Abstract
SummaryMycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells.
Highlights
Mycobacterium tuberculosis (Mtb) remains the leading cause of bacterial mortality world-wide [1]
Infection with Mtb H37Rv resulted in the induction of necrosis similar to the Triton-X 100-treated positive control but this was not reduced by the addition of antifractalkine (Figure 2d)
Our findings suggest that the Mtb-mediated influx of uninfected niche cells allows the bacteria to infect new host cells, disseminate and to set up a foothold of infection within the human lung
Summary
Mycobacterium tuberculosis (Mtb) remains the leading cause of bacterial mortality world-wide [1]. Rapid availability of niche host cells early on (i.e. during the first 24e48 h) is essential for early establishment of infection and subsequent bacillary dissemination. A chemotactic call from the infected “Trojan horse” aggregating more of these naive cells could increase niche availability, cellular infection and bacterial dissemination. It is increasingly recognised that chemotaxis-driven aggregation of macrophages is essential for establishment of the infectious niche and early bacillary spread in the Mycobacterium marinuminfected zebrafish [3]. This pioneering study reported how early granuloma formation (“macrophage infiltration and aggregation”) in the zebrafish resulted in increased bacterial growth and spread.
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