DESCRIPTION (Applicant's Abstract): Innate antimicrobial mechanisms of resident alveolar macrophages (AM) and control bacterial replication early in pulmonary tuberculosis, prior to the expression of adaptive immunity. The goal of this project is to study how AM suppress growth of Mycobacterium tuberculosis (Mtb). Our preliminary data indicate that growth of intracellular mycobacteria is efficiently restricted when AM undergo apoptosis, whereas necrosis promotes unrestricted extracellular bacterial replication. Apoptosis induced by several different pathways has been linked to this antimicrobial effect by other investigators as well, but a mechanism of this effect has not been proposed. We previously discovered that infection with Mtb directly activates TNFa death signaling in AM which we postulate limits bacterial growth by i) sequestering bacilli in apoptotic bodies and ii) marking infected cells for engulfment by phagocytes that recognize apoptotic epitopes. Phagocytosis of free Mtb is associated with arrested phagosome maturation and unrestricted intracellular growth of bacilli. We hypothesize that mycobacteria packaged by apoptosis are attacked by intracellular antimicrobial effector systems more effectively than occurs when free bacilli are internalized. It has recently been discovered that human dendritic cells efficiently present antigen derived from apoptotic cells by a process called "antigen cross-priming." Experiments in this project examine cooperative antimicrobial when naive AM are presented with Mtb by apoptotic AM, a process that we call "pathogen cross-priming." This system mimics events that occur in the lung in vivo where initial infection of AM by Mtb promotes recruitment of naive AM and other mononuclear phagocytes to the site of infection. The cellular requirements, apoptosis-specific epitopes, and intracellular effector mechanisms triggered by these interactions will be investigated. Together, these studies will characterize a novel host defense mechanism in tuberculosis that may represent a fundamental process relevant to a variety of intracellular lung pathogens.