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Innate immunity including Efferocytosis

Efferocytosis, the process of clearing dead cells by phagocytes, is crucial to maintenance of homeostasis. Defective efferocytosis is often the underlying cause of several chronic inflammatory diseases. Despite profound advances in research on mechanisms of apoptotic cell recognition and uptake, several key areas regarding the role of efferocytosis in host defense is poorly understood. It has been seen in some infectious diseases, such as tuberculosis (TB), that the infected cells can undergo alternative fates of apoptosis or necrosis, that can lead to beneficial or detrimental outcomes for the host. My research encompasses studying the role of efferocytosis in the outcome of disease using TB as a disease model. Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death caused by a single infectious agent. Despite TB being a preventable and curable disease, approximately 1.5 million deaths are caused by TB annually. Alveolar macrophages (AM) are considered the first line of defense against Mtb as they are the first cells that the invading-Mtb encounters. However, Mtb has been hypothesized to exploit AM as a protective niche for survival and replication. To control the bacteria, the host induces apoptosis of infected cells but virulent Mtb strains suppress host-induced apoptosis of infected cells which instead undergo necrosis resulting in pathogenesis. It has been shown in vitro that of infected macrophages, and not apoptosis per se, leads to better Mtb control. However, neither the exact mechanistic role of AM in the pathogenesis of Mtb infection, nor the role of efferocytosis in Mtb control in vivo, has been demonstrated. “Eat-me signals” (e.g., exposed phosphatidylserine on cell surface), receptors (e.g., MerTK) that recognize “eat-me” molecules, and “don’t-eat-me” signals (e.g. CD47) determine efferocytosis efficiency. Studies show that CD47 is upregulated in cancer and atherosclerosis through unknown mechanism. Role of CD47 in efferocytosis by AM in Mtb pathogenesis is a relatively unventured field but shows considerable promise.

This project aims to look at the effects of efferocytosis on the outcome of Mtb infection in vivo. There is some preliminary data by Yu-Jung Lu (graduate student) with MerTK KO mice showing that the mice deficient in MerTK (receptor bringing about efferocytosis) show increased bacterial burden and higher number and frequencies of CD4 and CD8 T cells compared to their wildtype counterparts. Tasfia Rakib (graduate student) is now trying to look at efferocytosis and further investigate the mechanism by which CD47 is upregulated in virulence strains of Mtb, causing detrimental effects on the host.