Mycobacterium aviumInfection and Modulation of Human Macrophage Gene Expression

Abstract

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-α 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.

A role for c-Myc in regulating anti-mycobacterial responses

“…These results further verified previous uncharacterized microarray data obtained from cells infected with M. avium (18,19). Indeed, the levels and kinetics of Myc expression vary among different experiments.…”

Common and Unique Gene Expression Signatures of Human Macrophages in Response to Four Strains ofMycobacterium aviumThat Differ in Their Growth and Persistence Characteristics

“…While this type of classification of M. avium strains proved to be robust, in that three different methods of evaluation (MAP kinase phosphorylation, TNF-␣ secretion, and size of infection-induced transcriptome) showed consistent results with four different isolates, we found no straightforward association of a specific macrophage response signature with the pathogenicities of the infecting strains, as measured by their intracellular replication rates in vitro. Therefore, the virulence of the species M. avium is not mirrored by a stereotypic, speciesspecific macrophage response, as previously suggested (28). Nor is virulence of M. avium invariably a unique failure to activate macrophages, as hypothesized previously (24,49).…”

“…Total RNA was isolated 4 h postinfection. We and other workers have previously noted the donor-dependent variability of macrophage responses to M. avium (9,28). To minimize donor-dependent confounding effects, equal amounts of total RNA obtained from cells of five individual donors were pooled to perform biotin-labeled target synthesis for array hybridization.…”

Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms

“…Mycobacterium avium complex (MAC) is ubiquitous in the environment and, normally, nonpathogenic in healthy subjects [46,47].…”