Researchers at Texas Biomed have recently received five National Institutes of Health (NIH) grants totaling more than $23 million to study fundamental mechanisms and innovative solutions to treat tuberculosis (TB) and HIV.
The highly competitive “R01” grants provide sustained support for research projects over three to five years. Each project builds on many years of previous research and enables critical questions to be explored about TB, HIV and the interplay between them.
“In academic biomedical research, these grants are some of the most prestigious and hard to get and we congratulate our faculty on their awards,” says Professor Shelley Cole, Texas Biomed’s Interim Vice President of Research. “Collectively, the awards reflect our Institute’s strength in the TB and HIV research fields as we strive to improve global health.”
More than 10.6 million people develop active TB, which is caused by the bacterium, Mycobacterium tuberculosis (M. tb), annually. About 1.6 million people die from TB each year, including about 187,000 people with HIV. TB is the leading cause of death for people with HIV.
The majority of infected individuals do not develop active TB disease but contain the bacterium in a dormant state, a condition called latent TB infection (LTBI). The number of people with LTBI is estimated to be 2 billion – representing a massive potential global health burden. Latent TB can reactivate later in life when a person becomes immunocompromised, such as becoming infected with HIV, undergoing immunotherapy for cancer, or through aging processes. Finding new ways to prevent or treat TB and HIV is critical to minimize the public health impacts of these two diseases.
Professor Smriti Mehra, Ph.D., and her team will investigate if blocking a protein naturally found in the body can improve outcomes for patients with both HIV and active TB. The protein, called IDO (short for Indoleamine-2,3-dioxygenase), normally suppresses the immune system, preventing it from causing excessive inflammation and organ damage. Inhibiting IDO for short intervals of time has led to more successful cancer treatments. In previous studies, Dr. Mehra has shown that inhibiting IDO in conjunction with antibiotics helps improve TB treatment, and does not interfere with antiretroviral therapy for SIV, the nonhuman primate equivalent of HIV. Now, she will be able to determine what happens when IDO is blocked in conjunction with both antibiotics and antiretroviral therapy at the same time – more closely mimicking the clinical standard of care to treat both diseases.
Professor Jordi Torrelles, Ph.D., Professor Larry Schlesinger, M.D., and collaborators will study the earliest stages of TB infection in people living with HIV, and how the altered lung environment influences the progression of infection to active TB. Previous research in the Torrelles’ lab has shown that the lung environment, specifically the alveolar lining fluid, shapes the cell surface of M. tb and this affects how well the immune system controls infection. The team will use a variety of innovative models – including the alveolar macrophage-like (AML) cell model developed in Texas Biomed Professor Larry Schlesinger’s lab, miniature lung-on-a-chip organoids developed by collaborator Dr. Vivek Thacker at the University Hospital Heidelberg, and nonhuman primates in collaboration with Texas Biomed Professor Deepak Kaushal – to systematically determine how the alveolar lining fluid of people living with HIV alter interactions between lung immune cells and M. tb, determining the early stages of infection. The goal is to identify potential therapies, such as restoring properly functioning proteins found in the lung, to help people living with HIV better control TB.
Professor Deepak Kaushal, Ph.D., Professor Shabaana Khader from the University of Chicago, and collaborators are developing and testing a live-attenuated TB vaccine, which in previous studies has shown to be effective at preventing granulomas, a distinct cellular structure that is unique to TB, from forming in the lungs and resulting in disease. The next phase of testing will explore precisely how the vaccine prevents granulomas from forming and protects against the bacteria. The team will use advanced single cell RNA sequencing and spatial biology techniques to clarify the immune cell interactions at very high resolution. Specifically, they will explore the role of a group of immune molecules, collectively called type 1 interferon, and clarify if these molecules help or hinder the immune response to TB infection or the TB candidate vaccine. Along with clarifying how the vaccine is so successful, they anticipate the research will also reveal secrets of the innate immune system that can inform the development of other TB treatments.
Dr. Kaushal and Professor Marcus Horwitz at University of California, Los Angeles received a separate R01 earlier this year to test an ultra-short treatment regimen to prevent reactivation of latent TB following SIV co-infection, the nonhuman primate equivalent of HIV. The standard TB treatment requires large amount of antibiotics taken for nine months. The team has been exploring different anti-TB drug combinations – with the help of artificial intelligence – that can be administered for one to four weeks and prevent reactivation of latent TB following HIV co-infection. The nonhuman primate studies will provide critical preclinical data that can inform human clinical trials and if successful, lead to a major shift in how latent TB is treated.
Assistant Professor Diako Ebrahimi, Ph.D., and his team are conducting a comprehensive analysis of genetic variations in both humans and HIV to uncover the molecular mechanisms driving disparities in HIV disease outcomes. His team has analyzed data from over 2,500 diverse human donors to identify genomic and transcriptomic variations in a family of human DNA-editing enzymes, known as APOBEC3, which contribute to a significant number of mutations in HIV DNA. Simultaneously, they have employed advanced analytical techniques to map the mutational profiles of over 37,000 HIV genomes from people living with HIV. They will systematically test key mutation combinations in the lab to identify how specific interactions enable some individuals to control HIV without the need for medications, while others develop drug resistance. This research aims to provide key molecular insights to help develop targeted therapies tailored to the genetic makeup of both the donor and the virus to which they are exposed.
Associate Professor Shouxiong Huang, Ph.D., will seek to identify small molecules called metabolites that could be leveraged to fight infection and cancer. Specifically, he and his team are searching for bacterial and human metabolites that can activate an unusual group of T cells to help fight tuberculosis and cancer. Typical T cells take weeks to activate as part of the body’s adaptive immune system, but these unusual T cells, called mucosal-associated invariant T (MAIT) cells, rapidly respond to infection. The key is to find which metabolites can trigger a MAIT response against TB infection and cancer cells. Dr. Huang will use advanced liquid chromatography mass spectrometry techniques to isolate metabolites and then test them in a high throughput manner to trigger effective MAIT cell responses. The work on cancer is also supported by a pilot grant from the Cancer Prevention and Research Institute of Texas.
Some of the above studies will involve the Southwest National Primate Research Center, which is supported by the Office of the Director, National Institutes of Health under award number P51OD011133.