Abstract
The pathogenesis of tuberculosis is complex and its manifestations diverse, reflecting a lifetime of dynamic interactions between mycobacterial virulence factors and the human immune system. The pathogenic mycobacteria have developed strategies to circumvent the major killing mechanisms employed by macrophages and take advantage of the enclosed environment within its host cell to avoid humoral and cell-mediated immune responses. Secretory proteins play a major role in host-pathogen interactions. The eis (Rv2416c) gene has been identified as a secretory protein, and it has been shown that it enhances intracellular survival of Mycobacterium semgmatis in the macrophage cell line. The main aim of this study was to gain insight into the biological role of Eis in the host. Stimulation of T-cells with Eis recombinant protein of Mycobacterium tuberculosis inhibits Con A-mediated T-cell proliferation in vitro. Treatment of T-cells with Eis inhibits ERK1/2, JAK pathway, and subsequent production of tumor necrosis factor-alpha and interleukin-4. On the contrary, there is increased production of interferon-gamma and interleukin-10, which indicates that immunity in response to Eis treatment is skewed away from a protective T(H)1 response and Eis disturbs the cross regulation of T-cells.
Highlights
Virulence of mycobacteria is a multifaceted phenomenon based on the expression of multiple genes involved in various stages of host-pathogen interactions including adhesion, invasion, intracellular replication, and dissemination to other sites
We found that the purified Eis recombinant protein inhibits the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and subsequent production of TNF-␣ and IL-4
Given that MAPKs are critical factors mediating cellular responses to external stimuli and because of the importance of these pathways in inflammatory and other immune responses, we examined the role of Eis protein of M. tuberculosis in the induction of MAPK signaling pathways
Summary
Virulence of mycobacteria is a multifaceted phenomenon based on the expression of multiple genes involved in various stages of host-pathogen interactions including adhesion, invasion, intracellular replication, and dissemination to other sites. Both virulent and avirulent mycobacteria are internalized by monocytes and macrophages [1, 2], only pathogenic mycobacteria survive and replicate intracellularly [3]. Proteins that are actively secreted have regained center stage in host-pathogen interactions as they are involved in mounting of specific protective immune responses [7,8,9,10]. The production of IFN-␥ and IL-10 by Eis stimulated T-cells was found to be enhanced
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