Immunogenetic determinants of response to drug-susceptible tuberculosis treatment

About This Grant

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of death worldwide from a single infectious agent, Mycobacterium tuberculosis (Mtb). Despite the development of effective multidrug regimens, many persons with pulmonary drug-susceptible (DS)-TB disease do not achieve durable cure at the end of treatment. The aim of this proposal is to define host immunological and transcriptional factors associated with treatment outcomes. We will use the time to stable culture conversion (TTSCC) as an endpoint to define these factors. TTSCC is the duration of treatment it takes a person with DS-TB to achieve two consecutive negative Mtb cultures from sputum samples. We will leverage existing samples and datasets from two seminal trials: the Predict TB (NCT02821832) Phase 2B and Study 31/A5349 (NCT02410772) Phase 3 trials, as well as samples from a prospectively recruited cohort of participants with DS-TB from the A5409/RAD-TB (NCT06192160) Phase 2 trial. These trials offer a unique opportunity to identify pathways linked to TTSCC across all treatment regimens or specific to certain regimens. In the first aim, we will use transcriptional profiling of whole blood to define pathways, and the genetic regulatory networks that govern them, that are associated with shorter TTSCC. We will validate the top candidate hits associated with TTSCC by assessing Mtb sterilization in CRISPR/Cas9- edited primary human macrophages compared to their isogenic counterparts in the presence of antibiotics. In the second aim, we will define the abundance and functional profiles of immune subsets in the blood that predict TTSCC in the A5409/RAD-TB clinical trial. We will also use a novel measure of Mtb sterilization, which is the modeled change in the time to positivity of serial sputum cultures over the first two months of treatment. This measure is a novel early efficacy endpoint being used in A5409/RAD-TB and several other clinical trials registered with the U.S. Food and Drug Administration. The data from these analyses will help identify (i) novel treatment strategies, potentially adding adjunct host-directed therapies to reduce time to Mtb sterilization and improve treatment outcomes, and (ii) inform the development of biomarkers to triage persons with DS-TB to different treatment regimens and duration. These findings will have a significant impact on changing the ‘one size fits all’ treatment paradigm for DS-TB, which renders many persons with TB at a high risk of unfavorable treatment outcomes or risk of overtreatment and toxicity. The Division of HIV, Infectious Diseases, and Global Medicine and the Division of Experimental Medicine at the University of California, San Francisco are an ideal setting to conduct the proposed activities due to their depth of content expertise and collaborations in the control of TB.