contains many unique repeats which promote FIRRE interaction Transcriptome analyses of human blood samples have
with heterogeneous nuclear ribonucleoproteins (hnRNP) and identified many lncRNAs which localize into the exosomes
chromatin localization (Hacisuleyman et al., 2016). In summary, through an unknown mechanism. Exosomal lncRNA like
nuclear lncRNAs regulate transcriptional expression of target genes MALAT1 (Liu J. et al., 2021), growth arrest-specific 5 (GAS5)
in cis or in trans or at epigenetic level by being tethered to the (Patel et al., 2022), H19 (Wang et al., 2020), HOTAIR (Yang
chromatin in membrane-less nuclear domains. et al., 2019), small ubiquitin-like modifier 1 SUMO1 pseudogene
3 (SUMO1P3) (Li et al., 2021b) and X-inactive specific transcript
(XIST) (Lan et al., 2021) were previously shown upregulated in the
4.2 Cytoplasmic lncRNAs blood, lung and breast tissues of cancer patients (Li et al., 2021b). It
is noteworthy that the gut microbiota (Dı́az-Garrido et al., 2021;
Cytoplasmic lncRNAs are expected to perform regulatory roles Park et al., 2021), intracellular pathogens like Salmonella
in the cytoplasm and may share the same processing and export Typhimurium (Imamura et al., 2018), Mycobacterium tuberculosis
pathways with mRNAs. Cytoplasmic lncRNAs are sorted into either (Liu M. et al., 2021) and obligate intracellular pathogens like
organelles, or distributed in the cytoplasm, or interact with different Chlamydia psittaci (Radomski et al., 2019), Rickettsia spp. (Liu Y.
RNA-binding proteins (RBPs) or microRNAs (Rackham et al., et al., 2021) and Anaplasma phagocytophilum are internalized into
2011). Linc-MD1 regulates muscle differentiation timing by host cells via endocytosis (Zhou et al., 2020). They communicate
sponging two miRNAs. LncRNA H19, Linc-MD1 and PTENP1 with DCs and phagocytes’ host-derived factors through the
act as microRNA decoy of let-7, miR-133b and PTEN respectively exosome for activation of antibacterial immunity. A
to inhibit their transcription. LincRNA-p21 is both cytoplasmic and transcriptome analysis of serum derived exosomes during
ribosomal lncRNA that negatively regulates JUNB and CTNNB1 Orientia tsutsugamushi infection showed downregulation of Let7
translation in HeLa cells (Noh et al., 2018). LncRNA co-localization family of microRNAs (a type of non-coding RNA). Let7 regulates
with ribosomes or endoplasmic reticulum (ER) regulates translation immune response and cytokine activation by modulating TLR-4

signaling pathway (Jiang et al., 2020). These findings suggest that genes (Statello et al., 2021). For instance, KCNQ1 overlapping
exosomal lncRNAs may modulate host immune response to transcript 1 (KCNQ1OT1) and HOTAIR binds to PRC2, to
intracellular bacterial infections. regulate its target gene expression (Ahmad et al., 2021). LncRNA
In summary, lncRNAs have complex spatio-temporal TCF7(transcription factor 7) recruits the SWItch/Sucrose Non-
regulation within the cell that is linked to sequence encoded Fermentable (SWI/SNF) complex to the promoter of TCF7 that
localization signals. All these findings may help in prediction of activates the Wnt signaling pathway to promote self-renewal of liver
their mechanism of functioning in the cell. cancer stem cells (Gao et al., 2020).
5 Molecular mechanisms of 5.4 Scaffolds

functioning of lncRNA
LncRNAs act as scaffold (Figure 2D) by providing structural
As discussed previously, lncRNAs regulate different cellular support in assembly of regulatory protein complexes like ribo-
functions at transcriptional, post-transcriptional, translational or nucleoprotein (RNAP) complex (Statello et al., 2021). They
epigenetic level depending on their sub-cellular localization facilitate the assembly of RNAP complex to either
(Statello et al., 2021). Briefly, they primarily function as: transcriptionally inhibit or activate target protein-coding genes
(Statello et al., 2021). For example, lncRNA TERC scaffolds the
assembly of telomerase complex and associated accessory proteins
5.1 Signals with reverse transcriptase in a single RNAP (Wang and Chang,
2011). Under certain events, lncRNAs like MALAT1, ANRIL, and
LncRNAs which are expressed at a specific time and cellular TUG1 act as molecular scaffolds to PRC1 and PRC2 to
location in response to stimuli are signal lncRNAs (Figure 2A). transcriptionally repress or activate target genes (Balas and
They can interact with CME such as histone methyltransferases Johnson, 2018).
to silence their target genes either by inhibition of transcription Several lncRNAs act as scaffold for the assembly of nuclear
or through heterochromatin formation (Wang and condensates. Nuclear condensates are membrane-less
Chang, 2011). compartments encompassing RNA-protein complex involved in
regulation of cellular activities (Statello et al., 2021). NEAT1 act as
scaffold for organization and function of paraspeckles (Jiang et al.,
5.2 Decoys 2017; Yamazaki et al., 2018). NEAT1_2 is essential for assembly of
paraspeckles (Yamazaki et al., 2018). The middle region (8–16.6 kb)
Decoy lncRNAs act as transcriptional repressors in an indirect of NEAT1_2 comprises of two sub-domains of (~12–13 kb) and
way by reducing the availability of the regulatory factors (Figure 2B) (~15.4–16.6 kb) length that act as scaffold to the paraspeckle core
that includes: microRNA (miRNA), CME complexes, catalytic proteins NONO and SFPQ (Yamazaki et al., 2018). The mechanism
proteins, and TFs (Ahmad et al., 2021). For instance, the decoy behind the structural assembly of NEAT1_2 into the paraspeckles is
lncRNA PANDA (P21 associated ncRNA DNA damage activated) not clear. LncRNA can also act as scaffold to bring distal chromatin
regulates p53-dependent apoptosis. NFYA (Nuclear Transcription regions into proximity. For example, FIRRE is transcribed from X
Factor Y Subunit Alpha) is a TF that activates transcription of chromosome. It functions in trans as scaffold with the nuclear
apoptosis-related genes. PANDA binds to NFYA which prevents its matrix factor hnRNPU to maintain a nuclear domain
binding to the promoter of apoptosis related genes (Liu J. et al., (Lewandowski et al., 2019).
2018). Taurine upregulated 1 (TUG1) and MEG3 are other
instances of lncRNAs decoys miRNA from target mRNA (Balas
and Johnson, 2018; Da et al., 2021). LncPRESS1 (lncRNA p53 5.5 Enhancers
regulated and ESC associated 1) is a pluripotency-associated
lncRNA. lncPRESS act a decoy of deacetylase Sirtuin-6 and LncRNAs that act as enhancers can be broadly categorized into
sequesters it from the chromatin, which promotes transcriptional enhancer-RNAs (eRNAs) and enhancer-associated lncRNAs
activation by H3K56ac and H3K9ac of pluripotency-related genes (elncRNAs). eRNAs are unstable, short, bidirectional capped and
(Jain et al., 2016). unspliced transcripts that lacks a 3’ poly-A tail (Statello et al., 2021).
ElncRNAs are mostly unidirectional, 3’-polyadenylated and spliced.
eRNAs can drive directly the expression of target genes through
5.3 Guides chromatin looping and interaction with scaffold proteins
(Figure 2E). This interaction leads to regulatory contacts between
LncRNA as guides (Figure 2C) regulate the expression of target enhancers and promoters of the distally located target genes
genes by reprogramming CME complex or regulating the (Statello et al., 2021). For instance, eRNA P53BER (p53-bound
recruitment of epigenetic modifiers to the regulatory loci of target enhancer region) (Melo et al., 2013) and elncRNA SWINGN (SWI/

FIGURE 2
Mechanisms of action of lncRNAs. (A) Signals; lncRNAs receive a signal in response to stimuli to interact with chromatin-modifying enzyme (CME)
complex to inhibit transcription. (B) Decoys; lncRNAs can interact with ribonucleoprotein (RNAP) complex or CME complex or miRNA to inhibit
these regulatory factors from binding to the target gene and inhibiting its transcription. (C) Guides; lncRNAs can recruit RNAP complex and
transcription factors to a specific genomic location and help to regulate chromatin arrangement for gene activation. (D) Scaffolds; lncRNAs can
assemble several RNAP complex to inhibit or activate gene transcription. (E) Enhancers; enhancer lncRNA (elncRNA) enhance interaction of RNAP
complex and chromatin to promote gene activation. (F) Sponges; LncRNA can act as sponges of miRNA. They have sequence complementary to
miRNA and therefore can bind to miRNA, limiting its availability to transcription complex for regulation of target gene transcription.
SNF interacting GAS6 eRNA) (Grossi et al., 2020) recruit 5.6 Sponges
chromatin-activating complexes to the promoters of the target
protein-coding genes. In response to oestrogen receptor (ER) LncRNAs as sponges contain sites complementary to miRNA
transcription activation, eNRIP is another bi-directionally for interaction (Figure 2F). This results in reduced miRNA
transcribed eRNA, that recruits cohesin to form chromatin loops. availability to target mRNAs (Statello et al., 2021). For instance,
This interaction promotes contact between the eNRIP1 and the lncRNA PNUTS contains seven complementary sequences to
promoters of nuclear receptor interacting protein 1 (NRIP1) and miRNA-205, which reduces the availability of miRNA-205 to
trefoil factor 1 (TFF1) (Li et al., 2013). bind and inhibit mRNAs of the zinc finger E-box-binding

homeobox 1 (ZEB1) and ZEB2 (Grelet et al., 2017). The sponging of to discuss the role of these lncRNAs in regulation of immune
miRNA-205 by lncRNA PNUTS leads to increased expression of response, and further investigate their role in obligate intracellular
ZEB1 and ZEB2 which promotes epithelial to mesenchymal bacterial infections.
transition, and breast cancer cell migration and invasion (Grelet
et al., 2017). LncRNA CCAT1 is sponge for miRNA-7 which
6.1 LncRNAs in TLR- NF-kB
upregulates the expression of the TF homeobox gene B1, thereby
dependent immunity
promoting the proliferation and metastasis of esophageal squamous
cell carcinoma (Gao et al., 2020).
eLncRNA IL-1b and lncRNA IL-1b-RBT46 act as enhancers of
In conclusion, the review discusses different classes of lncRNA,
IL1b after TLR4-MyD88-NFkB activation by LPS (Walther and
their subcellular localization, and mechanism of action and how
Schulte, 2021). Nuclear-lncRNA PACER is a positive feedback
these characteristics determine the functionality of lncRNAs, their
regulator that acts as decoy of NF-kB p50 subunit to promote
target genes expression and downstream immune signaling events
NF-kB p50/p65 heterodimer formation. This leads to immune gene
in host cells.
expression in human macrophages in TLR-4 dependent manner
(Krawczyk and Emerson, 2014). lncRNA CARLR is induced upon
LPS-treatment which binds to p65 subunit of NF-kB to promote
6 Role of lncRNAs in regulation pro-inflammatory gene expression (Castellanos-Rubio et al., 2017).
of immune response against IL7-AS as described previously acts as chromatin modifier by
microbial components association with p300 and SWI/SNF complex to drive expression
of CCL2 and IL-6 in TLR-MAPK/NF-kB pathway (Walther and
Macrophages and DCs are the central players of host innate Schulte, 2021). LincRNA- tumor necrosis factor alpha-induced
immune defense against pathogens. They recognize specific protein 3 (TNFAIP3) interacts with chromatin regulator HMGB1
pathogen-associated molecular patterns (PAMPs) on invading to form HMGB1/NF-kB complex. This interaction facilitates NFkB
pathogens through their pattern recognition receptors (PRRs). binding to promoter region of IL-6 (Ma et al., 2017). LncRNA
PRRs like lipopolysaccharide (LPS), bacterial nucleic acids, EPAV act as decoy of SFPQ protein from the p65 promoter of NF-
lipoproteins and peptidoglycan upon host recognition trigger kB to regulate NF-kB activation in mouse (Walther and
specific immune signaling pathways mediated either by TF, NF- Schulte, 2021).
kB or the Interferon regulatory factor (IRF) family of proteins (Li LincRNA-Cox2 can act as positive and negative regulator of
and Wu, 2021). IRF mediates selective expression of interferons NF-kB through different mechanisms. It promotes IkBa
(IFN) and AIM2 inflammasomes which leads to activation of degradation which causes translocation of NF-kB into the nucleus
apoptotic and cell autonomous immunity against intracellular for pro-inflammatory cytokine expression (Xue et al., 2019). It
pathogen (Li and Wu, 2021; Pant et al., 2022) like Listeria negatively regulates TLR-induced ISG CCL5 expression by binding
monocytogenes, Legionella pneumophila (Omotade and Roy, to hnRNPA/B and A2/B1 in the nucleus and inhibiting RNA
2020), Salmonella Typhimurium, Francisella spp., Rickettsia spp., polymerase II recruitment to the CCL5 promoter in Pam3CSK4-
Anaplasma phagocytophilum (Rikihisa, 2011) and Orientia stimulated cells (Figure 3A). In another study, in vitro assays
tsutsugamushi (Deretic, 2011; Ko et al., 2013). Type-I IFN can revealed a physical association between NF-kB subunits (RelA
also dampen inflammasome signaling and promote bacterial and p50) and the SWI/SNF complex in LPS-stimulated murine
infection like Mycobacterium tuberculosis (Novikov et al., 2011). macrophages. siRNA knockdown of lincRNA-Cox2 showed
NF-kB activation usually results in acute activation of pro- decreased association between NF-kB subunits and the SWI/SNF
inflammatory pathways. Infact, NF-kB mediated induction of complex (Hu et al., 2016). These findings indicated lincRNA-Cox2
host responses is known to be modulated by other pathogens like can bind the SWI/SNF complex to modulate chromatin remodeling,
Coxiella burnetii to trigger anti-apoptotic pathways; dampen and NF-kB dependent transcription of CCL5 (Figure 3A). LncRNA
inflammatory cell damage; and promote selective survival in IL1a-AS upon TLR activation with LPS, Pam3CSK4 or poly (I:C) in
bacterial replicative niche (Lührmann and Roy, 2007). cells recruits RNA polymerase II to induce expression of IL1a
Many aspects of signaling response are regulated both at (Chan et al., 2015). LncRNA FIRRE is induced upon macrophage
transcriptional and post-transcriptional level which allows fine- treatment with LPS, which promotes hnRNPU dependent
tuning of immune response against infections (Yoshinaga and transcriptional stabilization of IL-1b, IL-12b and VCAM1(Lu
Takeuchi, 2019). Recent studies have shown lncRNAs et al., 2017). TMC3-AS1 negatively regulates IL-10 by interacting
involvement in regulation of differentiation and activation of with p65 in the nucleus, which prevents its binding to the NF-kB in
macrophages, DCs and adaptive immune cells like T- and B- the promoter region of IL-10 in macrophages and intestinal
lymphocytes (Walther and Schulte, 2021). Several high- epithelial cell lines (Ye et al., 2020).
throughput sequencing studies have deciphered lncRNAs LncRNAs can also dampen the activation of PRR induced NF-
regulatory effect on immune response upon infection or PRR kB gene expression. lincRNA-EPS and GAPLINC are
based stimulation in vitro and in vivo (Walther and Schulte, downregulated in vitro upon TLR-MyD88-NFkB activation
2021). In addition, functional conservation of these immune (Walther and Schulte, 2021). LncRNA THRIL was previously
signaling pathways in different infection models makes it essential shown to be downregulated upon Pam3CSK4 stimulation

A B
FIGURE 3
LncRNA in regulation of immune response against microbial components. Examples of cytoplasmic and nuclear lncRNAs acting as positive and
negative regulators of NF-kB and IFN signaling pathway in PRR dependent pathway is illustrated in the figure. Examples of murine and human
lncRNAs are represented in red and blue fonts respectively. (A) In response to Pam3CSK4 or LPS stimulation, lncRNAs positively or negatively
regulate the activation of NF-kB signaling via TLR-1, 2 or 4. This leads to downstream regulation of cytokines expression. For instance, lincRNA-
Cox2 is upregulated in murine phagocytes. It binds to heterogeneous nuclear ribonucleoprotein (hnRNP)A/B and hnRNPA2/B1 leading to both the
activation and repression of different genes. LincRNA-Cox2 can bind the SWItch/Sucrose non-fermentable (SWI/SNF) complex, leading to activation
of late inflammatory genes. Human IL-1b-RBT46 is upregulated following LPS stimulation, which leads to enhanced expression of IL-1b and CXCL8.
(B) Upon LPS stimulation, lncRNAs like MaIL1, Lnczc3h7a, and lnc-Lsm3b positively and negatively regulate the activation of Interferon (IFN)
regulatory factor 3 (IFN3) which leads to subsequent regulation of IFN production. lincRNA- EPS is downregulated following LPS stimulation leading
to the upregulation of IFN stimulatory genes (ISGs).
(Figure 3A). This study suggested THRIL forms a transcriptional activation promotes type-I IFN production (Figure 3B) by
complex with hnRNPL at the promoter of TNF-a to drive its supporting de-methylation and inactivation of PP2A (IRF3
expression (Li et al., 2014). LncRNA Mirt2 is a negative feedback inhibitor) by the PME1 protein (Zhou et al., 2019). LncRNA
regulator of TLR-MyD88 pathway that interacts with TRAF6 and LSM3B negatively regulates RIG-I signaling through binding with
inhibits its auto-ubiquitination and oligomerization in the RIG-I monomers to limit IFN production (Jiang et al., 2018).
cytoplasm (Du et al., 2017). LncRNA lncFAO is another negative LincRNA-EPS interacts with chromatin repressor hnRNPL at
regulator which binds to the mitochondrial enzyme HADHB that target promoters to inhibit cytokine, chemokine and ISG
promotes fatty acid oxidation and downregulates IL-1b to reduce expression (Figure 3B). Upon TLR-MyD88-NF-kB activation,
inflammation (Nakayama et al., 2020). lincRNA-EPS is repressed which leads to immune gene activation
(Atianand et al., 2016).
6.2 LncRNAs in IFN dependent immunity

6.3 LncRNAs in phagocyte differentiation
A study showed macrophage interferon-regulatory lncRNA 1 and polarization
(MaIL1) positively regulates TRIF-TBK1-IRF3 induced type-I IFN
expression in human macrophages after treatment with LPS. MaIL1 Myeloid specific human transcript HOTAIRM1 was previously
activates type-I IFN production (Figure 3B) through formation of reported as upregulated during granulocytic differentiation and
complex with optineurin in a TLR4-MyD88-NF-kB dependent regulated expression of the myeloid differentiation markers
manner (Aznaourova et al., 2020). This results in ubiquitin- CD11b and CD18 (Walther and Schulte, 2021). Morrbid
dependent aggregation of the optineurin signaling platform and negatively regulates expression of the pro-apoptotic factor Bim in
phosphorylation of TF IRF3 by TBK1(Aznaourova et al., 2020). In cis, by promoting PRC2 binding to the Bim promoter (Kotzin et al.,
clinical settings, MaIL1 expression correlated with IFNb levels in 2016). Morrbid deletion in vivo showed reduced counts of
broncho-alveolar lavage from pneumonia patients (Aznaourova eosinophil, neutrophil, and monocytes suggesting its role in life
et al., 2020). LncRNA NRIR is highly expressed in LPS treated span of myeloid cells. lnc-DC is a lncRNA which interacts with TF
human macrophages in TLR-4 dependent manner to promote ISG STAT3 to promote STAT3 phosphorylation by preventing its de-
(CXCL10) expression through an unknown mechanism (Walther phosphorylation by SHP1 (Walther and Schulte, 2021). A study
and Schulte, 2021). Murine macrophage systems have identified an showed NEAT1 is required for LPS-dependent maturation of DCs
array of lncRNA in IRF activation such as lncRNA Lnczc3h7a. It (Dai et al., 2021). Lnc-M2 was previously reported to be upregulated
acts as a molecular scaffold to TRIM25 ubiquitin ligase and RIG-I in differentiated macrophages (activated with M-CSF, Th2
(Lin et al., 2019). LncRNA LRRC55-AS upon STAT-dependent cytokines IL-4 and IL-13) compared to M0 macrophages in a

STAT3-dependent manner. It forms a complex with protein kinase PAMPs and bacterial nucleic acids. However, a better
A (PKA) to promote its phosphorylation and M2 polarization understanding of the role of these lncRNAs during acute
(Chen Y. et al., 2020). These findings suggest roles of lncRNAs pathogenic infections across different species may provide critical
beyond PRR dependent immunity to developmental role in host insights into designing innovative therapeutic strategies to target
myeloid cell differentiation, polarization and repair. these infections.
Besides the role of lncRNAs in immune cell response and
differentiation, they are also engaged in regulation of epithelial
cells, endothelial cells and fibroblast’s PAMP induced inflammatory
responses (Agliano et al., 2019). The lncRNAs involvement in PRR 7 Role of lncRNAs during infection by
induced phagocytic and DCs immune signaling pathways may also intracellular pathogens
contribute to regulatory functions in the other cell types and
adaptive immunity. However, these questions are unexplored and LncRNAs are either host-derived or expressed by pathogens
have not been discussed in this review. and their response may play a crucial role in modulating bacterial
Collectively, this section discusses several examples of lncRNA infections. The general outcome of intracellular pathogenic
playing a central role in the regulation of immune responses to infection may depend upon how these lncRNAs modulate target
TABLE 1 LncRNAs and mammalian immune response during bacterial infection.
LncRNA Cell type Nature of Immune Mechanism of action Cellular Organism Reference
regulation response localization
regulated
Salmonella Typhimurium
IFNG-AS1/ CD4+ Th1, Up IFN-g regulation Promotes histone methylation Unknown Human, (Gomez
Tmevpg1/NeST CD8+ T, NK at the IFN-g locus via interaction Mouse et al., 2013)
cells with WDR5
NEAT1_2 HeLa Up facilitates Reduced NEXT exosome Nuclear Human (Imamura

paraspeckle mediated et al., 2018)
formation and nuclear RNA decay
immune gene
expression
Mycobacterium tuberculosis
lncRNA-CD244 CD8+ T cells Up Regulates TNF-a Interacts with chromatin Unknown Human (Wang et al.,
and modification enzyme enhancer of 2015)
IFN-g expression zeste homolog 2 (EZH2), which
catalyzes H3K27me3 at promoters
of IFN-g and TNF-a to inhibit
their production
PCED1B-AS1 CD14+ Down Enhance autophagy Sponge of miRNA-155 in Unknown Human (Fathizadeh
monocytes and reduce caspase- macrophages to relieve its effect et al., 2020)
from Mtb 3 expression to on Forkhead Box O3 (FOXO3)
patients inhibit apoptosis and Ras Homolog MTORC1
binding (Rheb)
NEAT1_1; Th cells from Up Regulates IL-6 Unknown Nuclear Human (Agliano

NEAT1_2 (both Mtb patients; expression and et al., 2019)
isoforms of Macrophages promotes Mtb
NEAT1) intracellular
replication
LncRNA B cells Up positively regulates Unknown Unknown Human (Fathizadeh

XLOC_012582 SOCS3 which led to et al., 2020)
increased cytokine
expression in TB
patients
Mycobacterium bovis BCG
lincRNA-EPS Monocytes; Down Inhibition of Enhances signaling of JNK/ Nuclear Mouse (Ke et al.,
Macrophages apoptosis and MAPK pathway and IFN-g 2020)
enhanced production
autophagy
(Continued)

TABLE 1 Continued
regulated
MEG3 Macrophages Down Increased Unknown Unknown Human (Pawar et al.,
autophagy and 2016)
bacterial clearance
lincRNA-Cox2 Macrophages Up Bacterial clearance Regulates M1 polarization/ Cytoplasm/ Mouse (Carpenter

in TLR4-MyD88 nitric oxide production; Nuclear et al., 2013)
dependent manner mediates of NF-kB/p65/p50
complex
to the iNOS promoter; increased
interaction with SWI/SNF
complex
Mycobacterium smegmatis
MEG3 Macrophages Up Decrease TGF-b Increase mTOR-mediated Unknown Human (Agliano

expression and phosphorylation of ribosomal et al., 2019)
inhibit selective protein S6 kinase beta-1(p70-S6K)
autophagy at Thr389 and decrease
accumulation of p62
Listeria monocytogenes
AS-IL1a Macrophages Up IL-1a regulation RNA polymerase II recruitment Unknown Mouse (Chan et al.,
to 2015)
the IL-1a promoter to increase its
expression
lincRNA-EPS Macrophages; Down Activation of pro- Regulates ISGs, TNF-a and IL-6 Unknown Mouse (Agliano
Dendritic cells inflammatory via direct interaction with et al., 2020)
response to limit chromatin repressor hnRNPL
infection in TLR4-
MyD88-NF-kB
dependent manner
lincRNA-Cox2 Macrophages Up Activates NF- kB Increase interaction with SWI/ Cytoplasm/ Mouse (Carpenter
dependent pro- SNF complex and hnRNA-A/B Nuclear et al., 2013)
inflammatory gene and A2/B1
expression for
bacterial clearance
lncRNA-SROS1 Macrophages Down Regulates JAK- miRNA-1 degrades Sros1, relieves Unknown Mouse (Li et al.,
STAT and MAPK CAPRIN1 binding to Stat1, 2021a)
pathways for leading to STAT1 translation and
bacterial clearance enhanced IFN-g signaling
Legionella pneumophila
MaIL1 Macrophages Up Activates type-I Forms a complex with optineurin Cyto Human (Aznaourova
IFN production in (OPTN) to trigger ubiquitin- et al., 2020)
TLR4-MyD88-NF- dependent phosphorylation of
kB dependent IRF3 by TBK1
manner for
bacterial clearance
Linc01215 Macrophages Up Activates type-I Unknown Unknown Human (Aznaourova

IFN production in et al., 2020)
TLR4-NF-kB
dependent manner
for bacterial
clearance
Pseudomonas aeruginosa
MEG9 Bronchial Down Unknown Unknown Unknown Human (Balloy et al.,

primary 2017)
epithelial cells
from
(Continued)

TABLE 1 Continued
regulated
cystic fibrosis
patients
BLACAT1 Bronchial Down Unknown Unknown Unknown Human (Balloy et al.,

primary 2017)
epithelial cells
from
cystic fibrosis
patients
MEG3 isoform-4 Macrophages; Down Decoy of miR-138 Infection downregulates MEG3 Unknown Mouse (Li et al.,
epithelial isoform-4 to 2018)
cells; lung release miR-138 that inhibits IL-
1b
and reduce inflammation
Brucella spp.
Gm28309 Macrophages Down Act as sponge of Activates NF-kB and TGF-b Cytoplasm Human (Deng et al.,
miR-3068-5p signaling leading to assembly of 2020)
NLRP3 inflammasome and IL-1b
and IL-18 secretion.
IFNG-AS1/ PBMC Up IFN-g regulation Promotes histone methylation Unknown Human (Gheitasi
Tmevpg1/NeST at the IFN-g locus via interaction et al., 2019)
with WDR5
Rickettsia conorii
NONMMUT013718 Macrophages, Up Enhancer of Id2 Interacts with the promoter Unknown Mouse (Chowdhury
endothelial (inhibitor of DNA region et al., 2019)
cells binding 2)
NONMMUT024103 Macrophages, Up EnhancerApol10b Interacts with the promoter Unknown Mouse (Chowdhury
endothelial (apolipoprotein region et al., 2019)
cells 10b),
Anaplasma phagocytophilum
lincRNA-TUCP PBMC Unknown Unknown Overlaps with the TNF/LT gene Unknown Human (Rennoll-
locus; Potentially regulates its Bankert
expression et al., 2015)
Clamydia trachomatis
ZFAS1 HeLa cells Up Inhibits host cell Silences ZFAS1; leads to decrease Unknown Human (Wen et al.,
apoptosis via in pORF5 mediated apoptosis and 2020a)
induction of bacterial virulence
MAPK/p38
pathway
MIAT HeLa cells Up Inhibits Increases expression of Bcl-2, and Unknown Human (Luo et al.,
mitochondria reduces caspase-3 expression 2022b)
mediated host cell
apoptosis and
promotes bacterial
replication
ZEB1-AS1 HeLa cells Up Inhibits apoptosis Acts as sponge for miRNA-1224- Unknown Human (Luo et al.,
and promotes 5p;Transcriptionally activates 2022a)
bacterial replication MAP4K4 to inhibit apoptosis
lncRNA-IRF1 HeLa cells Up Inhibits apoptosis Unknown Unknown Human (Luo et al.,
and promotes 2022b)
bacterial replication
FGD5-AS1 HeLa cells Up Promotes DNA Positively regulates the expression Unknown Human (Wen et al.,
replication; Inhibits of Wnt/b-Catenin via unknown 2021)
apoptosis and mechanism
promotes bacterial
replication

genes to either promote or restrict the pathogens’ replication inside (p70-S6K) at Thr389 and increased accumulation of p62 compared
host (Agliano et al., 2019). to uninfected macrophages which is necessary for induction of
In this review, we discuss the functions of lncRNAs by selective autophagy (Pawar et al., 2016). In summary, the evidences
categorizing them in response to infections caused by (a) suggest regulatory control by these lncRNAs in production of IFN-g
facultative intracellular pathogens, (b) obligate intracellular and autophagic clearance of Mtb or Mbv in the host.
pathogens, and (c) commensals. It highlights the functions of Therapies to improve CD8+ T cell functioning is one of the
discovered lncRNAs in infection models like M. tuberculosis, L. promising strategy against Mtb infection (Fathizadeh et al., 2020).
monocytogenes and S. Typhimurium. These discovered lncRNAs LncRNA-CD244 is found exclusively in humans and it overlaps
could also be investigated for their role in regulation of host with 5’-UTR of glutathione S-transferase theta-1 (GSTq1) in CD8+
immune response against different obligate intracellular bacterial T cells (Wang et al., 2015). LncRNA-CD244 has been suggested as a
infections. A list of these lncRNA in regulation of immune response potential target in anti-TB therapy. CD244+ CD8+ T cells isolated
to several bacterial infections is summarized in Table 1 of from peripheral blood mononuclear cells (PBMCs) of TB patients
the review. expressed higher levels of co-stimulatory molecule CD244 and
lncRNA-CD244 compared to healthy controls through an
unknown mechanism (Fathizadeh et al., 2020). Silencing of this
7.1 LncRNAs during infection by facultative lncRNA resulted in restricted Mtb growth. Moreover,
intracellular pathogens immunoprecipitation studies in CD8+ T cells isolated from TB
patients showed lncRNA-CD244 interacted with chromatin
7.1.1 Mycobacterium tuberculosis modification enzyme enhancer of zeste homolog 2 (EZH2)
Previous studies in TB patients and in vitro infected samples (Figure 4A), which catalyzed H3K27me3 at promoters of IFN-g
showed differential expression of several lncRNA and mRNA. and TNF-a to inhibit their production (Wang et al., 2015). Previous
Functional analysis of these transcripts showed majority of the studies have also shown that both the isoforms of NEAT1 were
lncRNA regulate immune signaling pathways such as TGF-b, IFN- upregulated in T-helper (Th) cells derived from TB patients
g, JAK-STAT; T- and B- cells differentiation and adaptive immune compared to healthy controls and its deletion resulted in reduced
responses (Fathizadeh et al., 2020). PCED1B-AS1 is a lncRNA that survival of Mtb in macrophages (Agliano et al., 2019). LncRNA
act as sponge of miRNA-155 in macrophages to relieve its effect on XLOC_012582 positively regulates SOCS3 which led to increase in
Forkhead Box O3 (FOXO3) and Ras Homolog MTORC1 binding cytokine expression in B cells from TB patients (Fathizadeh
(Rheb). This results in inhibition of apoptosis and increase in et al., 2020).
autophagy to clear Mtb. Previously reported study on CD14+ RNA-sequencing studies from TB patients showed reduced
monocytes isolated from TB patients showed downregulation of expression of LncRNA-TGS1-1 and increased expression of
PCED1B-AS1 which led to enhanced autophagy and reduced miRNA-143 which represses downstream immune gene activation
caspase-3 expression to attenuate apoptosis (Yao et al., 2014). (Fathizadeh et al., 2020). Microarrays studies from plasma of TB
These findings proposed PCED1B-AS1 as an early diagnostic patients have also identified NR_038221, ENST00000427151 and
biomarker for Mtb infection (Fathizadeh et al., 2020). LincRNA- ENST00000354432 as potential biomarkers for early detection of
EPS was previously reported as downregulated in monocytes TB (He et al., 2017).
isolated from Mtb patients. Further a knockdown of lincRNA-
EPS in RAW264.7 macrophages followed by infection with M. bovis 7.1.2 Salmonella Typhimurium
(Mbv) BCG (Bacillus Calmette–Gué rin) showed inhibition of Nettoie Salmonella pas Theiler’s (NeST) or Tmevpg1 is an
apoptosis and increase in autophagy due to enhanced signaling of antisense lncRNA located within IFN-g and is expressed in CD4+
JNK/MAPK pathway and IFN-g production (Ke et al., 2020). On Th1 cells, CD8+ T cells, and natural killer (NK) cells in humans and
the contrary, lincRNA-Cox2 silencing in RAW264.7 cells showed mice (Agliano et al., 2019). NeST expression is enhanced during
increased intracellular growth of Mbv BCG. LincRNA-Cox2 STm infection and this promotes bacterial clearance in vivo (Gomez
upregulation was linked to enhanced binding of NF-kB to the et al., 2013). Transgenic B10.S mice expressing either SJL/J- or
promoter of inducible Nitric Oxide Synthase (iNOS) and increases B10.S-derived NeST RNA demonstrated decreased STm
nitric oxide (NO) production and M1 macrophage polarization. pathogenesis compared to WT B10.S without NeST. This study
This resulted in bactericidal activity against Mtb or Mbv infection further showed that co-transfection of NeST with WD repeat
(Fathizadeh et al., 2020). Previous studies have also shown domain 5 (WDR5) cDNA in transgenic B10.S resulted in
pathogen-specific regulation by MEG3. MEG3 was downregulated interaction of NeST with WDR5. These mice during STm
in IFN-g-treated THP1-derived-macrophages after infection with infection showed increased H3K4me3 marks at IFN-g locus in
Mbv BCG, but it was upregulated in M. smegmatis (Msm) infected activated CD8+ T cells. Further, polymorphisms in NeST resulted in
cells (Agliano et al., 2019). In vitro silencing of MEG3 showed difference in T-cell mediated responses which modulated the
increased conversion of LC3-I to LC3-II during Mbv BCG infection inflammatory activities of cells to confer resistance against STm
in human macrophages to induce autophagy (Figure 4A). The study infection (Gomez et al., 2013). RNA-sequencing studies on STm-
also showed that MEG3 knockdown in cells resulted in reduced infected HeLa cells showed significant upregulation of NEAT1_2
mTOR-mediated phosphorylation of ribosomal protein S6 kinase compared to uninfected cells. NEAT1_2 was also induced in

A B
C D
FIGURE 4
LncRNA in modulation of host immune response to facultative and obligate intracellular bacterial infection. (A) (left panel) During Mycobacterium
tuberculosis infection, lncRNA-CD244 in human CD8+ T lymphocytes is upregulated in a CD244-dependent manner. LncRNA-CD244 interacts with
the chromatin modification enzyme enhancer of zeste homolog 2 (EZH2), which leads to trimethylation of H3K27 at the tumor necrosis factor alpha
(TNF-a) and interferon gamma (IFN-g) loci. This represses the expression TNF-a and IFN-g and promotes Mycobacterium replication. (right panel)
Maternally expressed gene 3 (MEG3) is downregulated in THP-1 cells during M. bovis Bacillus Calmette–Guerin (BCG) infection. MEG3 increases
LC3A/B conversion. LC3s decorate the Mycobacterium containing phagosomes and activate autophagy for bacterial clearance. (B) During Brucella
abortus infection, PAMPSs on B. abortus activate the TLRs and TGF-b signaling. The TLRs via unknown mechanism inhibit expression of Gm28309
(LncRNA in mouse)/P33714 (human ortholog of Gm28309). Gm28309 sponges miR-3068-5p in steady state. During infection, downregulation of
Gm28309 leads to release of miR-3068-5p in cytoplasm that degrades kB-Ras2 (an inhibitor of NF-kB) inducing p65 phosphorylation. In parallel,
TGF-b activates TAK1 and IKK kinase mediates phosphorylation of IKB-a and p65, leading to translocation and activation of NF-kB signaling pathway.
This leads to assembly of NLRP3 inflammasome, and secretion of IL-1b and IL-18. (C) Chlamydia trachomatis infection leads to upregulation of
lncRNAs; MIAT, ZFAS1 and ZEB-AS1 via unknown mechanism. MIAT and ZFAS1 activate p38/MAPK/ERK signaling pathway through unclear
mechanisms. ZEB1-AS1 activates p38/MAPK/ERK axis by acting as sponge of miR-1224-5p, which in turn cannot bind to MAP4K4-mRNA to inhibit its
translation. FGD5-AS1 is also upregulated in response to infection. It activates the Wnt/b-Catenin pathway via unknown mechanism. The
upregulation of these lncRNAs is linked to inhibition of apoptosis and increased C. trachomatis replication. (D) Rickettsia conorii infection in mouse
phagocytic cells upregulates enhancer-lncRNA (elncRNA); NONMMUT013718 and NONMMUT024103 via unknown mechanism. They have been
associated with an increase in the expression of Id2 (inhibitor of DNA binding 2) and Apol10b (apolipoprotein 10b). These genes contribute to
activation of Type I-IFN signaling through unknown mechanisms.
response to heat-killed STm which suggested that NEAT1_2 7.1.3 Listeria monocytogenes
upregulation was as a result of PRR response of HeLa cells to Lm infection leads to increased expression of AS-IL1a which
STm PAMPs (Imamura et al., 2018). Knockout and knockdown of transcriptionally activates IL-1a by recruiting RNA polymerase II
NEAT1_2 in HeLa cells resulted in reduced expression of TNF to IL-1a promoter (Chan et al., 2015). LincRNA-EPS was
superfamily member 9 (TNFSF9) and CCL2 that led to increased previously reported as downregulated during Lm infection.
susceptibility to STm infection. In normal HeLa cells, NEAT1_2 is Further, lincRNA-EPS deficient BMDM and DCs when infected
readily degraded into unstable transcripts by MTR4 and RRP6 with Lm displayed reduced bacterial replication and increased
(components of nuclear exosome targeting (NEXT)-RNA exosome expression of TNF-a, IL-6, and iNOS (Agliano et al., 2020). This
pathway). During STm infection, MTR4 and RRP6 levels is reduced concluded that lincRNA-EPS downregulation is essential for
leading to decreased degradation of NEAT1_2 (Imamura et al., activation of NF- kB dependent pro-inflammatory response to
2018). Intracellular pathogens hijack metabolic pathways to foster limit Lm infection (Atianand et al., 2016). LincRNA-Cox2 is
replication in host cells. Recent research identified glucose another well characterized lncRNA which is upregulated during
transporters were encoded by genes SLC2A3 and SLC2A14. They Lm infection in vitro and in vivo. It also promotes Lm clearance via
are located near NEAT1_2 loci and were significantly upregulated activation of NF- kB dependent pro-inflammatory gene expression
in STm-infected HeLa cells and were essential for STm intracellular through increased association with SWI/SNF complex and
replication (Agliano et al., 2019). interactions with hnRNA-A/B and A2/B1 (Carpenter et al., 2013).
Sros1 is a lncRNA that was reported as downregulated in IFN-g-

stimulated and Lm-infected macrophages. In uninfected cells, Sros1 increased expression of NeST and IFN-g in PBMCs isolated from
regulates JAK-STAT and MAPK pathways (Li et al., 2021a). patients with brucellosis (Gheitasi et al., 2019).
However, Lm infection activates miRNA-1 that degrades Sros1,
which in turn relieves RNA binding protein Cell Cycle Associated
Protein 1 (CAPRIN1) from Stat1. This stabilizes Stat1 transcription 7.2 LncRNAs during colonization
and increases STAT1 translation leading to enhanced IFN-g by commensals
signaling and bacterial clearance (Li et al., 2021a).
Commensals are obligate anaerobic opportunistic pathogens
7.1.4 Legionella pneumophila that constitute the human microbiota. They regulate many host
cellular processes like metabolism, immune response, physiology
Lp is an intracellular pathogen that employs a Dot/IcM Type IV
secretion system (T4SS) apparatus to infect and replicate inside and dysbiosis can lead to autoimmune disorders and microbiota
associated cancers (Hou et al., 2022). LncRNAs are also emerging as
human phagocytes. Recent studies have discovered lncRNAs MaIL1
and Linc01215 are induced during Lp infection in a TLR4-NF-kB a factor to regulate microbiota composition and host-microbiota
interaction (Dı́az-Garrido et al., 2021). Of them, A recent study has
dependent manner to activate type-I IFN production and limit Lp
replication inside macrophages. Concurrently, MaIL1 knockdown proposed lncRNA can act as molecular signatures in gut tissues and
their spatio-temporal expression patterns could serve as biomarker
in macrophages resulted in an increased Lp intracellular replication.
The growth could be restricted following treatment of Lp-infected to differentiate between a healthy and dysbiotic gut (Liang et al.,
2015). It is noteworthy; these commensals triggered lncRNAs could
macrophages with type-I IFN (Aznaourova et al., 2020). C. burnetii
(Cb) is phylogenetically related to Lp and infects phagocytes in a also be explored in pathogenesis by obligate intracellular pathogens
and therefore are discussed in this review.
similar mechanism using the T4SS. We hypothesize the signaling
mechanisms involved in Lp pathogenesis would be similar in Cb One of the attributing factors to colorectal cancer (CRC) is
overgrowth of Fusobacterium nucleatum (Fn). Recent trancriptome
infection. Although the type-I IFN response could counter or
dampen Cb infection in a tissue-specific manner unlike Lp analysis of Fn-infected CRC cells revealed 43 upregulated lncRNAs
that includes Keratin 7 antisense RNA (KRT7-AS) and endogenous
infection. It would be interesting to explore type-I IFN dependent
lncRNA MaIL1 and other discovered lncRNAs in regulation of retroviral-associated adenocarcinoma lncRNA (EVADR) (Chen S.
Cb pathogenesis. et al., 2020). KRT7-AS promotes metastasis by CRC cells in nude
mice by upregulating KRT7 in NF-kB dependent manner. CRC
infection with Fn leads to upregulation of EVADR leading to
7.1.5 Pseudomonas aeruginosa increased metastasis of CRC cells both in vivo and in vitro.
Transcriptome analysis of Pa-infected bronchial epithelial cells EVADR acts as scaffold to Y-box binding protein 1 (YBX1)
from patients with cystic fibrosis (CF) compared to non-CF leading to increased translation of SNAIL, SLUG, and ZEB1,
epithelial cells revealed 108 differentially expressed lncRNAs. Of which are required for epithelial to mesenchymal transition
them, MEG9 and BLACAT1, and MEG3 were significantly (EMT) (Lu et al., 2022). Another RNA sequencing analysis found
downregulated (Balloy et al., 2017) MEG3 was also reported as 75 lncRNAs and 49 lncRNAs in probiotic and pathogen mediated
downregulated in lung tissues from Pa-infected mice in TLR4-NF- carcinogenesis. Four lncRNAs: FRMD6-AS2, DIRC3, LIFR-AS1,
kB dependent manner. Pa infection downregulates MEG3 isoform- and MRPL23-AS1 were proposed as unique signatures to CRC
4 which relieves miRNA-138. The miRNA-138 binds to IL-1b to prognosis. LINC00355, KCNQ1OT1, LINC00491, and HOTAIR
reduce its expression, and thereby control inflammation and were associated with poor survival of CRC cells (Wen et al., 2020b).
promote bacterial colonization in vivo (Li et al., 2018). Fn is also an etiological agent for oral squamous cell carcinoma
(OSCC). lncRNA MIR4435-2HG-5p was previously reported to be
7.1.6 Brucella abortus upregulated in Fn-infected OSCC cells. It act as sponge to miRNA-
Trancriptome analysis of THP-1 cells infected with B. abortus 296-5p, leading to activation of serine/threonine kinase Akt2 and
S2308 strain showed downregulation of lncRNA Gm28309 in a Akt2 induced tumorigenesis (Zhang et al., 2020).
TLR4 dependent manner. The reduced expression of Gm28309 Enterotoxigenic Bacteroides fragilis (ETBF) can induce tumor in
resulted in the activation of the NF-kB pathway and increased dysbiotic gut. LncRNA Bacteroides fragilis-associated lncRNA1
expression of TGF-b. TGF-b signaling activates TAK1 and IKK (BFAL1) was previously reported to be upregulated in ETBF-
kinase mediated phosphorylation of p65. Also, Gm28309 act as infected CRC cells. BFAL1 over-expression promoted
sponge to miR-3068-5p in steady state. However, during infection tumorigenesis by acting as sponge to microRNAs; miR-155-5p
miR-3068-5p is relesaed in the cytoplasm that binds and degrades and miR-200a-3p, which in turn activated RHEB/mTOR pathway
kB-Ras2, promoting p65 phosphorylation (Figure 4B). The (Bao et al., 2019).
activation of the NF-kB pathway recruits the NLRP3 Lnc-GNAT1 was reported to be downregulated in Helicobacter
inflammasome, and secretion of IL-1b and IL-18 to modulate Ba pylori (Hp) induced gastric cancer. It negatively regulates the Wnt/b-
infection in vitro (Deng et al., 2020). However, the exact role of Catenin signaling to regulate cancer cell proliferation (Liu L. et al.,
Gm28309 in Ba pathogenesis is unclear. Another study reported 2018). Lnc-SGK1 induces expression of glucocorticoid-inducible

kinase 1 (SGK1) to induce Th2 and Th17 differentiation and inhibit (FGD5-AS1) was upregulated during Ct infection. Gene ontology
Th1 differentiation in Hp-infected gastric cancer (Yao et al., 2016). analysis showed they enriched for DNA replication and Wnt
Previous serological studies have also identified potential lncRNA signaling pathway. FGD5-AS1 positively regulated the expression
signatures in Hp-infected cancer cells like H19, LINC00152, lncRNA of the Wnt/b-Catenin pathway (Figure 4C), inhibiting apoptosis
AF147447, RP11-169F17.1, and RP11-669 N7.2 (Wen et al., 2020b). and promoting intracellular replication of Ct in host (Wen
et al., 2021).
7.3 LncRNAs during infection by obligate 7.3.2 Rickettsia conorii

intracellular pathogens RNA-sequencing analysis to identify host lncRNA during
Rickettsia infection was previously conducted by Chowdhury et al.
Obligate intracellular pathogens include members of C3H/HeN mice were infected with R. conorii (Rc) and
Anaplasma, Rickettsia, Orientia, Wolbachia, Chlamydia, and C. transcriptome analysis was conducted from the infected lung
burnetii. Although lncRNA research in obligate intracellular tissues. This analysis identified 74,964 non-coding RNAs, out of
pathogenesis is at nascent stage, recent studies have identified which 206 lncRNAs were upregulated, and 277 were
some lncRNAs role during infection and are discussed in the downregulated. The study identified two highly upregulated
current section. elncRNAs NONMMUT013718 and NONMMUT024103.
NONMMUT013718 and NONMMUT024103 interacted with the
7.3.1 Chlamydia trachomatis promoter regions of Id2 (inhibitor of DNA binding 2) and Apol10b
Ct is an obligate intracellular pathogen which is a leading cause (apolipoprotein 10b) respectively to enhance their transcription
of sexually transmitted infection and reproductive complications. It (Figure 4D). Further, in vivo and in vitro infection with Rc showed
infects host cells by modulating host cellular responses at increased expression of both lncRNAs and their associated genes in
transcriptional and translational level (Dzakah et al., 2021). the macrophages. These findings were the first experimental
Previous transcriptome analyses of Ct-infected HeLa cells have evidence demonstrating regulatory role of lncRNAs in
identified lncRNAs in inhibition of host cell apoptosis. For modulation of protective immunity against Rc infection
instance, lncRNA zinc finger antisense 1 (ZFAS1) was previously (Chowdhury et al., 2019).
reported as upregulated in Ct infection. It was predicted to regulate
MAPK pathways and its silencing led to decrease in Chlamydia 7.3.3 Wolbachia
plasmid protein pORF5-mediated-apoptosis and Ct virulence Wolbachia is an obligate intracellular pathogen that infects
(Figure 4C). The study concluded pORF5 crucial role in Aedes aegypti. Genome wide analysis of A. aegypti Aag2 cells
activation of lncRNA ZFAS1, and ZFAS1 mediated induction of infected with Wolbachia identified 3035 differentially expressed
MAPK/p38 pathway to inhibit host cell apoptosis (Wen lncRNAs. Gene enrichment and network analysis revealed that
et al., 2020a). the identified lncRNAs acted in trans to target genes and belongs
A microarray analysis of IFN-g-treated HeLa cells infected with to oxidative phosphorylation pathway. Further, competitive
Ct revealed 1718 lncRNAs as differentially expressed. Gene endogenous RNA (ceRNA) network analysis showed these
enrichment analysis showed these lncRNAs regulated host lncRNA enriched for cellular oxidant detoxification pathway. Of
pathways involved in apoptosis, NOD-like receptor, TNF and them, lncRNA aae-lnc-7598 had the highest upregulation (Mao
RIG-I-like receptor signaling (Luo et al., 2022b). LncRNAs MIAT, et al., 2022). Silencing of aae-lnc-7598 resulted in significant
ZEB1-AS1, and IRF1 were silenced in HeLa which resulted in downregulation of antioxidant catalase 1B (CAT1B) gene and
increased apoptosis. MIAT-silenced cell lines showed reduced increase in mitochondria-mediated reactive oxygen species (ROS)
expression of Bcl-2, and increased activation of caspase-3. This in host cells. Another lncRNA, aae-lnc-0165 was downregulated
indicated MIAT was involved in inhibition of mitochondria- after Wolbachia infection in host cells, which increased expression
mediated cellular apoptosis to promote Ct intracellular growth of REL1 through binding of aae-miRNA-980-5p, leading to Toll
(Luo et al., 2022b). A follow-up study by Luo et al. studied the activation (Mao et al., 2022). Notably, these lncRNAs activate the
molecular mechanisms of ZEB-AS1 in Ct infection. siRNA anti-Dengue Toll pathway during Wolbachia infection. Wolbachia
mediated silencing of ZEB1-AS1 increased host cell apoptosis and doesn’t infect human, but it can stay as an endosymbiont in vectors
impeded Ct growth. This was marked by downregulation of Bcl-2/ like A. aegypti. A. aegypti is a major vector responsible for
Bax ratio that led to reduced mitochondrial membrane potential, transmission of Dengue virus. Taken together, we propose that
release of cytochrome c, and caspase-3 activation. Further analysis these Wolbachia regulated lncRNAs could be explored as potential
revealed ZEB1-AS1 acted as a sponge for miRNA-1224-5p which therapeutic markers to limit Dengue virus infection (Bensaoud et al.,
transcriptionally activated MAP4K4 (Figure 4C). In conclusion, 2021; Mao et al., 2022).
ZEB1-AS1 regulated miR-1224-5p/MAP4K4 axis to inhibit cellular
apoptosis and promoted intracellular Ct infection (Luo 7.3.4 Anaplasma phagocytophilum
et al., 2022a). Ap infects the host via tick bite. It replicates within neutrophils
A previous microarray study also showed lncRNA FYVE, and modulate host signaling responses mediated by secreted
RhoGEF, and PH domain containing five antisense RNA1 effectors such as AnkA. AnkA recruits HDAC1 to deacetylate H3

leading to transcriptional repression of several host immune inside exosomes, tissue-specificity and often their response is
response genes (Rennoll-Bankert et al., 2015). A previously disease-specific. The criteria are ideal for development of lncRNA
reported AnkA-binding-CHIP sequencing analysis showed AnkA based biomarkers (Mosquera-Heredia et al., 2021). This may also
binding sites in the intergenic regions of target genes and lead to the development of highly specific disease markers leading to
transcriptionally regulated their expression in cis. NONCODE other research questions including- could these discovered
databases alignment showed AnkA binding sites in the promoter lncRNAs be used to develop infection specific biomarkers for
region of TNF/LT. The locus overlapped with a lncRNA named as bioterror agents like C. burnetii?
lincRNA-TUCP. Further studies are required to dissect role of The most recent technique of targeting lncRNA for therapeutics
lincRNA-TUCP in regulation of TNF/LT locus during Ap is based on the use of antisense oligonucleotides (ASOs). ASOs
infection (Dumler et al., 2016). There is also a limited specifically binds lncRNA based on their sequence
understanding on how intracellular pathogens may regulate the complementarities that induce RNase H mediated cleavage of
expression of lncRNAs. AnkA effector of Ap was found to regulate lncRNA (Lai et al., 2020; Lee and Mendell, 2020). However, ASO
the TNF/LT locus and the locus overlaps with linc-TUCP (Dumler mediated targeting of lncRNA in clinical settings hasn’t been
et al., 2016). Future research could probe the prospective role of successful due to in vivo toxicity and lack of proper delivery
AnkA as a nucleo-modulin in regulating the linc-TUCP/TNF/LT systems. Current researches have attempted to improve the
locus during Ap infection. More studies should be conducted to pharmacological properties of ASOs by chemically modifying
investigate and identify bacterial effectors in regulation of host them to enhance the binding affinity to their target lncRNA,
lncRNAs and their impact on downstream signaling pathways thereby increasing resistance to degradation by nucleases and
during infection. reducing immunostimulatory activity (Seth et al., 2008). Fused
aptamers may also be used for enhanced specificity in the
intracellular delivery of oligo-based drugs (Dassie and
8 LncRNAs as therapeutic targets Giangrande, 2013). Another strategy is the use of small molecules
for targeting lncRNAs. This strategy of targeting lncRNA has been
LncRNAs linked to host-pathogen interaction are promising less successful because of the complexity associated with
targets for development of diagnostic and prognostic biomarkers. development of a high affinity small molecule that can bind
This possibility is supported by the clinical advantages represented lncRNA. Additionally, it requires identification of RNA motifs
by several of their molecular characteristics such as high tissue- which can be only achieved from complete understanding of the
specificity and regulation of specific biological targets in the host lncRNA structure (Warner et al., 2018). Often, these lncRNAs fold
which circumvents undesired effects that arises from using protein- into several molecular domains and can engage in different
based drugs. Additionally, the non-translational nature, low molecular interactions making it difficult for designing a small
endogenous expression and fast transcriptional turnover of molecule targeting the lncRNA (Statello et al., 2021).
lncRNA can result in greater biological effects with lower doses.
Some obligate intracellular pathogens and parasites infect via
exosomes that are internalized by cells to form endosomes. 9 Conclusion
Exosomes from gut microbes have been shown to improve
metabolic functions (Li et al., 2021b). Conversely, fecal exosomes Advancements in RNA biology techniques, single cell sequencing
from mice infected with Pseudomonas panacis promotes glucose and CHIP-seq assays have shown that lncRNAs are central regulators
intolerance and insulin resistance (Li et al., 2021b). There is growing for innate immune activation, inflammasome assembly, and host-
evidence on the regulation of cellular responses by exosomal pathogen interactions. However, the field of study is challenging due
lncRNAs. For instance, exosomal lncRNAs such as LNMAT2 to the complexities arising from the unstable nature of RNAs as well as
(lymph node metastasis associated transcript 2), MALAT1, lack of technological advancements in studying the 3-D conformation
Gm26809 and NEAT1 etc. have been involved in metabolic and the molecular interaction of RNA in vitro and in vivo. It is also
reprogramming of tumor microenvironment (Sun et al., 2018), becoming increasingly evident that their sequence, expression levels,
macrophage polarization and inflammatory diseases (Liu R. et al., processing, cellular localization, organization and interaction with
2018). Of note, MALAT1 over-expression suppresses macrophage other molecules can define their functionality. Another bottleneck in
activation, IL-10 response during Leishmannia and Plasmodium lncRNA research is the poor sequence conservation across species.
infection (Hewitson et al., 2020). Depletion of NEAT1_2 in HeLa Therefore, it becomes difficult to correlate and extrapolate results
cells promotes increased STm replication (Imamura et al., 2018). between human and mouse experimental systems. This is partially
Furthermore, NEAT1_1 and NEAT1_2 knockout in macrophages mitigated by initial screening, synteny and motif conservation analysis
have previously shown decreased IL-6 levels and delayed Mtb among the lncRNAs from different species. Additionally, the existing
clearance (Huang et al., 2018). MALAT1 and NEAT1 are well databases and computational tools require improvement in the current
characterized regulators of immune response in different algorithms to not only precisely assess orthologs of lncRNAs but also
pathogenic infection models. They may also be studied in predict their functional conservation and interactome across species
regulation of inflammatory response, metabolic reprogramming (Zheng et al., 2021). One promising strategy to overcome this
and macrophage polarization during obligate bacterial infections. limitation could be the use of humanized mice models to study
One advantage of targeting exosomal lncRNA is their stability lncRNAs in response to infections. For instance, the role of lncRNA-

CD244 in Mtb infection was studied in severe combined immuno- Funding

deficiency mice (SCID) mice engrafted with lncRNA-CD244-
depressed human CD8+ T cells. Comparable studies can vastly This review was supported by the Defense Threat Reduction
expand the knowledge in the field. Agency, contract no. HDTRA1210002. The views expressed in this
The review of current literature suggests that lncRNAs regulate article are those of the authors and do not reflect the official policy
cell specification and disease. These functions require deeper or position of the US Department of Defense or the US Army.
understanding of physio-pathological processes so that they can be
therapeutically targeted with high specificity. Cellular RNA may be a
promising target for drug discovery. Synthesizing functionally Acknowledgment
relevant motifs of lncRNAs or the whole RNA complementary to a
target host molecule for drug development may prove to be an All the figures in this review were created using Biorender.com.
effective strategy for lncRNA-directed therapeutics. For example, (a)
lncRNAs as sponges of miRNAs or affecting the splicing mechanisms
of a protein coding gene, or (b) compounds that could regulate Conflict of interest
biological processes in host for clinical development. The advantage
of such lncRNA-directed therapeutics would be that these The authors declare that the research was conducted in the
oligonucleotides may target complex and undruggable cellular absence of any commercial or financial relationships that could be
targets. Overall, development of better tools for comprehensive construed as a potential conflict of interest.
molecular understanding of lncRNAs in regulation of immune
responses and host-pathogen interaction might help in
development of lncRNA-based therapeutics for intervention of Publisher’s note
infectious and inflammatory diseases.
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
Author contributions organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
AA wrote the review. All authors contributed to the article and claim that may be made by its manufacturer, is not guaranteed or
approved the submitted version. endorsed by the publisher.
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2023 The Emerging Roles of Long Non-Coding RNA in Host Immune Response and Intracellular Bacterial Infections

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PUBLISHED 21 April 2023

The emerging roles of long non-

Frontiers in Cellular and Infection Microbiology 01 frontiersin.org

Frontiers in Cellular and Infection Microbiology 02 frontiersin.org

Frontiers in Cellular and Infection Microbiology 03 frontiersin.org

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4.3 Mitochondria associated lncRNAs

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5 Molecular mechanisms of 5.4 Scaffolds

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Frontiers in Cellular and Infection Microbiology 08 frontiersin.org

6.2 LncRNAs in IFN dependent immunity

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TABLE 1 LncRNAs and mammalian immune response during bacterial infection.

NEAT1_2 HeLa Up facilitates Reduced NEXT exosome Nuclear Human (Imamura

NEAT1_1; Th cells from Up Regulates IL-6 Unknown Nuclear Human (Agliano

LncRNA B cells Up positively regulates Unknown Unknown Human (Fathizadeh

Mycobacterium bovis BCG

Frontiers in Cellular and Infection Microbiology 10 frontiersin.org

lincRNA-Cox2 Macrophages Up Bacterial clearance Regulates M1 polarization/ Cytoplasm/ Mouse (Carpenter

MEG3 Macrophages Up Decrease TGF-b Increase mTOR-mediated Unknown Human (Agliano

Linc01215 Macrophages Up Activates type-I Unknown Unknown Human (Aznaourova

MEG9 Bronchial Down Unknown Unknown Unknown Human (Balloy et al.,

Frontiers in Cellular and Infection Microbiology 11 frontiersin.org

BLACAT1 Bronchial Down Unknown Unknown Unknown Human (Balloy et al.,

Frontiers in Cellular and Infection Microbiology 12 frontiersin.org

Frontiers in Cellular and Infection Microbiology 13 frontiersin.org

Frontiers in Cellular and Infection Microbiology 14 frontiersin.org

Frontiers in Cellular and Infection Microbiology 15 frontiersin.org

7.3 LncRNAs during infection by obligate 7.3.2 Rickettsia conorii

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Frontiers in Cellular and Infection Microbiology 17 frontiersin.org

CD244 in Mtb infection was studied in severe combined immuno- Funding

Frontiers in Cellular and Infection Microbiology 18 frontiersin.org

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Frontiers in Cellular and Infection Microbiology 21 frontiersin.org

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