Case Western Reserve University School of Medicine experts and colleagues in the United States and Africa have received an $11 million, five-year federal grant to understand why some people living with HIV (the human immunodeficiency virus) in Africa avoid becoming infected with the bacterium that causes tuberculosis (TB)—despite exposure to high-TB-risk circumstances.
Learning what causes this resistance to infection with TB bacteria has a potentially significant global health impact because TB is the leading cause of death worldwide among people living with HIV, as well as a primary cause of death among all people in many developing nations. People who are infected with HIV are 20 to 30 times more likely to develop active TB and one in three HIV deaths globally are estimated to be due to TB.
“Living with both HIV and TB bacterial infection has been called the ‘duet of death,’” said the project’s lead researcher, W. Henry Boom, director of the Tuberculosis Research Unit at Case Western Reserve University School of Medicine. “Becoming infected with TB bacteria can be highly lethal to people living with HIV. Yet earlier my colleagues and I found that some HIV positive people not only don’t get sick or die from TB; they don’t even become infected in the first place. Our aim is to find out why.”
Tuberculosis is caused by a bacterium called Mycobacterium tuberculosis (Mtb). Most people who are heavily exposed to airborne Mtb become infected and develop latent Mtb infection as measured by a positive tuberculin skin test.
Yet Boom and his colleagues (a team of epidemiologists, systems biologists, geneticists, immunologists, microbiologists, and infectious diseases and pulmonary physicians) previously found that in urban Uganda, about 9 percent of people living in a home with someone with TB did not themselves become infected during two years of follow-up.
Similarly, in South Africa, they identified miners who did not become infected despite more than 20 years of working under conditions with the highest Mtb infection pressure in the world. In both Uganda and South Africa, some of these TB “resisters” were people living with HIV.
Under the grant, the researchers will be testing their hypothesis that genetic variations, possibly producing unconventional T-cells, enable macrophages to resist or kill off Mtb infection. Moreover, these pathways should be more readily identified in HIV positive persons. Macrophages are “scavenger” cells that dispose of dead cells and foreign particles through the process of phagocytosis—essentially, the engulfing of those cells and particles.
“The fact that HIV positive resisters, with clearly compromised immune systems, are unaffected by TB infection means that whatever is present in HIV negative resisters should logically be more prevalent in immune-compromised HIV positive resisters,” said co-investigator, Catherine Stein, PhD, associate professor of epidemiology and biostatistics at Case Western Reserve.
Boom and colleagues will screen as many as 12,500 people with a goal of identifying about 60 HIV positive resisters. From there the researchers will sequence the DNA of the resisters They hypothesize that the HIV positive subjects will possess more of the unconventional T-cells than will analogous numbers of HIV negative resisters and others serving as control groups.
“Identifying resistance mechanisms to Mtb infection in HIV positive and HIV negative people will provide new insights into our understanding of how TB operates within the body, point to novel approaches to TB vaccine and treatment, and identify biomarkers of resistance to and/or clearance of Mtb infection,” said Boom.
Mtb typically attacks the lungs, but other parts of the body such as the kidneys and brain are vulnerable too. The disease is transmitted through the air when a person with TB of the lungs or throat coughs, sneezes, talks, or spits. Those nearby may inhale TB bacteria and become infected. TB is not spread by sharing food or drink, shaking hands, or kissing.
According to the World Health Organization, 9.6 million people had TB and 1.5 million died from it in 2014. About one-third of people living today have latent Mtb infection, which means they have been infected by Mtb but aren’t sick (yet) and can’t spread it. TB occurs in all parts of the world but is most common in Africa, with 281 cases per 100,000 people in 2014 (compared with a global average of 133).
Additional project researchers are Thomas Hawn, associate professor of medicine at the University of Washington; Harriet Mayanja, professor of medicine at Makerere University’s College of Health Sciences in Uganda; and Robert Wallis and Gavin Churchyard, both professors of medicine in South Africa at the Aurum Institute, Johannesburg.
Separately, Boom and his colleagues have received an NIH training grant to provide PhD and master’s level training in microbiology and immunology, including tuberculosis and HIV, to Ugandan students. This new training program builds on a 28-year training partnership between Case Western Reserve University and Uganda-based Makerere University and Joint Clinical Research Center. Master’s level training will primarily take place in Uganda and PhD training will primarily occur in Cleveland.
This research is supported by National Institutes of Health grants RO1AI124348 and Fogarty International Center D43TW010319.