ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans

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.

Cell death and autophagy in tuberculosis

“…CXC3CL1, lysophosphatidylcholine, sphingosine-1-phosphate, ATP, and UTP) that attract phagocytic cells for the clearance of apoptotic bodies [85]. Which of these or other possible signals operate in TB is presently conjectural but available data hint at a role for CX3CL1 and its receptor CX3CR1 [86]. While ATP/P2X7R interactions are implicated in TB defense [87], P2Y2 is the sensor for the small amounts of nucleotides released from apoptotic cells and so far this receptor has not been linked to TB.…”

Identification of candidate host serum and saliva biomarkers for a better diagnosis of active and latent tuberculosis infection

“…Both Fractalkine and VEGF are expressed by endothelial cells to mediate lymphocyte chemoattraction and adhesion in mucosal tissues [ 43 ] and promote formation of new blood vessels [ 44 ], respectively. Although the role of these proteins during TB infection has not been established, previous studies in animal models suggested that Fractalkine could mediate cellular infection and spread of Mtb bacilli [ 45 ] and VEGF has been suggested as a mechanism for Mtb spreading [ 46 ]. All this suggests that endothelial cells have an influence on the markers detected in saliva, and could be indirectly related with Mtb spreading in active TB patients.…”

Infect and Inject: How Mycobacterium tuberculosis Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1

“…First discovered by Bazan et al in 1998 (67), fractalkine is a rather unusual chemokine and in a class of its own, having a strange stalk-like structure that can also tether host cells. It has been reported to attract naive macrophages to the lung, and fractalkine production from M. tuberculosis -infected cells has been determined to be ESX-1 regulated (68). This study also linked fractalkine levels to the influx of naive macrophages during TB infection using bronchoalveolar lavage samples taken directly from the lungs of TB patients.…”

“…This study also linked fractalkine levels to the influx of naive macrophages during TB infection using bronchoalveolar lavage samples taken directly from the lungs of TB patients. Other cytokines are likely involved in this influx, such as ESX-1-regulated IL-1R (66, 68, 69).…”

“…If M. tuberculosis ESX-1 mediates fractalkine production from the infected macrophage, what is the effector protein responsible for triggering its production? This appears to be ESAT-6, which activates the tyrosine kinase Syk (53); Syk functions in an upstream activation pathway to produce fractalkine, and its inhibition can stop M. tuberculosis ESX-1-mediated fractalkine production and the resulting monocytic infiltration (68). The fractalkine axis has been proposed as a treatment target via the inhibition of monocyte infiltration and thus in-flammation in diseases such as Crohn’s (70), and a vaccination approach has successfully been used to protect against respiratory syncytial virus infection in an animal model (71).…”