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: World TB day: statement of U.S. National Institute of Allergy and Infectious Diseases

March 24, 2011

Statement of Christine F. Sizemore, Ph.D., and Anthony S. Fauci, M.D.
National Institute of Allergy and Infectious Diseases: National Institutes of Health

The theme of World TB Day 2011—"On the move against TB: Transforming the fight towards elimination"—reflects renewed momentum to approach the global problem of tuberculosis with greater intensity and seriousness of purpose. This growing interest is broad-based, emerging from leaders in public health to laboratory scientists, from physicians to activists.
Today, about one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. Most people have no symptoms because the bacterium is inactive, or latent, but individuals with symptoms of active TB disease can infect others. According to World Health Organization (WHO) estimates, in 2009 more than 14 million people had active TB, leading to 1.7 million deaths, or 4,600 deaths each day. Among people infected with the bacteria, those who have certain other conditions, such as HIV/AIDS and diabetes, are more likely to develop active TB and to die from it. Because of this deadly synergy, TB has become the leading cause of death among people with HIV/AIDS.
Although TB control programs have led to a decline in cases worldwide, the emergence and spread of drug-resistant strains of Mtb challenge the way we currently approach TB diagnosis and treatment. Extensively drug-resistant TB, while relatively rare, has been confirmed in 58 countries, including the United States, and likely is present in many more. It has become necessary not just to identify the infection but also to determine the proper therapy for patients at the earliest stages of disease.
Recent developments have created confidence that TB control strategies can be improved to stay abreast of the changing nature of the pandemic. For the first time in decades, a robust pipeline of candidate TB drugs, vaccines, diagnostics, and treatment and prevention strategies are being evaluated in clinical trials. WHO recently endorsed a diagnostic test that enables health care providers to identify drug-resistant TB directly from patient specimens within about two hours rather than waiting months for a conclusive diagnosis. Drugs are being developed that, when combined in novel ways, may significantly improve the way we treat patients with TB. Vaccines are being developed that may one day prevent the disease, even in persons who are already infected with Mtb.
While such advances are crucial to improve patient care, a true transformation in the fight against TB can occur only if we simultaneously deepen our understanding of TB as a disease. For example, a noninvasive means to determine whether an individual is containing the infection or progressing to active disease—what’s called a biomarker—would be of enormous benefit to patient care and for conducting clinical trials of therapies and vaccines. Additionally, although 90 percent of people infected with Mtb never develop active disease, latent TB infection remains largely mysterious. Increasing our knowledge in these and other fundamental areas is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. New and improved laboratory and clinical tools, as well as collaborations between all disciplines of biomedical research, are now being engaged to characterize the interactions at play during the course of Mtb infection and TB disease. The extraordinary complexity of the TB disease process makes it well-suited to being examined as an integrated whole, an approach successful in yielding insights into other complicated diseases.
Together with our global partners, we at NIAID are encouraged by recent progress in TB research. By fostering a comprehensive TB research agenda and innovation at all levels, and by addressing TB with research tools appropriate to the health care challenges we face in the 21st century, we can continue to make great strides. World TB Day reminds us that although TB has afflicted mankind for millennia, we have yet to understand it in modern terms. We must use cutting-edge technologies to ask and answer fundamental questions that have never been adequately addressed. Only in this way will we transform our fight against TB towards elimination of this ancient scourge.

Anthony S. Fauci, M.D., is director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. Christine F. Sizemore, Ph.D., is chief of the Tuberculosis and Other Mycobacterial Diseases Section in the NIAID Division of Microbiology and Infectious Diseases.

http://www.niaid.nih.gov/news/newsreleases/2011/Pages/WorldTBDay11.aspx

TUBERCULOSIS: Promising New Approach to a TB Vaccine (H56)

Jan. 25, 2011
C Aagaard et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nature Medicine. DOI: 10.1038/nm.2285 (2011).


A team of European and U.S. researchers have found that a new vaccine strategy tested in mice provides improved protection from tuberculosis (TB) infection than the vaccine currently used in humans, known as BCG. Their findings were published online on January 23rd in the journal Nature Medicine.
Led by scientists at the Statens Serum Institut (SSI) in Denmark, the study was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the Bill & Melinda Gates Foundation. The NIAID support was through the TB Vaccine Testing and Research Materials program at Colorado State University, an initiative to speed the development of new TB vaccines and treatments.
Caused by the bacterium Mycobacterium tuberculosis (Mtb), TB remains one of the major causes of disability and death worldwide, with an estimated 1.7 million deaths in 2009 and increasing rates of drug-resistant disease. The BCG vaccine, the only one approved for human use, provides limited protection against immediate TB illness but does not prevent reactivation of latent infection, in which Mtb persists in human cells for years and may later develop into active disease.
In this study, researchers at SSI combined two proteins that had previously been tested with a new component, a stress response protein that Mtb produces during latent infection. This three-component vaccine, known as H56, was administered to uninfected mice before and after Mtb infection. The multistage vaccine not only protected against initial illness, but controlled reactivation of latent infection and reduced Mtb levels in the lungs more effectively than BCG alone. Because of the success of this study, the vaccine candidate is now entering clinical development.

Christine Sizemore, Ph.D., chief of the Tuberculosis, Leprosy and other Mycobacterial Diseases Section at NIAID, is available to comment on this article. To schedule interviews, please contact Nalini Padmanabhan, 301-402-1663, niaidnews@niaid.nih.gov.
http://www.niaid.nih.gov/news/newsreleases/2011/Pages/TBvaccineCollaboration.aspx

BIOTERRORISM: Crimean-Congo Haemorrhagic Fever

New Delhi, Jan 23 (IANS)
Further research needs to be done to come up with an antidote to the Crimean-Congo Haemorrhagic Fever (CCHF) that has claimed at least three lives in Gujarat, a senior health official has said.
'We have suggested some strong anti-viral drugs to counter the symptoms, but more research will have to be done on the blood samples collected to come up with an absolute solution,' Doctor A.C. Mishra, director of National Institute of Virology (NIV), said.
'We have also suggested isolation of patients and usage of masks for doctors and other medical staff treating the patients as well as for the relatives of patients. This is a must as the virus is highly infectious,' Mishra told IANS over phone from Pune.
'The virus that has so far killed three people in Gujarat is a category 4 virus, the most dangerous of all,' Mishra added.
Three people died in Gujarat's Sanand early January in the country's first reported attack of the Congo virus.
The three deaths are of Amina Momin, Gagan Senke, the doctor who treated her at a hospital in Ahmedabad, and a nurse in attendance.
Since then, three more patients, who include Amina's husband Rehman and a male nurse, are undergoing treatment in the isolation ward, besides another female patient, said Dr M.M. Prabhakar, superintendent of Ahmedabad's Civil Hospital.
BJ Medical College in Ahmedabad has been designated as the dedicated hospital for isolation and treatment of suspected cases. Its dean Dr Bharat Shah, when contacted, refused comment.
The Pune-based NIV is testing 132 samples received from Gujarat, of which 58 samples were found negative, reports said.
The Gujarat government is screening the Sanand area where the infection was first reported.
In its initial report, the NIV has said the Congo Virus has the potential of killing 20 to 90 percent people. The virus causes multi-organ failure and affects the brain, triggering epileptic convulsions and death.
Dr V.M. Katoch, director general of Indian Council for Medical Research (ICMR), said: 'Antibodies in animals have been seen, which show that the virus is present in the country.'
The Crimean-Congo Haemorrhagic Fever (CCHF) first came to light in 1944, when it infected over 200 Soviet military personnel who were assisting peasants in war-devastated Crimea in Ukraine.
Since then the infection has been surfacing in Africa, Europe and Asia, with outbreaks being recorded in Kosovo, Albania, Iran, Pakistan, South Africa and now for the first time in India.
CCHF is a a tick-borne viral disease. Ticks are blood-sucking parasites often found in tall grass where they wait to attach to a passing host, an animal. Although CCHF causes a mild fever in the animal briefly, the effect is severe in humans.
Examples of similar infections include rabies that infect humans through a dog or monkey bite. Anthrax infects ruminants (grass eaters) namely goats, cattle, sheep and horses and can be transmitted to humans by contact with infected specimens or their products.
According to Dr Nata Menabde, World Health Organisation's representative in India, the presence of CCHF in the country is not unexpected because cases have been reported in neighbouring Pakistan.
The Financial Daily of Pakistan has reported that the first CCHF suspected case in the country surfaced Sep 14, 2010.
Since then, 5,000 more such patients have been hospitalised, of whom 3,000 were tested positive by the NIH (National Institute of Health) in Pakistan, the report said.
Initial human symptoms of CCHF include fever, aching muscles, dizziness, stiffness, backache, headache, sore eyes and sensitivity to light. They may be followed by nausea, vomiting and sore throat, later diarrhoea and abdominal pain, according to health experts.
Over the next few days, the patient experiences mood swings, becoming confused and aggressive. Gradually, sleepiness, depression and langour may replace restlessness with localised abdominal pain and an enlarged liver. The liver, kidney and lung may fail after the fifth day of illness.
Outbreaks are usually attributable to humans handling infected animals and people. Clusters of illness typically appear after people treat, butcher or eat infected livestock, particularly ruminants and ostriches.
As a precautionary measure, US Army personnel maintain special stocks of ribavirin to protect themselves from the infection in Afghanistan and Iraq.
Significantly, CCHF is also listed as a 'potential bioterrorism agent,' classified as a Category C Disease/Agents by the National Institute of Allergy and Infectious Diseases (NIAID) in the US, according to globalsecurity.org.
'These emerging pathogens could be engineered for mass dissemination in the future because of availability, ease of production, dissemination and potential for high mortality rates and major health impact,' the website said
http://www.sify.com/news/research-for-congo-virus-antidote-on-health-expert-news-health-lbxtEfeicig.html

BIOTERRORISM: Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents

The highest priority of the National Institute of Allergy and Infectious Diseases (NIAID) is the development of countermeasures against bioterrorism agents that are highly infectious when dispersed in aerosol form. However, the development of drugs to prevent or treat illnesses caused by bioterrorism agents requires that their effectiveness be tested in animals because human clinical trials would be unethical. At the request of NIAID, the National Research Council conducted a study of appropriate testing in animals. The report provides recommendations to researchers on selecting animal models, aerosol generators, and doses of bioterrorism agents to closely mimic disease processes in humans. It also urges researchers to fully document experimental parameters in the literature so that studies can be reproduced and compared. The report recommends that all unclassified data on studies of bioterrorism agents--including unclassified, unpublished data from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)--be published in the open literature. The report also calls on the Food and Drug Administration to improve the process by which bioterrorism countermeasures are approved based on the results of animal studies.
http://www.nae.edu/19582/Reports/25541.aspx?layoutChange=Normal