TUBERCULOSIS: EspC vaccine

18 March 2011
A protein which could be targeted for a tuberculosis vaccine has been discovered by scientists at Imperial College London.

TB is caused by bacteria and the only vaccine against it, the BCG jab, is not very effective.
The disease of the lungs kills approximately two million people worldwide each year.
The charity, TB Alert, said the research was promising, but a vaccine was a long way off.

A better option
Scientists are aware that the BCG vaccine is not good enough.
Professor Ajit Lalvani, who led the research at Imperial College London, said: "Despite most of the world's population having had a BCG vaccination, there are still nine million new cases of TB every year, so we urgently need to develop a more effective vaccine for TB."
Researchers are trying to find new proteins which can be used in a vaccine to trigger an immune response and provide long-term protection against Mycobacterium tuberculosis.

The study, to be published in Proceedings of the National Academy of Sciences, identifies a new protein called EspC.
Professor Lalvani said: "We've shown that EspC, which is secreted by the bacterium, provokes a very strong immune response, and is also highly specific to Mycobacterium tuberculosis. This makes it an extremely promising candidate for a new TB vaccine that could stimulate broader and stronger immunity than BCG."
Consultant chest physician Dr Peter Davies, who is the secretary of TB Alert, said it was "promising" research.
He told the BBC: "We know of two other targets and the researchers have found a third, which could be useful.
"The trouble is it will take 10 years to find out if it will result in vaccine and whether that vaccine is any better than BCG."

http://www.bbc.co.uk/news/health-12789022

TUBERCULOSIS: Cracking the secrets of the tuberculosis germ

N. Gopal Raj
A team of Indian researchers has discovered a way in which the tuberculosis bacterium is able to remain dormant for many years in the bodies of those it infects, emerging to cause disease when their immune system weakens.

The World Health Organisation estimates that one-third of the world's population is infected with Mycobacterium tuberculosis. But the vast majority of its victims do not ever become sick. In others, however, the disease can manifest after several years.
Figuring out how the microbe is able to survive in people for long periods of time, fending off their immune response, could lead to new therapies for latent infections.

Infection process
When a person with active tuberculosis coughs, sneezes, speaks or spits, the germs get spewed out. Other people get infected by inhaling some of these germs.
As the bacterium sets about establishing itself in its new and unwilling host, cells of the person's immune system rush in to kick out the interloper.
If the immune system is unsuccessful in doing so, as is often the case, a small clump of cells, known as a granuloma, forms in the course of the tussle.
The bacteria get confined to the granuloma and their spread is checked.
A team of scientists — led by Gobardhan Das of the International Centre for Genetic Engineering and Biotechnology in Delhi — has now found that a class of stem cells, known as mesenchymal stem cells (MSCs), plays a complicated role in maintaining the granulomas.
The team's work is appearing this week in the Proceedings of the National Academy of Sciences of the United States of America.

Dual role
MSCs are like the two-headed Roman god Janus, Dr. Das said when he spoke to this correspondent. On the one hand, they limit bacterial replication within the granuloma. On the other, they also inhibit the immune system's T cells, preventing them from clearing up the infection.
In the early stages, when some of the cells of the immune system's quick-response team themselves become infected by the microbe, they raise an alarm by producing signalling molecules called chemokines. The MSCs are attracted to the granuloma by these chemokines.
The MSCs surround the granuloma, positioning themselves between the infected immune cells and the T cells that target the pathogens.
In addition, the MSCs produce nitric oxide. Although nitric oxide is toxic to the bacteria, it is produced only in quantities sufficient to check their replication, not kill them.
The nitric oxide, however, also inhibits the T cell responses, Dr. Das added.
When the immune system weakens — as happens during infection with the Human Immunodeficiency Virus (HIV), which causes AIDS — this can influence the MSCs to stop producing nitric oxide.
As a result, the bacteria can begin to proliferate and the tuberculosis infection gets reactivated.
Consequently, the MSCs could be potential targets for therapeutic intervention in tuberculosis, the scientists note in the paper.
The research was an important step towards better understanding the pathology of tuberculosis, said K.N. Balaji of the Indian Institute of Science in Bangalore, who also studies the bacterium but was not involved in the work.
The tuberculosis bacterium has many immune evasion strategies.
“This happens to one of the new ones, which has not been reported earlier,” he pointed out.

http://www.thehindu.com/health/medicine-and-research/article936113.ece

TUBERCULOSIS: THE PATHOGENESIS OF TUBERCULOSIS

Tuberculosis patients relapse if treatment is not continued for 6 months, because chemotherapy fails to convert the patients' response from the necrotizing pattern characteristic of disease (Koch phenomenon) to the nonnecrotizing bactericidal function required for optimal immunity. We need to understand the nature of these two immunological states and how to convert one to the other. Studies in mice and humans implicate differences in cytokine profiles and in metabolism of adrenal steroids. Either enhanced susceptibility or protection can be evoked in mice with appropriate doses of a killed environmental saprophyte. This emphasizes the importance of shared epitopes and may explain the geographically variable efficacy of Mycobacterium bovis Bacillus Calmette Guérin vaccination. Unlike soluble antigens of M. tuberculosis itself, which tend to evoke necrosis, the shared mycobacterial epitopes evoke little skin-test reactivity in patients. Preparations of these epitopes show potential as immunotherapeutic agents to convert the response from necrotic to bactericidal mode
http://www.annualreviews.org/doi/abs/10.1146/annurev.micro.50.1.259

TUBERCULOSIS: the granuloma

Background
In response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts.
Methodology/Principal Findings
We studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNγ, TNFα, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of ~ two-thirds of all genes induced in early lesions was later repressed.
Conclusions/Significance
The transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012266

TUBERCULOSIS: Molecular profiling

Thanks to molecular profiling, scientists now have a better idea about how a mass killer selects its victims. And the new analysis suggests that the killer, TB, may use a different murder weapon than researchers previously believed.
Mycobacterium tuberculosis infects one-third of people worldwide. But only about 10 percent of people infected will actually get sick with a debilitating lung disease. Until now, scientists had no way to predict who would become ill.
Now, an international consortium of researchers has compiled profiles of genetic activity in the blood of people with dormant TB infections, people with active infections, and healthy people. Those profiles show how the immune system deals with tuberculosis and point to some surprising culprits responsible for awakening a slumbering infection. Such profiles may help predict who will succumb to TB, the researchers report in the Aug. 19 Nature.
“This is literally the way to tell who is going to get sick,” says Clifton Barry, chief of the tuberculosis research section at the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Md. This study could revolutionize TB diagnosis in the same way that breast cancer treatments were forever changed by the discovery that some tumor cells make molecules that respond to estrogen, and that those molecules can serve as targets for chemotherapy, Barry says.
In the new study, researchers drew blood from TB patients and from healthy people in London and analyzed gene activity in the blood cells. People who had active infections had 393 genes with activity different from that seen in healthy people. The team could classify people into groups—no infection, latent infection or active illness—just by looking at the gene activity profiles in their blood. The findings were replicated in a separate group of patients from Cape Town, South Africa. The TB signature disappeared as people were treated with antibiotics.
About 10 to 25 percent of people with latent infections had signatures similar to those of people with active infections, indicating that people with the active profile may go on to develop the disease even if their infection is currently dormant, says study coauthor Matthew Berry of the MRC National Institute for Medical Research in London. The researchers are planning to follow people with latent infections to see if those with the signature really are the same ones who develop active infections later. If the results hold up, the blood profiles could be the first means of predicting who is likely to get sick from TB.
That could spare people from developing a lung-damaging infection, but may also mean that people who aren’t likely to get sick won’t need to take anti-TB drugs that can damage the liver.
Blood cells called neutrophils also appeared in the new study to be important for spreading the disease. Previously, researchers didn’t think that short-lived neutrophils could play any role in such a long-term infection as tuberculosis. The dogma in the field was that the bacterium infected only immune cells called macrophages, says study leader Anne O’Garra, also of the MRC National Institute for Medical Research. The new study indicates that genes turned on by a protein known as type 1 interferon become active in the neutrophils of people with full-blown TB. Interferon helps to fight off viral infections but may actually make bacterial infections such as TB even worse, O’Garra says.
These findings fit well with recent data from mouse studies implicating both neutrophils and interferon in serious disease caused by tuberculosis, says Andrea Cooper, an infectious disease immunologist at the Trudeau Institute in Saranac Lake, N.Y.
“We’re at a watershed here in changing what we think the disease is about,” she says.
TB’s molecular signature was distinct from the profiles of blood taken from people with autoimmune diseases, such as lupus, and from those with other infectious diseases like Streptococcus or Staphylococcus infections, the researchers found. The discovery was unexpected, as most researchers thought that different types of bacteria might change the activity of specific genes at the site of the infection but that those differences would not show up in the blood, Cooper says. The variety of signatures indicates that the immune system has developed multiple ways of dealing with infectious organisms.
“It highlights the beauty of the immune response and its finesse in dealing with different pathogens,” Cooper says.
http://www.usnews.com/science/articles/2010/08/19/gene-profiles-may-predict-tb-prognosis.html

MALARIA: Brazil's improved statistics

Malaria is still a major public health problem in Brazil, with approximately 306,000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.
http://www.malariajournal.com/content/9/1/115/abstract