Life and Death in a Macrophage: Role of the Glyoxylate Cycle in Virulence

Phagocytic cells of the innate immune system, such as mac- rophages and neutrophils, are a primary line of defense against microbial infections. Patients with defects in innate immunity, such as those with chronic granulomatous disease or neutro- penia, are extremely sensitive to a variety of infections. When a phagocyte recognizes the presence of an invading cell, it engulfs the microbe with its membrane to form the phago- some, an intracellular compartment containing the microbe. This compartment matures by fusion with lysosomes to create the phagolysosome, an organelle replete with antimicrobial compounds and an acidic pH. Internalization creates a hostile environment for the microorganism, which, of course, is the intent. The phagolysosome is a precarious neighborhood even be- fore the onslaught of antimicrobial compounds. Engulfment by the macrophage thrusts the microorganism into an alien mi- lieu, one devoid of key nutrients necessary for metabolism and division. Surviving the antimicrobial assault in the phagolyso- some depends on the microbe's ability to synthesize the pro- teins and other cellular components necessary to counteract these stresses. Thus, a pathogen must find the requisite nutri- ents to provide the building blocks for these complex macro- molecules and the energy with which to synthesize them. In this article we consider the initial responses of several microbes to nutrient deprivation inside the macrophage. The first of these, Mycobacterium tuberculosis, the bacterium that causes tuberculosis, resides for prolonged periods within the macrophage, in which it can proliferate and subsequently spread throughout the body. The second, the yeast Saccharo- myces cerevisiae, is killed efficiently by the macrophage. The third, the opportunistic fungal pathogen Candida albicans, sur- vives ingestion by changing rapidly from a yeast to a filamen- tous morphology, lysing the macrophage from the inside out. Once free, C. albicans cells are able to disseminate through the body. The interaction of C. albicans with the macrophage is transient, as opposed to the long-term persistence of M. tuber- culosis. Although the outcomes of this macrophage capture are quite different among the three microbes, the initial responses of all three to the internal environment are remarkably similar: induction of the glyoxylate cycle, a pathway that permits the utilization of compounds with two carbons (C2 compounds), such as acetate, to satisfy cellular carbon requirements.