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Mycobacterium avium Infection and Modulation of Human Macrophage Gene Expression

Teresa Greenwell-Wild^*, Nancy Vázquez^*, Davis Sim^*, Marco Schito, Delphi Chatterjee, Jan M. Orenstein and Sharon M. Wahl^1,*

^* Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Microbiology, Colorado State University, Fort Collins, CO 80523; and Department of Pathology, George Washington University, Washington, D.C. 20037

Mycobacterium avium is a facultative intracellular pathogen cleared rapidly via intact host defense mechanisms. In the absence of adequate T cell function, as occurs in HIV-1-induced immunodeficiency, M. avium becomes an opportunistic infection with uncontrolled replication and reinfection of macrophage hosts. How M. avium infects, survives, and replicates in macrophages without signaling an effective microbicidal counterattack is unresolved. To address whether M. avium signals the expression of molecules, which influence mycobacterial survival or clearance, human monocyte-derived macrophage cultures were exposed to M. avium. Within minutes, M. avium, or its cell wall lipoarabinomannan, binds to the adherent macrophages and induces a spectrum of gene expression. In this innate response, the most abundant genes detected within 2 h by cDNA expression array involved proinflammatory chemokines, cytokines including TNF- and IL-1, and adhesion molecules. Associated with this rapid initial up-regulation of recruitment and amplification molecules was enhanced expression of transcription factors and signaling molecules. By 24 h, this proinflammatory response subsided, and after 4 days, when some bacteria were being degraded, others escaped destruction to replicate within intracellular vacuoles. Under these conditions, inducible NO synthase was not up-regulated and increased transferrin receptors may facilitate iron-dependent mycobacterial growth. Sustained adhesion molecule and chemokine expression along with the formation of multinucleated giant cells appeared consistent with in vivo events. Thus, in the absence of T lymphocyte mediators, macrophages are insufficiently microbicidal and provide a nonhostile environment in which mycobacteria not only survive and replicate, but continue to promote recruitment of new macrophages to perpetuate the infection.

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