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Rebuilding BCG, the Tuberculosis Vaccine

A "TB free India" has been the vision of the Revised National Tuberculosis Control Program (RNTCP), a state-run tuberculosis (TB) control initiative of the Government of India. Around 2.7 lakh people succumb to the disease every year, and around 12 lakh new cases emerge, making Mycobacterium tuberculosis (MTB) not only the biggest health problem in India, but also the second largest infectious killer in the world. The World Health Organizationreported 1.5 million deaths caused by TB in 2014.

More than thirty percent of the world's population is infected with MTB,the TB bacterium. This may sound rather alarming, but it is also true that most people carry only "latent" infection, which is not contagious. However, the seemingly innocuous infection has the potential to become active and affect others years later. This impending risk, along with its capacity for resurgence and multi-drug resistance, makes it very important that we find an effective vaccine to prevent TB. 

MTB lives and reproduces within the tissues both at original and disseminated   sites of infection and thereby brings about the death of the host cell. This host cell is typically a macrophage. Macrophages are a type of white blood cells, key players in the human innate immune response to foreign particles in the body. The bacterium achieves this by the specific expression of certain genes, to make proteins, while growing within the macrophage. 

  Dr. Vijaya Satchidanandam, a professor at the Department of Microbiology and Cell Biology at the Indian Institute of Science, Bangalore (IISc) studies how MTB interferes with innate and adaptive immune systems of our body.

Her work focuses on understanding interactions between infective microorganisms and their hosts. In the case of MTB, this involves identifying virulence determining genes of the pathogen and their mechanism of subverting host-protective processes and pathways.

Generally, host-pathogen interactions in TB infections are studied using animal models of infection, either mice or guinea pigs. However, in the case of TB, the disease manifestation, and differences in TB susceptibility observed in the animal models differs largely from the human scenario.

One of the main features of the human immune response to MTB is the formation of organized structures called granulomas. When the lungs are infected by TB bacterium, our body's immune system contains the infected cells by building fortifications to form granulomas. Within this granuloma, the bacteria may remain for a long time in a dormant state, or get activated, depending on the immune status of the infected host, the latter causing tissue destruction.

"It is important to reduce   the inflammatory response of the host that causes this tissue destruction in the lungs, since an entire lobe in the lungs can be infected and damaged, necessitating its surgical removal, and the patient may end up with smaller lungs," says Vijaya.

To understand exactly what happens in the human body, Dr. Vijaya's team has worked largely with patients at the TB Sanatorium and Department of Chest Medicine, MS Ramiah Hospital. Their initial observations revealed that the staff at sanatorium -- even after years of working in the midst of the airborne bacteria – remained apparently healthy. In other words, they carried the infection, but they did not get the disease and did not infect others. They exhibited a form of protective immunity against the disease.

By building a gene library of the TB genome and screening this library with sera of tuberculosis patients and the staff at the sanatorium, the team was able to identify differentially expressed proteins of the TB bacterium  that stimulate protective immunity against TB. This discovery led to the development of an experimental recombinant BCG vaccine, which when tested in the guinea pig animal model, was more effective than the conventional BCG vaccine.

It is well documented that only 5-10% of those infected by Mycobacterium tuberculosis progress to disease, depending upon their HIV status. Further, it has been observed that an HIV-negative individual infected by MTB progressing to TB disease is a mere 10%. This observation testifies to the success of human immune mechanisms in preventing reactivation of persistent TB bacteria. Studying the immunology of tuberculosis in HIV-infected individuals and MTB-infected healthy individuals has helped her team to identify the role of host-protective immune mechanisms and the bacterial components that trigger such protective responses.

"Identifying these protective antigens and including them in TB vaccines may result in a novel vaccine against TB,"…"leveraging all these immunological factors, our next phase would be rebuilding the vaccine, Bacille Calmette-Guérin ( BCG)"says Dr. Vijaya when asked about her upcoming research areas.

The group also studied the role of a TB glycoprotein named Rv1860, in interfering with host’s immune response to TB. They discovered that in the presence of Rv1860, the BCG vaccine lost its protective efficacy against the disease. This led to the realization that by preventing the glycosylation (process by which sugars are chemically attached to proteins to form glycoproteins) of the Rv1860 protein in BCG, it may also improve its vaccine efficacy.

This is important because successful control of TB, either through drugs or effective preventive vaccines has not been achieved despite extensive research.

"Since BCG has an excellent track record of safety with minimal side effects in humans, improving it using our approach can keep production costs dramatically low, which is where our work is directed," adds Prof. Vijaya confidently.

About the Scientist

Dr. Vijaya Satchidanandam is currently a professor at the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore. With over 20 odd years of research experience in the fields of pathogenesis of Mycobacterium tuberculosis and Japanese Encephalitis Virus, she has published several papers and research articles.

She can be reached at vijaya@mcbl.iisc.ernet.in.

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