Expression of the ARPC4 subunit of human Arp2/3 severely affects mycobacterium tuberculosis growth and suppresses immunogenic response in murine macrophages.

BACKGROUND:The search for molecules against Mycobacterium tuberculosis is urgent. The mechanisms facilitating the intra-macrophage survival of Mycobacterium tuberculosis are as yet not entirely understood. However, there is evidence showing the involvement of host cell cytoskeleton in every step of establishment and persistence of mycobacterial infection. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that expression of a subunit of the Actin related protein 2/3 (Arp2/3) protein complex, severely affects the pathogen's growth. TEM studies display shedding of the mycobacterial outer-coat. Furthermore, in infected macrophages, mycobacteria expressing were cleared off at a much faster rate, and were unable to mount a pro-inflammatory cytokine response. The translocation of mycobacteria to the lysosome of the infected macrophage was also impaired. Additionally, the duanyu37C4 subunit was shown to interact with Rv1626, an essential secretory mycobacterial protein. analysis showed that upon expression of duanyu37C4 in mycobacteria, Rv1626 expression is downregulated as much as six-fold. Rv1626 was found to also interact with mammalian cytoskeleton protein, Arp2/3, and enhance the rate of actin polymerization. CONCLUSIONS/SIGNIFICANCE:With crystal structures for Rv1626 and duanyu37C4 subunit already known, our finding lays out the effect of a novel molecule on mycobacteria, and represents a viable starting point for developing potent peptidomimetics.

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