MALARIA: Genetic Basis Discovered For Key Parasite Function In Malaria

Anne A. Oplinger : NIH/National Institute of Allergy and Infectious Diseases

27 May 2011
Snug inside a human red blood cell, the malaria parasite hides from the immune system and fuels its growth by digesting hemoglobin, the cell's main protein. The parasite, however, must obtain additional nutrients from the bloodstream via tiny pores in the cell membrane. Now, investigators from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have found the genes that malaria parasites use to create these feeding pores.
The research was led by Sanjay A. Desai, M.D., Ph.D., of NIAID's Laboratory of Malaria and Vector Research. In 2000, Dr. Desai co-discovered the primary type of feeding pore on parasite-infected blood cells, an ion channel known as the plasmodial surface anion channel (PSAC). Ion channels are pore-forming proteins that allow the movement of calcium, sodium and other particles into or out of the cell. A report of the team's new findings, which build on this original discovery, is now online in Cell.
"Despite recent progress in controlling malaria worldwide, the disease continues to kill more than 700,000 people, primarily young children, every year," said NIAID Director Anthony S. Fauci, M.D. "Dr. Desai and his colleagues have discovered the genetic basis of a fundamental aspect of malaria parasite biology, and in doing so, they have opened up potential new approaches to developing antimalarial drugs."
Scientists have known for decades that malaria-infected red blood cells have greater nutrient uptake than non-infected cells, presumably to support parasite survival and growth, noted Dr. Desai. But, he added, "It was debated whether the parasite co-opts existing human channels or uses its own proteins to remodel the red blood cell membrane."
To answer this question, the NIAID team screened nearly 50,000 chemicals for their ability to block nutrient uptake by cells infected with either of two genetically distinct lines of Plasmodium falciparum malaria parasites, HB3 and Dd2. Most chemicals were equally active against the two lines, but one, ISPA-28, stood out because it was 800 times more active against the nutrient channels of Dd2-infected red blood cells than against those of HB3-infected cells.
If the PSAC protein is made by the parasite, the scientists reasoned, the strikingly different effects of ISPA-28 on the two lines may reflect genetic differences. To explore this possibility, the investigators measured how well ISPA-28 inhibited PSAC activity in daughter parasites resulting from a genetic cross between the HB3 and Dd2 lines. They found that most daughter parasites made channels that were identical to those of one or the other parent, indicating that parasite genes play an important role. The inheritance pattern of ISPA-28 action on channels led the researchers to chromosome 3, where they found two parasite genes, clag3.1 and clag3.2, that appear to encode the PSAC protein.
This genetic evidence was bolstered when they showed that individual parasites express either the clag3.1 gene or the clag3.2 gene, but not both simultaneously. They found that switching between the two genes produced changes in PSAC behavior that could be predicted. Malaria parasites use gene switching as a way to protect essential proteins from attack by the immune system, Dr. Desai explained.
"We were surprised to discover a role for clag genes in PSAC activity," said Dr. Desai. This family of genes, which do not look like other ion channel genes, was previously thought to be involved in helping infected cells adhere to the inner lining of blood vessels. Clag genes are found in all species of malaria parasites, noted Dr. Desai, and this fact, along with the discovery that the parasites can choose between one of two channel genes to ensure nutrient uptake, strongly suggest that PSAC is required for parasite survival within red blood cells.
The discovery of parasite genes required for PSAC activity opens up several new research directions, said Dr. Desai. For example, development of antimalarial drugs that target these channels could be accelerated. The NIAID team has already found PSAC inhibitors that kill malaria parasites. Dr. Desai's team also is exploring how the PSAC protein is transported from the parasite to the red blood cell membrane, as preventing this transport may be another way to kill malaria parasites.


In addition to funding from NIAID's Division of Intramural Research, this study was supported by Medicines for Malaria Venture, a not-for-profit public-private partnership headquartered in Switzerland.
References:
W Nguitragool et al. Malaria parasite clag genes determine nutrient uptake channel activity on infected red blood cells. Cell DOI: 10.1016/j.cell.2011.05.002 (2011).
SA Desai et al. A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature 406:1001-05 (2000).
http://www.medicalnewstoday.com/releases/226725.php

TUBERCULOSIS: Tuberculosis May Use Bone Stem Cells to Evade Immune System

By Elizabeth Lopatto -
Dec 6, 2010
Tuberculosis bacteria may use stem cells normally found in the bone marrow to hide in the lungs, researchers said as they pinpointed a possible new target for treatments to fight the infectious disease.
TB recruits mesenchymal stem cells to the lungs, where they help suppress the immune system that fights disease, the scientists said in a study released today by the Proceedings of the National Academy of Sciences. The stem cells produce nitric oxide, a chemical that reduces the type of white blood cells called T-cells, the researchers wrote.
About one third of the world’s people are infected with the bacteria that can cause TB, according to the World Health Organization, based in Geneva, said on its website. The disease is difficult to treat, especially with the emergence of drug- resistant strains. The study suggests that the mesenchymal stem cells are potentially a target for new treatments for TB, a malady that the scientists said kills 1.7 million people last year.
The findings “reveal a key role of mesenchymal stem cells” in TB’s ability to evade the immune system, and “identify these cells as unique targets for therapeutic intervention in tuberculosis,” wrote the researchers, led by Gobardhan Das, a New Delhi-based scientist for the International Centre for Genetic Engineering & Biotechnology, an organization with headquarters in Trieste, Italy.
Mesenchymal stem cells can generate bone, cartilage, fat and connective tissue, according to the website of the U.S. National Institutes of Health, based in Bethesda, Maryland.

To contact the reporter on this story: Elizabeth Lopatto in New York at elopatto@bloomberg.net.
To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net.
http://www.bloomberg.com/news/2010-12-06/tuberculosis-may-use-bone-stem-cells-to-evade-immune-system.html

TUBERCULOSIS: New dual recognition mechanism discovered in tuberculosis

by bjs
09. Sep, 2010
One third of the world’s population is infected with Mycobacterium tuberculosis (MTB), which leads to tuberculosis (TB), a leading cause of death world-wide. A new discovery, led by a team of researchers from Case Western Reserve University School of Medicine, offers hope for new approaches to the prevention and treatment of TB. The team’s discovery of a novel mechanism that may contribute to immune recognition of MTB is published in the September issue of Nature Structural and Molecular Biology.
Most individuals with TB recover from the initial infection and become asymptomatic, but the bacterium persists for years, surviving largely inside macrophages, a type of cell that resides in the immune system. This presents a public health problem in that TB can reactivate and cause serious disease or death. Researchers and physicians know the body’s immune system is capable of containing the infection but not curing it completely. It begs the question: “How does the organism survive in the human immune system for so many years?”
For the past 15 years, Drs. Clifford Harding and W. Henry Boom of Case Western Reserve have been seeking the answer to this question. Their work indicated that MTB can inhibit the ability of macrophages to stimulate infection-fighting immune responses, and they identified that a protein on macrophages called Toll-like receptor 2 (TLR2) is involved in this immune evasion mechanism. TLR2 seems to be a two-edged sword in the complex immune response to MTB, as it helps some immunity mechanisms and inhibits others. Understanding the balance of these effects and the role of TLR2 may provide insights to design therapies for TB.
“Understanding how MTB interacts with the immune system and how it can both activate and inhibit the immune response is critically important for the design of the next generation of TB vaccines. The persistence of infection is dependent on MTB’s ability to manipulate our immune system to its advantage. The paradox here is that the MTB molecule, LprG, stimulates TLR2, one of the major receptors we have to identify disease-causing microorganisms. In this case, too much stimulation through TLR2 actually favors MTB by causing parts of the immune response to shut down,” explains W. Henry Boom, MD, professor of medicine and director of the Tuberculosis Research Unit at Case Western Reserve School of Medicine.
The new studies show that the potency of LprG to induce these responses is explained by its combination of two mechanisms to activate TLR2: first, by directly stimulating TLR2 and, second, by serving as a carrier to deliver other molecules that stimulate TLR2. This dual mechanism may drive stronger regulation of immune responses by MTB, and future vaccine development may be enhanced by designing approaches to use such mechanisms. Furthermore, the work indicates that LprG contributes to the assembly of the bacterial cell wall, suggesting that it may be possible to develop molecules to interfere with LprG function and potentially serve as new antibiotics to fight TB. The development of new antibiotics is an increasingly important goal, since resistance to existing antibiotics is becoming widespread.
A multi-institutional partnership contributed to the overall success of this research initiative. Two important collaborative groups were led by James C. Sacchettini, PhD, Texas A&M University and D. Branch Moody, MD, Harvard Medical School. In addition, the project was spearheaded by Michael G. Drage and Nicole D. Pecora, two Case Western Reserve students in the MSTP Program, granting dual MD and PhD degrees, in collaboration with Jennifer Tsai, a graduate student in Dr. Sacchettini’s group.
“Our research team is composed of several collaborative groups that each contributed key components to this project. The synergistic way in which the team interacted was a perfect example of scientists working together to advance the study of a disease that detrimentally impacts the lives of so many across the globe. We look forward to continuing to advance this research together,” says Clifford V. Harding, MD, PhD, professor and interim chair of pathology at Case Western Reserve School of Medicine.
As they look to the future, the research team will work to gain a better understanding of immune responses in TB and hopefully design approaches to treat the deadly disease, including antibiotics or immunotherapies. Continued work will include study of the mechanism of immune-evasion by MTB with the hope of finding ways to reverse this mechanism so that it no longer causes a persistent infection.

http://scienceblog.com/38378/new-dual-recognition-mechanism-discovered-in-tuberculosis/

TUBERCULOSIS: Test offers hope of tuberculosis breakthrough

A blood test that can tell doctors whether someone is likely to develop the active and dangerous form of tuberculosis has become a realistic possibility.
Scientists believe they have finally found a way that could distinguish the 10 per cent of people infected with TB who will go on to develop the full-blown disease from the 90 per cent of healthy carriers who have the latent form of the lung infection.
It would mean that doctors could concentrate on treating the one in 10 infected people who are at high risk of becoming seriously ill, rather than attempting to give potent anti-TB drugs to everyone who is shown to be infected with the TB bacterium.
About two million people worldwide die each year from TB, mostly in the developing world, but the disease has also made a come-back in developed countries. In Britain 9,153 cases were recorded in 2009, the largest annual increase (5.5 per cent) since 2005, with nine out of 10 cases occurring in ethnic minorities.
The researchers, led by Anne O'Garra of the Medical Research Council's National Institute for Medical Research in London, found a "genetic signature" in the blood of people with active TB which could be used as the basis of a diagnostic test.
The study in the journal Nature also found the same genetic signature – evidence of certain infection-related genes being activated – in 10 per cent of people with the latent form of the disease. However, further work needs to be done to assess whether this 10 per cent will be the same 10 per cent of latent patients who go on to develop active TB, Dr O'Garra said.
"As an immunologist, what most intrigued me was that approximately a third of the world has been exposed or infected with the TB bacterium but only 10 per cent of these people get sick and the question is why – what determines when people get active tuberculosis?" Dr O'Garra said.
"What we've described is a distinct blood gene signature in active TB patients, and intriguingly this is absent in other infectious diseases and also in healthy individuals. But it is present in latent TB individuals, but only in 10 per cent of these individuals," she said.
The study involved a wide range of ethnic groups in London, where 3,500 cases of TB were diagnosed last year, about 40 per cent of all UK cases. More than 400 participants took part in the study, which also involved analysing the blood of TB patients in Cape Town in South Africa.
"By doing the study in London we were able to involve individuals with a really wide range of backgrounds and diverse ethnicity and thus make our findings more widely available to this global disease," said Matthew Berry, a consultant in respiratory medicine.
The blood signature found in active TB patients is independent of ethnicity, age and sex, and appears to reflect the severity and extent of the disease. The signature also disappears after successful treatment, Dr Berry said.
"What such a test would enable is very targeted treatment. Instead of trying to treat everyone with latent TB you could focus all of your efforts on that 10 per cent who would develop the disease," he said.
The genetic signature shows that certain genes in specialised blood cells called neutrophils have been turned on by the action of a molecule in the immune system known as type-1 interferon, which can aggravate bacterial infections, Dr O'Garra said. "Finding these molecules expressed in TB suggests that they may be contributing to make the disease worse," she said.
Robert Wilkinson of the University of Cape Town said that the existing diagnostic test for TB has not changed for 125 years. "We're excited by the study because it gives us greater insight into how tissue damage might occur in tuberculosis. It also raises the prospect of developing a diagnostic test or a way of learning who is most at risk of TB," he said.
http://www.independent.co.uk/news/science/test-offers-hope-of-tuberculosis-breakthrough-2056374.html

MALARIA: Keeping the plasmodium in the red cell

Boston, MA -- Harvard School of Public Health (HSPH) researchers and colleagues seeking to block invasion of healthy red blood cells by malaria parasites have instead succeeded in locking the parasites within infected blood cells, potentially containing the disease.
The findings reveal an essential step in the biology of the most common and severe malaria parasite, Plasmodium falciparum, and offer a new drug target for fighting one of the world's most common and dangerous infections.
Malaria sickens up to one half billion people every year and kills up to one million, mostly children in sub-Saharan Africa. The high fevers, shaking chills, flu-like symptoms, and anemia can be fatal unless treated quickly. Malaria has grown resistant to a long list of drugs, and vaccines are still in experimental stages.
Working with the malaria parasite and human blood in test tubes and lab dishes, the research team identified a single fast-acting protein in the parasite that enables it and several dozen of its offspring to escape from a human red blood cell in preparation for quick invasion of many more healthy blood cells. Eliminating that protein traps the parasites in the cell.
After an infected mosquito bites a person, malaria parasites move into the liver, where they silently mature and multiply within weeks. Malaria parasites make people sick weeks or months later when they enter red blood cells and begin an exponential expansion. In a single cell, a parasite produces up to 32 offspring in about two days, which burst out to infect more red blood cells.
"This is the stage where things have to happen very fast for the parasite," said senior author Manoj Duraisingh, HSPH assistant professor of immunology and infectious diseases and senior author of the paper in the May 14 Science. "The parasite doesn't like to spend much time outside the cell. It grows and matures, and immediately following rupture, enters a new cell. It was a surprise that this protein kinase, which we thought would be involved in red blood cell invasion, turns out to be essential for the parasite getting out of the cell."
The study helps define the exit of the parasite from a blood cell as a highly choreographed process and distinguishes the egress and invasion steps, the researchers said.
"When the parasite gets out of the red blood cell, it has a matter of seconds or minutes to get into new red blood cells, or it will be cleared or killed by the human immune system," said first author Jeffrey Dvorin, a postdoctoral research fellow in the Duraisingh Lab at HSPH and a clinical fellow in pediatric infectious diseases at Children's Hospital Boston. "We found an important trigger for the parasite to exit cells that may be independent from the invasion trigger."
Even better, the protein is found in the parasite and in plants, but not in humans, which means a drug targeted to that protein may be less toxic for people. The protein belongs to a family of Plasmodium falciparum calcium-dependent protein kinases, or PfCDPK5 for short in this case. Other members of the family have been implicated in parasite egress of red blood cells, but this is the first study using a genetic technique to validate a protein critical for parasite egress of red blood cells, according to the researchers.
Many companies and labs are looking for inhibitors of parasite egress and invasion of red blood cells, but no anti-malarial drugs yet target these stages of the parasite lifecycle, Dvorin said.
The paper also demonstrates the usefulness of a new tool that can be used to evaluate additional members of the kinase family, as well as other signaling pathways that regulate key events in the blood stage of malaria infection. As of 2002, "we have a malaria genome of about 6,000 genes," said Duraisingh. "We need a means of prioritizing specific gene candidates for further drug development."
http://www.sciencecodex.com/new_twist_on_potential_malaria_drug_target_acts_by_trapping_parasites_in_cells

MALARIA: Adaptive mechanisms of P Falciparum

Malaria parasites have to survive and transmit within a highly selective and ever-changing host environment. Because immunity to malaria is nonsterilizing and builds up slowly through repeated infections, commonly the parasite invades a host that is immunologically and physiologically different from its previous host. During the course of infection, the parasite must also keep pace with changes in host immune responses and red-blood-cell physiology. Here, we describe the "selection landscape" of the most virulent of the human malaria parasites, Plasmodium falciparum, and the adaptive mechanisms it uses to navigate through that landscape. Taking a cost-benefit view of parasite fitness, we consider the evolutionary outcomes of the most important forces of selection operating on the parasite, namely immunity, host death, drugs, mosquito availability, and coinfection. Given the huge potential for malaria parasite evolution in the context of the recently renewed effort to eradicate malaria, a deeper understanding of P. falciparum adaptation is essential.
http://www.sciencemag.org/cgi/content/abstract/328/5980/866

TUBERCULOSIS: Proteasome research

UPTON, NY — Scientists looking for new ways to fight tuberculosis (TB) have their sights set on a structure essential to the bacterium's survival. Disabling this structure could kill the microbes in the infected host and thwart TB infections. In a study appearing online May 11, 2010, in EMBO J, the journal of the European Molecular Biology Organization, scientists from the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, Stony Brook University (SBU), and Weill Cornell Medical College describe new features of how this structure, known as a proteasome, is put together and how it works. These details could assist researchers working to develop anti-TB drugs.
"Mycobacterium tuberculosis, the bacterium that causes TB, infects one person in three worldwide, so finding new ways to battle this pathogen is a major public health priority —particularly in developing nations where active TB infections are endemic," said study co-author Huilin Li, a Brookhaven biophysicist and associate professor at SBU.
Earlier studies by Li and his collaborators revealed important structural details of the Mycobacterium tuberculosis proteasome, a piece of cellular machinery that carves up unwanted or damaged proteins, allowing the bacterium to evade a key defense of the human immune system.* The team has even identified small molecules that might be incorporated into drugs to inhibit the proteasome. "The primary aim of this new study was to look at how the proteasome, comprised of 28 proteins, is constructed," said Li.
http://www.eurekalert.org/pub_releases/2010-05/dnl-ndo051010.php

MALARIA: Why vaccines have failed

Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants.
Methodology/Principal Findings
We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally.
Conclusions/Significance
We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications for accelerated local eliminations of malaria, and significantly increases potential for eradication.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010685

MALARIA: locking in the parasite!

Harvard School of Public Health (HSPH) researchers and colleagues seeking to block invasion of healthy red blood cells by malaria parasites have instead succeeded in locking the parasites within infected blood cells, potentially containing the disease.
The findings reveal an essential step in the biology of the most common and severe malaria parasite, Plasmodium falciparum, and offer a new drug target for fighting one of the world's most common and dangerous infections.
Malaria sickens up to one half billion people every year and kills up to one million, mostly children in sub-Saharan Africa. The high fevers, shaking chills, flu-like symptoms, and anemia can be fatal unless treated quickly. Malaria has grown resistant to a long list of drugs, and vaccines are still in experimental stages.
Working with the malaria parasite and human blood in test tubes and lab dishes, the research team identified a single fast-acting protein in the parasite that enables it and several dozen of its offspring to escape from a human red blood cell in preparation for quick invasion of many more healthy blood cells. Eliminating that protein traps the parasites in the cell.
After an infected mosquito bites a person, malaria parasites move into the liver, where they silently mature and multiply within weeks. Malaria parasites make people sick weeks or months later when they enter red blood cells and begin an exponential expansion. In a single cell, a parasite produces up to 32 offspring in about two days, which burst out to infect more red blood cells.
"This is the stage where things have to happen very fast for the parasite," said senior author Manoj Duraisingh, HSPH assistant professor of immunology and infectious diseases and senior author of the paper in the May 14 Science. "The parasite doesn't like to spend much time outside the cell. It grows and matures, and immediately following rupture, enters a new cell. It was a surprise that this protein kinase, which we thought would be involved in red blood cell invasion, turns out to be essential for the parasite getting out of the cell."
The study helps define the exit of the parasite from a blood cell as a highly choreographed process and distinguishes the egress and invasion steps, the researchers said.
"When the parasite gets out of the red blood cell, it has a matter of seconds or minutes to get into new red blood cells, or it will be cleared or killed by the human immune system," said first author Jeffrey Dvorin, a postdoctoral research fellow in the Duraisingh Lab at HSPH and a clinical fellow in pediatric infectious diseases at Children's Hospital Boston. "We found an important trigger for the parasite to exit cells that may be independent from the invasion trigger
http://www.sciencedaily.com/releases/2010/05/100514171912.htm

MALARIA: Historical aspects

Kicking off proceedings was LSHTM’s Professor Brian Greenwood, a legend in malaria research, who painted a picture of how malaria treatment used to be – and how much it has changed.
Forty years ago almost every African child had malaria, with an estimated prevalence of 95 per cent (though Greenwood reckoned it was nearer to 100 per cent in reality). Yet, at the time, confidence in malaria treatments was high. The front-line anti-malaria drugs such as chloroquine were effective and anti-malarials for prophylaxis were widely sold. “We didn’t have seminars about malaria,” said Greenwood, “People didn’t feel there needed to be [any]”.
But that was before the spectre of anti-malaria drug resistance emerged. Following the first report in 1968, resistance spread rapidly through the continent, rendering many of the front-line treatments ineffective and forcing a major rethink of treatment strategies.
A serious barrier was changing doctors’ behaviour. Despite the fact that resistance was widely acknowledged, chloroquine continued to be (mis-)used. Why?
“Everyone liked chloroquine,” said Greenwood, “Doctors had confidence in it from years of effective use, and doctors are very conservative by nature. Getting them to change their minds was a hard task.”
Moreover, chloroquine had benefits beyond malaria. It is an effective anti-inflammatory, one of the reasons the drug was always prescribed, even if the patient didn’t have malaria. Said Greenwood, “It was thought to be fine to do so as they were always likely to benefit”.
Furthermore, there was a widespread (erroneous) belief that having a few parasites circulating in the body ‘stimulated the immune system’. It was common practice in many places to give patients just one day of a three-day course of chloroquine.
We now know that many of these practices are detrimental to health and a boon to increasing the resistance of the parasite to the drug. The patient could develop anaemia or the parasite could recover and cause another bout of malaria.
By the 1990s the malaria community had learnt that treatment should eliminate all parasites. This was in no small part due to pioneering research by scientists such as Professor Nick White from the Wellcome Trust’s Major Overseas Programme in Thailand (in South-east Asia the idea of leaving parasites around for immunity was never fully accepted). Also, from treating tuberculosis, researchers and healthcare workers soon realised that the use of mono-therapies – and overuse of them at that – was helping to increase drug resistance.
We now know the importance of diagnosing and only treating those who really have malaria, yet the relative slowness with which the community recognised these dangers was disastrous. Even today the idea of leaving a few parasites in the body has not completely been dispelled. As Greenwood said, it’s taken a long time to learn those messages and we are mostly there now, but the message must continue to be broadcast.
http://wellcometrust.wordpress.com/2010/04/26/counting-malaria-out-malaria-treatment-as-it-used-to-be/

Poverty & Pneumonia

Pneumonia often strikes those who have weakened immune systems. In poor countries, where countless children die of pneumonia, their immune systems are compromised. But why is this so?
The answer is that it is because they live in poverty – be it a consequence of malnutrition, unsanitary conditions, or poor environmental conditions. The conclusion to be drawn, in a sense, is that poverty is the disease. Poverty is what makes the people in these poor countries prone to this disease.
Consider that 11 million children under the age of 5 die each year because of preventable diseases and malnutrition. Children without food are children without a strong immune system, unable to defend themselves against diseases. According to the World Food Program (WFP), malnutrition is one of the causes of death for 10 million children under five. It is estimated that 53% of deaths in children under the age of 5 are due to undernutrition. The following chart shows the percentage of deaths that are ultimately caused by malnutrition:

According to the WFP, there are two types of acute hunger. Acute hunger or starvation is the result of emergencies, such as wars or natural disasters – however, “emergencies account for just eight percent of hunger’s victims”. Daily undernourishment affects many more people – where people are chronically hungry and live on less than the 2,100 recommended calories a day. Every minute, 21 children die somewhere in the world because of malnutrition related causes. This is one of the reasons that 5-10% of children in developing countries will develop pneumonia each year (amounting to 154 million cases of pneumonia in children in developing countries each year), why 2 million of these children under age 5 will die, and why pneumonia is associated with 15-40% of all childhood deaths.
http://worldtodayshow.wordpress.com/2010/04/07/poverty-and-pneumonia-and-malnutrition/