Source: 

http://www.sciencedaily.com/releases/2009/08/090816170913.htm

Needle-Free, Inhalant Powder Measles Vaccine Could

Save Thousands Of Lives
Scientists have developed the first dry powder inhalable vaccine for measles. The inhaler is easy
to use. (Credit: Aktiv-Dry, LLC)

ScienceDaily (Aug. 18, 2009) — The first dry powder inhalable vaccine for measles is moving
toward clinical trials next year in India, where the disease still sickens millions of infants and
children and kills almost 200,000 annually, according to a report presented at the 238th National
Meeting of the American Chemical Society (ACS).

Robert Sievers, Ph.D., who leads the team that developed the dry-powder vaccine, said it's a
perfect fit for use in back-roads areas of developing countries. Those areas often lack the
electricity for refrigeration, clean water and sterile needles needed to administer traditional liquid
vaccines.

"Childhood vaccines that can be inhaled and delivered directly to mucosal surfaces have the
potential to offer significant advantages over injection," Sievers said. "Not only might they
reduce the risk of infection from HIV, hepatitis, and other serious diseases due to unsterilized
needles, they may prove more effective against disease."

"Many serious infections, such as the measles virus, can enter the body through inhalation.
Measles vaccine dry powders have the potential to effectively vaccinate infants, children and
adults by inhalation, avoiding the problems associated with liquid vaccines delivered by
injection," he added.

Although made for developing countries, the technology eventually could become the basis for a
new generation of inhalable — and ouchless vaccines — in the United States and elsewhere. So
far, an inhalable vaccine is available for only one disease. It is a wet mist vaccine for influenza.

Sievers, once an atmospheric scientist and who now is with Department of Chemistry and
Biochemistry and Center for Pharmaceutical Biotechnology, University of Colorado, Boulder,
took inspiration for the new vaccine from research on how people inhale tiny airborne droplets of
air pollutants.

To create an inhalable vaccine, Sievers and his team of students and researchers developed a
patented process known as the "Carbon Dioxide-Assisted Nebulization with a Bubble Dryer,"
called CAN-BD. The weakened measles virus is mixed with "supercritical" carbon dioxide —
part gas, part liquid — to produce microscopic bubbles and droplets, which then are dried to
make an inhalable powder.
The powder is puffed into a small, cylindrical, plastic sack, with an opening like the neck of a
plastic water bottle, and administered. "By taking one deep breath from the sack, a child could be
effectively vaccinated," Sievers said.

In animal tests, the inhaler has been just as effective in delivering measles vaccine as the
traditional injection, the researchers say. They now are working on an inexpensive dry powder
inhaler that would deliver measles or influenza vaccines to developing nations and could be used
elsewhere. In replacing injections, the new method also would help reach those who refuse
inoculations because of their fear of needles. The researchers say that the vaccine could be
produced for about 26 cents a dose.

If the inhaler passes final safety and effectiveness tests, the Serum Institute of India Ltd. expects
a demand growing to 400 million doses of measles vaccine a year, according to Sievers.

"Human clinical trials are expected to begin next year in India, after animal safety studies are
completed this year," Sievers said. "About two-thirds of the world's deaths due to measles occur
in that nation. Worldwide, several hundred people die every day from measles-related disease,"
he added.

In earlier research in the 1980s in Mexico during a measles outbreak, 3 million children received
a measles vaccine by inhaling a wet mist aerosol and those who took part in the test had a lower
rate of developing measles than those who received a vaccine by injection, according to Sievers.
"The problem with that method," he said, "was that the wet mists required power or batteries to
generate the aerosol and the liquid vaccines had to be freshly made up and kept on ice and the
nebulizer that delivers the dose had to be cleaned. The new, inexpensive dry aerosol dispenser
doesn't need to be cleaned and doesn't require power," he said.

The study has been conducted with a grant from the Foundation for the National Institutes of
Health as part of the Grand Challenges in Global Health Initiative of the Bill and Melinda Gates
Foundation.

Story Source:

Adapted from materials provided by American Chemical Society, via EurekAlert!, a service of

AAAS.
Source:      http://www.sciencedaily.com/releases/2010/03/100322083850.htm

Controlling HIV: Highly Promising New Compound

Developed
ScienceDaily (Mar. 23, 2010) — A compound that can inhibit the transfer of HIV from one cell
to another has been developed by researchers at the Institut de Biologie Structurale Jean-Pierre
Ebel (CNRS/Université Joseph Fourier/CEA). It acts by saturating a receptor called DC-SIGN,
which is used by HIV to ensure its transmission throughout the body.

A patent has been filed for this compound, and an article on the subject is published in ACS
Chemical Biology.

Despite the major advances achieved in the control of HIV, this infection still causes millions of
deaths each year. The search for new cellular targets for novel antiviral therapies remains an
important challenge.

Researchers at the Institut de Biologie Structurale (CNRS /Université Joseph Fourier/CEA) have
been working on a receptor called DC-SIGN which is found on the surface of dendritic cells:
immune cells which are present in contact zones with the exterior, such as the skin or mucous
membranes, and the first sites to encounter pathogens. DC-SIGN is implicated in the initial
phases of HIV infection and constitutes a potential therapeutic target that has not yet been
exploited.

What is the role of DC-SIGN? Under normal circumstances, it captures pathogens by

recognizing certain characteristic oligosaccharides present on their surface. The pathogens are
then internalized by dendritic cells that degrade them and present the fragments at their surface.
These cells then move to lymphoid tissues where they trigger an immune response by the body,
i.e. the production of T lymphocytes that can fight the pathogen. As for HIV, it uses DC-SIGN to
ensure its transmission in an intact form to the T lymphocytes that it will infect. In particular, it
attacks CD4+ T lymphocytes (carrying a molecule called CD4 that is susceptible to HIV) which
are the principal target used by the virus to ensure its spread.

The researchers have developed a compound that can inhibit the HIV transmission process to
CD4+ T lymphocytes. This tetravalent compound, endowed with four functional groups that
mimic the oligosaccharides of pathogens, is recognized by DC-SIGN, which thus prevents HIV
from using the receptor to travel to the lymphoid tissues. It has some particularly interesting
properties; e.g. high solubility in physiological media, negligible cytotoxicity and a long-lasting
effect (even after washing the cells, the inhibitory effect can persist for several hours).
Furthermore, the simple structure of the compound means that its large-scale production could
easily be envisaged.

Last but not least, DC-SIGN is also utilized by other pathogens to circumvent the immune
system. The compound developed by the research team could also be used to inhibit infection by
the hepatitis C, dengue, Ebola and SARS viruses, the Mycobacterium tuberculosis bacterium
(which causes tuberculosis) and a number of parasites. It may even prove to be more effective in
these cases than with HIV. This compound could therefore be added to the list of antiviral
compounds designed on the basis of oside structures that exist in nature, the glycomimetics, such
as Tamiflu which is used to control seasonal influenza.

Its efficacy has been proven in vitro to prevent the transmission of HIV from one cell to another.
The researchers have protected their compound with a patent filed jointly by CNRS and
Université Joseph Fourrier. The next step is to perform tests in animal models. Until they find a
partner, or themselves set up a structure that can manage these activities, the researchers are
continuing to enhance the efficacy of their compound to render it more specific to DC-SIGN and
increase its interaction with this receptor.

Story Source:

Adapted from materials provided by CNRS (Délégation Paris Michel-Ange).

Source: http://www.articlesbase.com/medicine-articles/pandoras-box-of-infectious-diseases-
292512.html

Pandora's Box of Infectious Diseases

By: Dr.T.V.Rao MD | Posted: Dec 28, 2007

Pandora’s BOX OF INFECTIOUS DISEASES

Dr.T.V.Rao MD
Department of Microbiology 
Jubilee Mission Medical College and Research Centre
Trichur

Despite the success in control of many infectious diseases, a wide range of microbes still
threatens the human health. Somehow Pandora box of infection is opened and continues to be a
challenge. The unexpected emergence of Novel pathogens named as emerging and reemerging
infectious diseases continue to strike any time, at any place. Before we learn about it, they
disappear and make a dent on human health and social structure. Above all we live in an
unpredictable nature - no rain, unwanted rain, and untimely cyclones - many attributed to global
warming. Inspite of several scientific advances, we are controlled by nature. Recently we have
experienced several communicable diseases like Chikungunya, Dengue, Leptospirosis, Hepatitis
A and E. Chikungunya championed the list of microbes; produced fear, death, social unrest and
political turbulence. Sudden emergence of epidemics exposed the facts that how vulnerable we
are and how poorly we coordinate to overcome the problems. The world is rapidly changing, so
are the microbes, as is the Chikungunya virus which originated in Africa, not a fatal disease to
begin with a very few crippling complications. When the virus traveled to Kerala and other parts
of India, became more vengeful, produced many cases of chronic morbidity and mortality. After
4 months of epidemic (October 2007) it subsided on its own. Today we do not know where it is
hiding or when is the next date of reemergence. 

In view of excessive urban migration narrow conditions of living initiates the epidemics. It is
observed that we struggle to live and neglect the society. This remains the source of starting
point. Epidemics frighten the society and infections attacking the young, old and pregnant
women are a great concern to medical profession. In particular pregnant women have a changing
physiology and immunity and are susceptible to or more prone to infectious diseases. The
paradox of pregnancy may induce a state of increased susceptibility to certain virus, intracellular
bacteria and parasites. One has to realize that any infection during pregnancy is a serious concern
to preserve the health of mother and fetus and appropriate timely treatment must be provided.
The ideal purpose of motherhood of giving love and wisdom has changed in the women infected
with HIV/AIDS. And women transmit virus to their unborn babies. It is becoming the
responsibility of the treating physician to screen the pregnant women for HIV antibodies to
practice preventive and curative intervention to reduce perinatal HIV transmission. 
To add to the existing epidemics, we have a serious challenge with Tuberculosis. At present
several patients present with Tuberculosis in association with HIV/AIDS. Non compliance,
irregular adherence to treatment regimen leads to multi drug resistant Tuberculosis (MDR – TB)
strains. We have several medical colleges, reputed medical institutions but we have no up to date
facilities to deal and diagnose drug resistant tuberculosis. If we do not wake up and control the
multidrug resistant strains, it will be much difficult to control X MDR tuberculosis strains (X
MDR- resistant to even second line of antibiotics). The Pandora box of infection is narrow and
deep. The question to control the infections remains with health education, hygiene, political will
and committed physicians. There is an emerging need to establish referral diagnostic centers
committed to research to identify and notify on events of infectious diseases. But it is certain
there are no short cut solutions or magical ideas to control epidemics. Are we united to control
the Epidemics? Who will close the Pandora’s box of infection?

The best solutions to control Epidemics are

1 Coordinated scientific approaches

2 Continuous monitoring of environment for prevalence of sub clinical infections
3 Referral Virology laboratories to overcome all diagnostic problems and precise diagnosis to
clarify all controversies 
4 Above all mass education on hygiene, simple social hand washing by all citizens.
5 A simple commonsense to protect the environment.

About the Author

Dr.T.V.Rao MD works as a Professor In an Indian Medical College, Interested in public issues

on Health and Disease. You can also visit my site at slideshare.com for interesting articles on
Infectious diseases.
Source:      http://www.sciencedaily.com/releases/2010/03/100322073538.htm

Toward a 3-in-1 'Dipstick' Test for Early Detection of

Parasitic Diseases
ScienceDaily (Mar. 21, 2010) — A new simple, inexpensive three-in-one test to diagnose a
terrible trio of parasitic diseases that wreak havoc in the developing world is passing preliminary
tests, scientists reported. Described during the 239th National Meeting of the American
Chemical Society, the test is for Chagas' disease, leishmaniasis, and "sleeping sickness" or
African trypanosomiasis.

This year will see about 800,000 new cases of Chagas disease, 2 million of leishmaniasis, and
70,000 of sleeping sickness (see sidebar). Most cases are discovered at a late stage, and together
they cause tens of thousands of deaths each year and untold suffering. The drugs used to treat
late-stage infections are often toxic and have potentially fatal side effects.

"Early diagnosis is the key to improving treatment of these diseases," said Ellen Beaulieu, Ph.D.,
a medicinal chemist in the Center for Infectious Diseases in the Biosciences Division of SRI
International in Menlo Park, Calif., who reported on the test. "Diagnosis with conventional tests
is difficult in developing countries where these diseases occur. We hope that our low-cost,
simple test will play a role in helping poorer parts of the world combat these diseases and the
poverty they engender."

One existing test for diagnosing the three diseases involves taking a blood sample from a patient
and examining it under a microscope for the parasites that cause the diseases. But the process is
complex, requiring medical laboratory equipment and specially trained health care workers.
Current blood tests are also time-consuming. In some cases, it can take up to 90 days to confirm
results. Other tests detect the parasites using antibodies. But they require expensive electronic
equipment that may not be available in remote areas of the developing world.

The new test exploits the common heritage of the parasites that cause Chagas, leishmaniasis, and
African sleeping sickness. All three are closely related members of what scientists know as the
trypanosomatidae family. Working together with Mary Tanga, Ph.D., Senior Director of
Medicinal Chemistry in SRI's Biosciences Division, Beaulieu and colleagues developed special
dyes that allow detection of an early disease stage, does not require the use of sophisticated lab
equipment, and can produce results in as little as one hour.

Initial tests under laboratory conditions show that the dyes reveal the presence of the parasite
marker and glow in ultraviolet light from a simple, handheld lamp. SRI researchers are making
progress toward improving the sensitivity of the dyes.

The goal is to develop a "dipstick" version of the test that allows detection of the parasite
metabolite using a simple paper strip like those used in urine tests for diabetes. Such a test could
allow health workers in remote areas to diagnose the diseases by dipping the strip in a drop of
blood and exposing it to ultraviolet light.
Source:      http://www.sciencedaily.com/releases/2010/03/100315091303.htm

Chemical in Bananas Identified as Potent Inhibitor of

HIV Infection
BanLec, a chemical isolated from bananas is identified as a potent new inhibitor of HIV
infection. (Credit: University of Michigan Medical School)

ScienceDaily (Mar. 16, 2010) — A potent new inhibitor of HIV, derived from bananas, may
open the door to new treatments to prevent sexual transmission of HIV, according to a newly
published University of Michigan Medical School study.

Scientists have an emerging interest in lectins, naturally occurring chemicals in plants, because
of their ability to halt the chain of reaction that leads to a variety of infections.

In laboratory tests, BanLec, the lectin found in bananas, was as potent as two current anti-HIV
drugs. Based on the findings published March 19 in theJournal of Biological Chemistry, BanLec
may become a less expensive new component of applied vaginal microbicides, researchers say.

New ways of stopping the spread of the HIV are vitally needed. The rate of new infections of
HIV is outpacing the rate of new individuals getting anti-retroviral drugs by 2.5 to1, and at
present it appears an effective vaccine is years away.

"HIV is still rampant in the U.S. and the explosion in poorer countries continues to be a bad
problem because of tremendous human suffering and the cost of treating it," says study senior
author David Marvovitz, M.D., professor of internal medicine at the U-M Medical School.

Although condom use is quite effective, condoms are most successful in preventing infection if
used consistently and correctly, which is often not the case.

"That's particularly true in developing countries where women have little control over sexual
encounters so development of a long-lasting, self-applied microbicide is very attractive,"
Markovitz says.

Some of the most promising compounds for inhibiting vaginal and rectal HIV transmission are
agents that block HIV prior to integration into its target cell.

The new research describes the complex actions of lectins and their ability to outsmart HIV.
Lectins are sugar-binding proteins. They can identify foreign invaders, like a virus, and attach
themselves to the pathogen.

The U-M team discovered BanLec, the lectin in bananas, can inhibit HIV infection by binding to
the sugar-rich HIV-1 envelope protein, gp120, and blocking its entry to the body.
Co-authors Erwin J. Goldstein, Ph.D., professor emeritus of biological chemistry at U-M and
Harry C. Winter, Ph.D., research assistant professor in biological chemistry at U-M, developed
the biopurification method to isolate BanLec from bananas. Following their work, the U-M team
discovered BanLec is an effective anti-HIV lectin and is similar in potency to T-20 and
maraviroc, two anti-HIV drugs currently in clinical use.

Yet therapies using BanLec could be cheaper to create than current anti-retroviral medications
which use synthetically produced components, plus BanLec may provide a wider range of
protection, researchers say.

"The problem with some HIV drugs is that the virus can mutate and become resistant, but that's
much harder to do in the presence of lectins," says lead author Michael D. Swanson, a doctoral
student in the graduate program in immunology at the University of Michigan Medical School.

"Lectins can bind to the sugars found on different spots of the HIV-1 envelope, and presumably
it will take multiple mutations for the virus to get around them," he says.

Swanson is developing a process to molecularly alter BanLec to enhance its potential clinical
utility. Clinical use is considered years away but researchers believe it could be used alone or
with other anti-HIV drugs as a vaginal microbicide that prevents HIV infection.

Authors say even modest success could save millions of lives. Other investigators have estimated
that 20 percent coverage with a microbicide that is only 60 percent effective against HIV may
prevent up to 2.5 million HIV infections in three years.

Story Source:

Adapted from materials provided by University of Michigan Health System.

Source:      http://www.sciencedaily.com/releases/2010/03/100311175036.htm

Children With Chronic Respiratory Illness Are

Vulnerable to Critical H1N1
ScienceDaily (Mar. 12, 2010) — As critical care professionals develop a better understanding of
the progression of H1N1, they are becoming better prepared to treat children with severe cases,
according to a new study that will be published in the March issue of Pediatric Critical Care
Medicine (PCCM).

Additionally, with careful management, the pediatric critical care system is expected to be able
to meet the increased demands of a flu pandemic, according to a resource modeling study
published in the same issue of PCCM. Both studies are available on www.pccmjournal.org.

The first H1N1 study focusing exclusively on critically ill children found that children with
chronic illness, especially respiratory illness, are more likely to develop H1N1 influenza that
requires critical care and that the virus is likely to change course as it attacks the lungs
throughout the course of the illness.

"The good news is that all of our patients survived, even though some needed mechanical
ventilators and heart medication," said senior author David G. Nichols, MD, professor of
anesthesiology/critical care medicine and pediatrics at the Johns Hopkins University School of
Medicine.

Compared to seasonal influenza, H1N1 influenza appears to have increased infection rates
among children and young adults and varies in severity.

The researchers reviewed cases of 13 critically ill children with H1N1 admitted to the Johns
Hopkins Hospital Children's Center pediatric intensive care unit during the spring and summer of
2009. They found that the vast majority (92%) of the children had an underlying chronic disease,
usually a lung disease such as asthma, before contracting H1N1 infection.

"Critical H1N1 disease in children has different and rapidly changing manifestations in the
patients' lungs," explained Dr. Nichols. "Some children behaved as though they were having an
asthma attack, while other children behaved as though they had severe pneumonia. Some
children had both or switched from one to the other. These variable and changing manifestations
of lung infection made life support with a mechanical ventilator challenging and required us to
constantly reassess and readjust treatments."

The researchers also found that children with H1N1 lung disease are at increased risk for
developing a second type of pneumonia.

Patients who received treatment with antiviral drugs such as Tamiflu within 48 hours of
admission did not have significantly different outcomes than those who received antiviral
treatment more than 48 hours following admission.
Study offers positive assessment of PICU surge capacity during pandemic flu

Even during the peak of a pandemic, adequate health care can be provided if patients are
managed appropriately. "An influenza pandemic for children can be managed, even allowing
emergency care for non-influenza-related acute care children, but only when firm decision-
making rules for hospital health care are followed and anti-viral therapy is used to reduce the
burden of the disease in the community," said lead author Raoul E. Nap, PhD, directorate of
medical affairs, quality, and safety at the University Medical Center Groningen, University of
Groningen in the Netherlands.

The researchers modeled pediatric surge capacity of health care facility and pediatric intensive
care unit (PICU) requirements over time to assess the adequacy of preparedness planning for an
influenza pandemic.

They noted a lack of published and detailed analyses of PICU needs and demands, raising
concern that PICU facilities will be a major limiting factor in the provision of care. "We show
that PICU surge capacity is likely to be adequate assuming that 'older children' [age > 7-8 years]
can be rerouted to an adult ICU environment preserving adequate bed space for 'younger
children', that enough adult ICU resources are available and that safe provision of care to
children can be guaranteed," said Dr. Nap.

The study's overall assessment that an influenza pandemic can be managed at the level of health
care institutions clearly contrasts with other sobering and daunting global analyses presented for
ICU capacity, according to Dr. Nap.

"We recommend that an adaptable planning model for pediatric surge capacity be an integral part
of a preparedness plan for a pandemic flu," Dr. Nap concluded.

"H1N1 has greatly impacted every pediatric critical care medicine program world-wide," said
PCCM editor Patrick M. Kochanek, MD, FCCM. "I view the dissemination of new information
on this disease as the top priority for our journal. The reports from both Baltimore and the
Netherlands in the March issue of Pediatric Critical Care Medicine present, respectively,
valuable information on the impact of critical respiratory disease produced by H1N1 in children
with underlying chronic conditions, and explores PICU surge capacity."

Story Source:

Adapted from materials provided by Society of Critical Care Medicine, via EurekAlert!, a

service of AAAS.
Source:      http://www.sciencedaily.com/releases/2010/03/100309112025.htm

Malaria in Pregnant Women: Step Towards a New

Vaccine
ScienceDaily (Mar. 12, 2010) — By managing to express the protein that enables red blood cells
infected with the malaria agent Plasmodium falciparum to bind to the placenta and by
deciphering its molecular mechanisms, a team of researchers from CNRS and the Institut Pasteur
has taken an important first step in the development of a vaccine against pregnancy-associated
malaria.

Their work was published in the journal Proceedings of the National Academy of Sciences.

In endemic areas where malaria is rife, the main victims are children less than three years old.
This is because adults acquire, in the course of their lives, an immunity that protects them against
the parasite. However, pregnant women, especially during a first pregnancy, have potentially
fatal reactions to P. falciparum. The parasites also prevent exchanges of gases and nutrients
through the placenta, thereby leading to spontaneous abortions, premature deliveries and
newborn babies with too low birth weight, which are serious conditions in countries where
infantile mortality is very high in the first year.

Following a bite by an infectious mosquito, the parasite first multiplies in the liver, before
entering the bloodstream where it invades the erythrocytes (or red blood cells). The parasite then
rapidly modifies the surface of its host erythrocyte with one of the sixty variable proteins of the
PfEMP1 (Plasmodium falciparum Erythrocyte Membrane Protein 1) family. These proteins
protect the parasite from the host's immune response and enable it to adhere to the host's cells.
The severity of pregnancy-associated malaria (PAM) has been associated with the ability of
parasitized erythrocytes to bind to a sugar present in the placenta, chondroitin sulfate A (CSA).
After several pregnancies, women acquire protective antibodies that block CSA-binding.

One of the potential vaccination strategies for PAM is to recreate this protective immunity, by
blocking the binding of parasitized erythrocytes to the placenta. Previous work carried out by the
team headed by Benoît Gamain, CNRS researcher at the Unité Bases Génétiques et Moléculaires
des Interactions de la Cellule Eucaryote (Institut Pasteur), has shown that one of the proteins of
the PfEMP1 family, known as var2CSA, plays an important role in PAM. It is thus the prime
target for a vaccine. However, the var2CSA protein shows considerable polymorphism, is very
large and has a very complex structure. These characteristics have, until now, prevented
researchers from reproducing it in the laboratory and studying it to elucidate its structure and its
action mechanisms. Only selected "chunks" of proteins involved in these binding areas, known
as domains, have been synthesized.
Gamain and his colleagues have, for the first time, succeeded in producing the entire var2CSA
protein for the purpose of studying it. This protein has shown specific, high-affinity binding to
CSA, more than a thousand times greater than that of the simple domains synthesized previously.
Therefore it is indeed a functional protein, with all the characteristics and functions of the
var2CSA protein expressed at the surface of parasitized erythrocytes. Structural studies
conducted in collaboration with researchers at EMBL (European Molecular Biology Laboratory)
in Grenoble then made it possible to observe the structure of this protein. Var2CSA has a
compact rather than a lengthened shape, as was assumed previously, and has a CSA-binding
pocket that is most probably created when the protein folds upon itself.

For the researchers, these results constitute a first step in the race to develop vaccinal or
therapeutic approaches aimed at protecting women during their first pregnancies as well as their
unborn fetuses. Their work, conducted within the European "Premalstruct" consortium headed
by Gamain, is now going to focus on the CSA-binding pocket, responsible for the adhesion of
parasitized erythrocytes to the cells of the placenta.

Story Source:

Adapted from materials provided by CNRS (Délégation Paris Michel-Ange).

Source:      http://www.sciencedaily.com/releases/2010/03/100307215534.htm

Vitamin D Crucial to Activating Immune Defenses

When the naïve T cell recognizes foreign molecules with its T cell receptor (TCR) it sends
activation signals to the VDR gene. The VDR gene now starts the production of VDR. VDR binds
vitamin D in the T cell and becomes activated. Vitamin D bound to activated VDR goes back into
the cell nucleus and activates the gene for PLC-gammal. PLC-gamma1 is produced and the T
cells can get started. (Credit: Professor of Immunology, Carsten Geisler)

ScienceDaily (Mar. 8, 2010) — Scientists at the University of Copenhagen have discovered that
Vitamin D is crucial to activating our immune defenses and that without sufficient intake of the
vitamin, the killer cells of the immune system -- T cells -- will not be able to react to and fight
off serious infections in the body.

For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells
must first be 'triggered' into action and 'transform' from inactive and harmless immune cells into
killer cells that are primed to seek out and destroy all traces of a foreign pathogen.

The researchers found that the T cells rely on vitamin D in order to activate and they would
remain dormant, 'naïve' to the possibility of threat if vitamin D is lacking in the blood.

Chemical Reaction that Enables Activation

In order for the specialized immune cells (T cells) to protect the body from dangerous viruses or
bacteria, the T cells must first be exposed to traces of the foreign pathogen. This occurs when
they are presented by other immune cells in the body (known as macrophages) with suspicious
'cell fragments' or 'traces' of the pathogen. The T cells then bind to the fragment and divide and
multiply into hundreds of identical cells that are all focused on the same pathogen type. The
sequence of chemical changes that the T cells undergo enables them to both be 'sensitized to' and
able to deliver a targeted immune response.

Professor Carsten Geisler from the Department of International Health, Immunology and
Microbiology explains that "when a T cell is exposed to a foreign pathogen, it extends a
signaling device or 'antenna' known as a vitamin D receptor, with which it searches for vitamin
D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T
cells cannot find enough vitamin D in the blood, they won't even begin to mobilize. "

T cells that are successfully activated transform into one of two types of immune cell. They
either become killer cells that will attack and destroy all cells carrying traces of a foreign
pathogen or they become helper cells that assist the immune system in acquiring "memory." The
helper cells send messages to the immune system, passing on knowledge about the pathogen so
that the immune system can recognize and remember it at their next encounter. T cells form part
of the adaptive immune system, which means that they function by teaching the immune system
to recognize and adapt to constantly changing threats.
Activating and Deactivating the Immune System

For the research team, identifying the role of vitamin D in the activation of T cells has been a
major breakthrough. "Scientists have known for a long time that vitamin D is important for
calcium absorption and the vitamin has also been implicated in diseases such as cancer and
multiple sclerosis, but what we didn't realize is how crucial vitamin D is for actually activating
the immune system -- which we know now. "

The discovery, the scientists believe, provides much needed information about the immune
system and will help them regulate the immune response. This is important not only in fighting
disease but also in dealing with anti-immune reactions of the body and the rejection of
transplanted organs. Active T cells multiply at an explosive rate and can create an inflammatory
environment with serious consequences for the body. After organ transplants, e.g. T cells can
attack the donor organ as a "foreign invader." In autoimmune disease, hypersensitive T cells
mistake fragments of the body's own cells for foreign pathogens, leading to the body launching
an attack upon itself.

The research team was also able to track the biochemical sequence of the transformation of an
inactive T cell to an active cell, and thus would be able to intervene at several points to modulate
the immune response. Inactive or 'naïve' T cells crucially contain neither the vitamin D receptor
nor a specific molecule (PLC-gamma1) that would enable the cell to deliver an antigen specific
response.

The findings, continues Professor Geisler "could help us to combat infectious diseases and global
epidemics. They will be of particular use when developing new vaccines, which work precisely
on the basis of both training our immune systems to react and suppressing the body's natural
defenses in situations where this is important -- as is the case with organ transplants and
autoimmune disease."

Most Vitamin D is produced as a natural byproduct of the skin's exposure to sunlight. It can also
be found in fish liver oil, eggs and fatty fish such as salmon, herring and mackerel or taken as a
dietary supplement. No definitive studies have been carried out for the optimal daily dosage of
vitamin D but as a large proportion of the population have very low concentrations of vitamin D
in the blood, a number of experts recommend between 25-50mg micrograms a day.

Story Source:

Adapted from materials provided by University of Copenhagen.

Web address:
     http://www.sciencedaily.com/releases/2010/03/
     100304121534.htm

Genetic Variant Offers Protection Against

Tuberculosis and Leprosy
enlarge

This thin section transmission electron micrograph (TEM) depicted the ultrastructural
details displayed by a number of Gram-positive Mycobacterium tuberculosis bacilli,
the causative agent for tuberculosis. (Credit: CDC/Elizabeth "Libby" White)

ScienceDaily (Mar. 4, 2010) — When people get exposed to the mycobacterium

responsible for tuberculosis (TB), some will become sick with a disease that is a
major cause of mortality around the world while others simply don't. Now, researchers
reporting in the March 5th issue of the journalCell, a Cell Press publication, can point
to one important reason for this variation in susceptibility or resistance: genetic
differences among individuals in levels of an immune enzyme (LTA4H) that is
involved in the production of leukotriene B, a pro-inflammatory fatty acid immune
signaling molecule.

It turns out individuals who are heterozygous for LTA4H, meaning they carry two
versions of the enzyme-encoding gene and produce an average amount of the enzyme
(not too little or too much), are less likely to succumb to tuberculosis. They also
appear to gain protection against leprosy, a disease which is also caused by
mycobacterial infection.

"TB is obviously a big problem," said Lalita Ramakrishnan of the University of

Washington. "There isn't a good vaccine, notwithstanding the fact that the TB vaccine
has been administered to more people than any other. On top of that, it requires long-
term treatment for cure and there is an epidemic of drug-resistant TB. Increasingly,
people are becoming infected with strains that are resistant to every antibiotic. On this
backdrop, it made sense to go back to the drawing board and try to understand the
pathogenesis of the disease."

In the new study, Ramakrishnan and her colleague David Tobin did just that, in an
unbiased screen for TB susceptibility genes in the zebrafish. They then collaborated
with University of Washington human geneticists Jay Vary, Thomas Hawn and Mary-
Claire King and others in Vietnam and Nepal to validate their findings in human
populations.

A second study in the same issue of Cell approached the question in another way.
Kanury Rao and his colleagues at the International Centre for Genetic Engineering
and Biotechnology in India used a genome-wide analysis to produce what now
becomes a resource for TB researchers everywhere. They uncovered all of the
"cellular machinery" within human macrophages -- the cells primarily targeted by TB
-- that interact with the infectious mycobacteria and allow the infection to stably
persist.

Rao's team uncovered 275 players within host cells that interact with each other to
form a dense network. That picture allowed the researchers to make a detailed
molecular-level description of what he refers to as "functional modules" within host
cells that are engaged and perturbed by TB infection. Interestingly, they showed that
the shape of that interaction varies depending on which isolated strain of TB one
considers, suggesting that the different strains rely on somewhat different tactics for
successful infection.

Rao's findings offer new leads in the fight against TB, he says. "We identify a core set
of molecules which can be targeted through drug development efforts to treat both
drug sensitive and multiple drug resistant forms of TB infection. Rather than targeting
the pathogen itself, our studies highlight an alternate strategy wherein the host factors
required to support pathogen survival can be used as targets for TB therapy."

The discovery of LTA4H as a TB susceptibility gene may have clinical implications

too, even if it doesn't offer a direct path to a better vaccine, Ramakrishnan says. For
one thing, the finding that medium activity of the immune enzyme is best when it
comes to TB might help to explain something that has been known but not well
understood in clinical circles: people with hard-to-treat TB sometimes improve when
they are given anti-inflammatory, immunosuppressive therapies along with more
standard drug treatments alone.
Ramakrishnan also notes that the same polymorphisms in LTA4H they uncovered
were earlier linked to heart disease. That suggests that drugs that target this pathway
in heart disease might be useful in the context of TB, she says.

The connection between infectious disease and heart disease also has implications for
understanding the evolution of the immune system's inflammatory responses. "In
general, people have thought that inflammation is a positive when it comes to fighting
infection, but then it can cause modern-day disease," Ramakrishnan says. The finding
that it is heterozygotes -- with intermediate activity of the immunity enzyme -- who
fare best in the context of TB and leprosy suggests that in these infections also,
inflammation has to be finely tuned for optimal protection.

The researchers include David M. Tobin, University of Washington, Seattle, WA; Jay
C. Vary, Jr., University of Washington, Seattle, WA; John P. Ray, University of
Washington, Seattle, WA; Gregory S. Walsh, Howard Hughes Medical Institute and
Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA;
Sarah J. Dunstan, Oxford University Clinical Research Unit, Hospital for Tropical
Diseases, Ho Chi Minh City, Vietnam, Oxford University, Oxford, UK; Nguyen D.
Bang, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh
City, Vietnam; Deanna A. Hagge, Mycobacterial Research Laboratory, Anandaban
Hospital, Kathmandu, Nepal; Saraswoti Khadge, Mycobacterial Research Laboratory,
Anandaban Hospital, Kathmandu, Nepal; Mary-Claire King, University of
Washington, Seattle, WA; Thomas R. Hawn, University of Washington, Seattle, WA;
Cecilia B. Moens, Howard Hughes Medical Institute and Division of Basic Science,
Fred Hutchinson Cancer Research Center, Seattle, WA; and Lalita Ramakrishnan,
University of Washington, Seattle, WA.

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Adapted from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

Journal References:
1. Tobin et al. The lta4h Locus Modulates Susceptibility to Mycobacterial
Infection in Zebrafish and Humans. Cell, 2010; 140 (5): 717-730
DOI: 10.1016/j.cell.2010.02.013
2. Kumar et al. Genome-wide Analysis of the Host Intracellular Network that
Regulates Survival of Mycobacterium tuberculosis. Cell, 2010; 140 (5): 731-743
DOI:10.1016/j.cell.2010.02.012
3. Marcel Behr, Erwin Schurr and Philippe Gros. TB: Screening for Responses to a
Vile Visitor. Cell, 2010; 140 (5): 615-618 DOI: 10.1016/j.cell.2010.02.030

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Cell Press (2010, March 4). Genetic variant offers protection against tuberculosis and
leprosy. ScienceDaily. Retrieved March 24, 2010, from
http://www.sciencedaily.com/releases/2010/03/100304121534.htm

Note: If no author is given, the source is cited instead.

Web address:
     http://www.sciencedaily.com/releases/2010/03/
     100303162906.htm

Climate Change One Factor in Malaria

Spread
ScienceDaily (Mar. 4, 2010) — Climate change is one reason malaria is on the rise in
some parts of the world, new research finds, but other factors such as migration and
land-use changes are likely also at play. The research, published in The Quarterly
Review of Biology, aims to sort out contradictions that have emerged as scientists try
to understand why malaria has been spreading into highland areas of East Africa,
Indonesia, Afghanistan and elsewhere.

"We assessed … conclusions from both sides and found that evidence for a role of
climate in the dynamics is robust," write study authors Luis Fernando Chaves from
Emory University and Constantianus Koenraadt of Wageningen University in the
Netherlands. "However, we also argue that over-emphasizing a role for climate is
misleading for setting a research agenda, even one which attempts to understand
climate change impacts on emerging malaria patterns."

Malaria, a parasitic disease spread to humans by mosquitoes, is common in warm

climates of Africa, South America and South Asia. The development and survival,
both of the mosquito and the malaria parasite are highly sensitive to daily and
seasonal temperature patterns and the disease has traditionally been rare in the cooler
highland areas. Over the last 40 years, however, the disease has been spreading to the
highlands, and many studies link the spread to global warming. But that conclusion is
far from unanimous. Other studies have found no evidence of warming in highland
regions, thus ruling out climate change as a driver for highland malaria.

Chaves and Koenraadt re-examined more than 70 of these studies. They found that the
studies ruling out a role for climate change in highland malaria often use inappropriate
statistical tools, casting doubt on their conclusions.

For example, an oft-cited 2002 study of the Kericho highlands of western Kenya
found no warming trend in the area. But when Chaves and Koenraadt ran the same
temperature data from that study through three additional statistical tests, each test
indicated a significant warming trend. Similar statistical errors plague other
comparable studies, the researchers say.
In contrast, most studies concluding that climate change is indeed playing a role in
highland malaria tend to be statistically strong, Chaves and Koenraadt found. But just
because climate is one factor influencing malaria's spread does not mean it is the only
one. What is needed, the researchers say, is a research approach that combines climate
with other possible factors.

"Even if trends in temperature are very small, organisms can amplify such small
changes and that could cause an increase parasite transmission," Chaves said. "More
biological data will improve our overall understanding of malaria and will allow
scientists to propose more general and accurate models on the impacts of climate
change on malaria transmission."

The authors cite numerous factors that could interact with climate to influence malaria
spread. They point to research showing that people migrating from lowlands may be
introducing the malaria parasite into highland regions. Changes in farming practices
may also play a role. Irrigation associated with more intensive farming may be
creating more places for mosquitoes to breed. Another example comes from two
studies that linked malaria increases in the Bure highlands of Ethiopia to increased
maize farming. There, the immature and aquatic stages of mosquitoes thrive on a diet
of maize pollen, and more mosquitoes can mean more malaria.

"A major future challenge will be to link up what happens with mosquitoes and
parasites at the household level with long-term climate change scenarios at the
continental scale," Koenraadt said.

The spread of malaria in highlands is of great concern to those who work to contain
the disease. But understanding the many factors that influence the spread of highland
malaria could help with efforts to control the disease worldwide, Chaves and
Koenraadt conclude.

"In the light of global efforts towards malaria elimination, highland areas will be
interesting starting points from where control efforts could interrupt transmission and
aid in shrinking the world's malaria map." Koenraadt said.

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 Adapted from materials provided by University of Chicago Press Journals,
via EurekAlert!, a service of AAAS.

Journal Reference:

1. Chaves et al. Climate Change and Highland Malaria: Fresh Air for a Hot
Debate. The Quarterly Review of Biology, 2010; 85 (1): 27 DOI: 10.1086/650284

Need to cite this story in your essay, paper, or report? Use one of the following
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University of Chicago Press Journals (2010, March 4). Climate change one factor in
malaria spread. ScienceDaily. Retrieved March 24, 2010, from
http://www.sciencedaily.com/releases/2010/03/100303162906.htm

Note: If no author is given, the source is cited instead.