Intracellular pathogens convert macrophages from death traps into hospitable homes

Abstract

Infectious microorganisms must find ways to escape or counteract the immune defenses of the host during the course of infection. The innate and adaptive immune functions of a healthy host represent serious threats for the invader and most microorganisms cannot survive in this hostile environment. One strategy to escape that is shared by many pathogenic bacteria, parasites and fungi is to hide in cells and turn them into welcoming refuges where they can multiply. In this context, the macrophage is a key cell to infect.Macrophages are at the crossroads of immune defenses, as they participate at the onset of the innate and adaptive immune responses. Innate immunity is a fast response triggered by the early detection of pathogen molecules, which involves the phagocytosis of the microorganisms for their destruction in the phagosome, and the secretion of cell factors that attack microorganisms outside and inside the macrophage and factors to attract other immune cells to the site of infection. Among these defense factors are toxic effector molecules (such as reactive oxygen species and nitric oxides, proteases, nucleases, lipases and others) and pro-inflammation chemokines and cytokines to attract or activate monocytes, neutrophils, lymphocytes and other immune cells. Together with other monocyte cells such as the dendritic cells, the macrophage presents protein peptides from the pathogen to helper T lymphocytes to stimulate the ones capable of responding to the infection by activating the B lymphocytes displaying the proper anti-pathogen antibodies. The macrophage can also cooperate with cytotoxic T lymphocytes for the destruction of cells infected with pathogens.This Minireview series on Intracellular Pathogens describes the intra-macrophagic escape and survival mechanisms developed by very different intracellular pathogens: the bacteria of the Chlamydiales order [1], the parasite Leishmania [2] and the fungus Histoplasma capsulatum [3]. All three pathogens are internalized into macrophages by receptor-mediated endocytosis, involving specific receptors for each microorganism [4][5][6]. They differentiate into a novel stage with very different biological properties. Chlamydiales change from infectious non-replicating elementary bodies to nonJulien Barbier is principal investigator at CEA, a biochemist and cell biologist. He studied animal and bacterial toxins for 15 years. He performed the high-throughput screen that led to the identification of inhibitors of intracellular retrograde transport. He is currently studying the mechanisms of transport inhibition, identifying inhibitors' cellular targets and screening for improved inhibitors.Jean-Christophe Cintrat is a senior scientist in bioorganic chemistry at CEA. He is an expert in drug discovery, molecule screening, medicinal chemistry and molecule labeling. He is currently working on the development of inhibitors of intracellular trafficking as broad-spectrum drugs against intracellular pathogens, and screening for novel anti-pathogen molecules.Daniel Gillet is a Re...

ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments

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