Identification of host TNF-α-dependent pathways involved in tuberculosis relapse
Infection with Mtb most frequently results in latent tuberculosis infection (LTBI) due to a healthy immune system that restricts bacterial replication and prevents disease. Macrophages are the predominant host reservoir of Mtb and as such, elucidating the mechanisms by which they are activated and modulated to impede Mtb growth and survival is vital in understanding the course of TB reactivation and relapse. It has been shown that interstitial macrophages (IMs) residing in the lung are important in restricting Mtb in an acute model of TB infection. TNF-ɑ is a pro-inflammatory cytokine that is a major activator of macrophage recruitment and is required for full microbicidal activity of mycobacteria-infected macrophages. It is known to be important in the protection against infection and reactivation of TB in humans, non-human primates and mice. However, its role in modulating the response of macrophages to Mtb during LTBI has yet to be elucidated. We have recently shown in a chronic mouse model of LTBI that IMs are essential in hindering the reactivation of latent Mtb to prevent disease. Knowing the importance of TNF-ɑ signaling in macrophage activation and TB disease, my goal is to use our paucibacillary mouse model of chronic LTBI to investigate its role on TB reactivation. I aim to first establish the role of TNF-ɑ on tuberculosis relapse (Aim 1). I will then perform single-cell RNA sequencing upon depletion of TNF-ɑ during latency to establish the immune cell landscape and immunometabolic reprogramming upon TNF-ɑ depletion (Aim 2), and to identify a TNF-ɑ-driven molecular signature that is associated with TB relapse (Aim 3). The proposed research program strives to understand these processes in an effort to reduce the reactivation of latent tuberculosis disease in patients undergoing anti-TNF-ɑ chemotherapy.