Infection with Mycobacterium avium subsp. paratuberculosis Results in Rapid Interleukin-1 Release and Macrophage Transepithelial Migration

Department of Veterinary Population Medicine, University of Minnesota, St Paul, Minnesota, USA.
Infection and immunity (Impact Factor: 3.73). 07/2012; 80(9):3225-35. DOI: 10.1128/IAI.06322-11
Source: PubMed


Pathogen processing by the intestinal epithelium involves a dynamic innate immune response initiated by pathogen-epithelial cell cross talk. Interactions between epithelium and Mycobacterium avium subsp. paratuberculosis have not been intensively studied, and it is currently unknown how the bacterium-epithelial cell cross talk contributes to the course of infection. We hypothesized that M. avium subsp. paratuberculosis harnesses host responses to recruit macrophages to the site of infection to ensure its survival and dissemination. We investigated macrophage recruitment in response to M. avium subsp. paratuberculosis using a MAC-T bovine macrophage coculture system. We show that M. avium subsp. paratuberculosis infection led to phagosome acidification within bovine epithelial (MAC-T) cells as early as 10 min, which resulted in upregulation of interleukin-1β (IL-1β) at transcript and protein levels. Within 10 min of infection, macrophages were recruited to the apical side of MAC-T cells. Inhibition of phagosome acidification or IL-1β abrogated this response, while MCP-1/CCL-2 blocking had no effect. IL-1β processing was dependent upon Ca(2+) uptake from the extracellular medium and intracellular Ca(2+) oscillations, as determined by EGTA and BAPTA-AM [1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester)] treatments. Thus, M. avium subsp. paratuberculosis is an opportunist that takes advantage of extracellular Ca(2+)-dependent phagosome acidification and IL-1β processing in order to efficiently transverse the epithelium and enter its niche--the macrophage.

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Article: Infection with Mycobacterium avium subsp. paratuberculosis Results in Rapid Interleukin-1 Release and Macrophage Transepithelial Migration

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    • "Within the submucosa MAP is then ingested by macrophages. Following an experimental infection, MAP translocation from the intestinal lumen into submucosal macrophages occurs in a matter of minutes to hours [35] (Figure 1). "
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    • "Toll-like receptors 2 and 4), which creates an inflammation anergic state in intestinal macrophages and may impact which genes are needed by MAP to survive [29-32]. More recently, we have elucidated a mechanism for MAP orchestrated macrophage transepithelial migration that is reliant on phagosome maturation concomitant with IL-1β production at the epithelial interface during early infection [33]. Taken together these data suggest that MAP’s first interaction within the host at the intestinal epithelium interface is a dynamic process that can be harnessed by the pathogen to achieve survival and dissemination within the macrophage. "
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    • "resisting host defense and multiplies intra-cellularly to reach very high numbers. This is mainly due to the MAP capacity to inhibit activation of macrophages, inhibition of phagosome acidification and attenuate presentation of antigens to the immune cells [49]. MAP is able to modulate the ruminant innate immune response for their survival [50] "
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