Pathogens and Infection

pathogensthat are capable of causing infectious diseases.

The collective of microorganisms that reside in or on an organism is
called the microbiota. Have a beneficial effect on the health of the
organism
The human body contains about 1013 human cells, as well as a
microbiota consisting of approximately 1014 bacterial, fungal, and
protozoan cells, which represent thousands of microbial species
the so-called normal flora.
The microbiota is usually confined to the skin, mouth, digestive
tract, and vagina. With the exception of microbes colonizing the
skin, it consists primarily of anaerobic bacteria, with distinct
communities of species inhabiting each body part.

 In mutualism, both the microbe and host benefit

In commensalism, the microbe benefits but offers no benefit and causes no harm
In parasitism, the microbe benefits to the detriment of the host, as is often the
case for pathogens
Primary pathogens can cause overt disease in most healthy people
opportunistic pathogens, in that they cause disease only if our immune systems
are weakened or if they gain access to a normally sterile part of the body.
Some bacteria replicate in an environmental reservoir such as water or soil and
only cause disease if they happen to encounter a susceptible host; these are called
facultative pathogens.
Others can only replicate inside the body of their host and are therefore called
obligate pathogens.

 In order to survive and multiply, a successful pathogen

must be able to: (1) enter the host (usually by breaking
an epithelial barrier); (2) find a nutritionally compatible
niche in the hosts body; (3) avoid, subvert, or
circumvent the hosts innate and adaptive immune
responses; (4) replicate, using host resources; and (5)
exit one host and spread to another

 Some viral and bacterial pathogens can cause or

contribute to chronic, life-threatening illnesses that are
not normally classified as infectious diseases. An
important example is cancer.
Rous sarcoma virus causes a form of cancer
(sarcomas) in chickens. One of the viral genes encodes
an overactive homolog of the host tyrosine kinase Src
(see Figure 363), which has been implicated in many
kinds of cancer.

 Bacteria are classified broadly by their shapeas rods, spheres (cocci), or spirals
as well as by their so-called Gram-staining properties, which reflect differences in the
structure of the bacterial cell wall. Gram-positive bacteria have a thick layer of
peptidoglycan cell wall outside their inner (plasma) membrane, whereas Gram-negative
bacteria have a thinner peptidoglycan cell wall. In both cases, the cell wall protects
against lysis by osmotics welling, and it is a target of host antibacterial proteins such as
lysozyme and antibiotics such as penicillin. Gram-negative bacteria are also covered
outsidethe cell wall by an outer membrane containing lipopolysaccharide (LPS) .
The surface of bacterial cells can also display an array of appendages, including flagella
and pili, which enable bacteria to swim or adhere to desirable surfaces, respectively.
Apart from cell shape and structure, differences in ribosomal RNA and genomic DNA
sequence are also used for phylogenetic classification. Because bacterial genomes are
smalltypically between 1,000,000 and 5,000,000 nucleotide pairs (compared to more
than3,000,000,000 for humans)they are now simple to sequence, making this
animportant new classification tool.

Bacterial Pathogens Carry

Specialized Virulence Genes
Genes that contribute to the ability of an organism to cause disease
are called virulence genes, and the proteins they encode are called
virulence factors.
Such virulence genes are often clustered together on the bacterial
chromosome; large clusters are called pathogenicity islands.
Virulence genes can also be carried on bacteriophages (bacterial
viruses) or transposons.
Pathogenic bacteria are thought to emerge when groups of virulence
genes are transferred together into a previously avirulent bacterium
by a process called horizontal gene transfer

 Horizontal transfer can occur by one of three

mechanisms: natural transformation by released naked
DNA, transduction by bacteriophages, or sexual
exchange by conjugation
that a bacterial species has both a core genome
common to all isolates within the species and a larger
pan-genome consisting of all genes present in the full
spectrum of isolates.

Bacterial Virulence Genes Encode Effector Proteins and

Secretion Systems to Deliver Effector Proteins to Host
Cells
virulence genes often encode secreted toxic proteins (toxins) that
interact with host cell structural or signaling proteins to elicit a
response that is beneficial to the pathogen.
Bacterial toxins are often composed of two protein
componentsan A subunit with enzymatic activity, and a B
subunit that binds to specific receptors on the host cell
surface and directs the trafficking of the A subunit to the
cytosol by various routes.
Apart from toxins, bacteria use specialized secretion systems to
secrete many other effector proteins that interact with host cells.

 Gram-negative bacteria have a general secretion

system and several classes of accessory secretion
systems (types IVI). A subset of these accessory
secretion systems, called contact-dependent
secretion systems, is present in many bacteria that
contact or live inside host cells.

Fungal and Protozoan Parasites Have

Complex Life Cycles Involving Multiple Forms
Fungi include both unicellular yeasts (such as
Saccharomyces cerevisiae and Schizosaccharomyces
pombe, which are used to bake bread and brew beer,
and as model organisms for cell biology research) and
filamentous, multicellular molds (like those found on
moldy fruit or bread). Most of the important pathogenic
fungi exhibit dimorphismthe ability to grow in either
yeast or mold form. The yeast-to-mold or mold-to-yeast
transition is frequently associated with infection.

 Protozoan parasites are single-celled eukaryotes with

more elaborate life cycles than fungi, and they
frequently require more than one host. Malaria is the
most devastating protozoal disease, infecting more than
200 million people every year and killing upward of
500,000. It is caused by four species of Plasmodium,
which are transmitted to humans by the bite of the
female Anopheles mosquito.

 Viral genomes typically encode three types of protein: proteins

for replicating the genome, proteins for packaging the genome
and delivering it to more host cells, and proteins for modifying
the structure or function of the host cell to enhance the
replication of the virus.
In general, viral replication involves (1) entry into the host cell,
(2) disassembly of the infectious virus particle, (3) replication of
the viral genome, (4) transcription of viral genes and synthesis
of viral proteins, (5) assembly of these viral components into
progeny virus particlesand (6) release of progeny virions. A
single virus particle (a virion) that infects a single host cell can
produce thousands of progeny.

 The recently discovered giant viruses of amoebae, called

pandoraviruses, are the largest known viruses, with 700
nm particles and double-stranded DNA genomes of over
2,000,000 nucleotide pairs. The virions of poxvirus are also
large: they are 250350 nm long and enclose a genome of
double-stranded DNA of about 270,000 nucleotide pairs. At
the other end of the size scale are the virions of parvovirus,
which are less than 30 nm in diameter and have a singlestranded DNA genome of fewer than 5000 nucleotides.

 When the capsid is packaged with the viral genome, the

structure is called a nucleocapsid. The nucleocapsids
of nonenveloped viruses usually leave an infected
cell by lysing it. For enveloped viruses, by contrast,
the nucleocapsid is enclosed within a lipid bilayer
membrane that the virus acquires in the process of
budding from the host-cell plasma membrane, which it
does without disrupting the membrane or killing the
cell.

 Extracellular pathogens can cause serious disease without entering host

cells. for example, adhere tightly to the epithelial lining via specific
adhesins, which are proteins or protein complexes that recognize and
bind to cell-surface molecules on the epithelium.
Many pathogens have to enter host cells to cause disease. These
intracellular pathogens include all viruses and many bacteria and
protozoa
While most RNA viruses replicate within the cytosol, most DNA viruses
replicate in the nucleus. Life inside a host cell has several advantages.
The pathogens are not accessible to antibodies, nor are they easy targets
for phagocytic cells

Viruses Enter Host Cells by Membrane Fusion, Pore

Formation, or Membrane Disruption
Some enveloped viruses enter the host cell by fusing their envelope
membrane with the plasma membrane. Most viruses, whether
enveloped or nonenveloped, activate signaling pathways in the cell
that induce endocytosis, commonly via clathrin-coated pits (see
Figure 137), leading to internalization into endosomes. Large
viruses that do not fit into clathrin-coated vesicles, such as
poxviruses, often enter cells by macropinocytosis, a process by
which membrane ruffles fold over and entrap fluid into
macropinosomes (see Figure 1350). Once inside endosomes, fusion
of the viral envelope occurs from the lumenal side of the endosome
membrane. The mechanism of membrane fusion mediated by viral
spike glycoproteins has similarities with SNARE-mediated membrane
fusion during normal vesicular trafficking (discussed in Chapter 13).

 Nonenveloped viruses use different strategies to enter host cellsstrategies

that do not rely on membrane fusion. Poliovirus, which causes poliomyelitis,
binds to a cell-surface receptor, triggering both receptor-mediated endocytosis
and a conformational change in the viral particle. The conformational change
exposes a hydrophobic projection on one of the capsid proteins, which inserts
into the endosomal membrane to form a pore. The viral RNA genome then
enters the cytosol through the pore, leaving the capsid in the endosome.
Other nonenveloped viruses such as adenovirus disrupt the endosomal
membrane after they are taken up by receptor-mediated endocytosis. One of
the proteins released from the capsid lyses the endosomal membrane,
releasing the remainder of the virus into the cytosol. During endosomal
trafficking and subsequent transport within the cytosol, adenoviruses undergo
multiple uncoating steps, which sequentially remove structural proteins and
ready the virus particles to release their DNA into the nucleus through nuclear
pore complexes

Bacteria Enter Host Cells by

Phagocytosis
Bacteria are much larger than virusestoo large to be
taken up either through pores or by receptor-mediated
endocytosis. Instead, they enter host cells by phagocytosis,
which is a normal function of phagocytes such as
neutrophils, macrophages, and dendritic cells.
These phagocytes patrol the tissues of the body and ingest
and destroy microbes; however, some intracellular bacterial
pathogens such as M. tuberculosis use this to their
advantage and have evolved to survive and multiply inside
macrophages.

 Some bacterial pathogens can invade host cells that are normally
nonphagocytic. One way they do so is by expressing an invasion protein that
binds with high affinity to a host-cell receptor, which is often a cellcell or cell
matrix adhesion protein
Listeria monocytogenes, which causes a rare but serious form of food
poisoning, invades host cells by expressing a protein that binds to the cellcell
adhesion protein E-cadherin. For both these bacterial species, binding of the
bacterial invasion proteins to the host cell adhesion proteins stimulates
signaling through members of the Rho family of small GTPases. This in
turnactivates proteins in the WASp family and the Arp 2/3 complex, leading to
actin polymerization at the site of bacterial attachment. Actin polymerization,
together with the assembly of a clathrin coat, drives the advancement of the
host cells plasma membrane over the adhesive surface of the microbe,
resulting in the phagocytosis of the bacteriuma process known as the zipper
mechanism of invasion.

 A second pathway by which bacteria can invade nonphagocytic cells

is known as the trigger mechanism. It is used by various pathogens
that cause food poisoning, including Salmonella enterica, and it is
initiated when the bacterium injects a set of effector molecules into
the host-cell cytosol through a type III secretion system. Some of
these effector molecules activate Rho family proteins, which in turn
stimulate actin polymerization, as just discussed. Other bacterial
effector proteins interact with host-cell cytoskeletal elements more
directly, nucleating and stabilizing actin filaments and causing the
rearrangement of actin cross-linking proteins. The overall effect is to
cause the formation of localized ruffles on the surface of the host
cell, which fold over and engulf the bacteria by a process that
resembles macropinocytosis.
The appearance of cells being invaded by use of the trigger
mechanism is similar to the ruffling induced by some extracellular
growth factors, suggesting that the bacteria exploit normal
intracellular signaling pathways.

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