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

Abstract

Classification of pathogenic species according to the distinct host transcriptional responses that they elicit may become a relevant tool for microarray-based diagnosis of infection. Individual strains of Mycobacterium avium, an opportunistic pathogen in humans, have previously been shown to differ in terms of growth and persistence. In order to cover a wide spectrum of virulence, we selected four M. avium isolates (2151SmO, 2151SmT, SE01, TMC724) that have distinct intramacrophage replication characteristics and cause differential activation in human macrophages. Following infection with each of these strains, the expression of 12,558 genes in human macrophages was systematically analyzed by microarray technology. Fifty genes (including genes encoding proinflammatory cytokines, chemokines, signaling, and adhesion molecules) were differentially expressed more than twofold in response to all of the M. avium isolates investigated and therefore constitute a common macrophage signature in response to M. avium. The magnitude of regulation of most of these genes was directly correlated with the host cell-activating capacity of the particular M. avium strain. The regulation of a number of genes not previously associated with mycobacterial infections was apparent; these genes included genes encoding lymphocyte antigen 64 and myosin X. In addition, individual response patterns typical for some M. avium isolates could be defined by the pronounced upregulation of interleukin-12p40 (IL-12p40) (in the case of 2151SmO) or the specific upregulation of SOCS-1 and IL-10 (in the case of SE01) in macrophages. TMC724, a strain of avian origin, could not be classified by any one of these schemes, possibly indicating the limits of pathogen categorization solely by immune response signatures.The outcome of infection is the net consequence of the immune defenses of the host and a pathogen's capacity to subvert them. Macrophages play a central role in regulating innate and acquired immune responses against pathogens, but several mycobacterial species have developed strategies to persist in these cells even in the face of fully developed T-cell immunity (reviewed in references 40 and 51). Mycobacterium avium is an environmental microorganism and an opportunistic pathogen in humans (33). M. avium causes lymphadenopathies in children, pneumonia in the context of predisposing lung conditions, and disseminated infections in advanced-stage AIDS patients (31, 34). M. avium has proven to be useful in mouse models of infection to define key requirements in mycobacterial infections (3,6,8,15,21,29).Of particular interest when host-pathogen relationships at the species level are compared, M. avium strains having different origins or morphotypes have been shown to differ widely in terms of replication and persistence, both in vitro and in vivo in a mouse model of infection (5,9,15,29,43,48,52), although the molecular basis for this variability in virulence remains undetermined. Previous studies demonstrated an inverse correlation between the virule...

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.…”

Gene expression patterns in blood leukocytes discriminate patients with acute infections

“…30 Broad similarities exist, with, for instance, dynamic cascades of cytokines and chemokines involved in the activation and recruitment of immune cells observed in the context of fungal, bacterial, or viral infections. [31][32][33][34][35] However, 2 factors contribute to the specificity of transcriptional responses to infections: (1) the diversity of the molecular mechanisms involved in pathogen recognition, and (2) alterations of host responses by pathogens. On activation, Toll-like receptor (TLR) family members trigger signaling pathways that share common components while retaining unique characteristics accounting for the specificity of transcriptional responses.…”

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“…Primary image analysis of arrays and data analysis were performed using GeneChip Microarray Analysis Suite Version 5.0, MicroDB and Data Mining Tool (Affymetrix, Santa Clara, CA) as described previously. 22 …”