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 Ca2+ uptake from the extracellular medium and intracellular Ca2+ 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 Ca2+-dependent phagosome acidification and IL-1β processing in order to efficiently transverse the epithelium and enter its niche—the

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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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    ABSTRACT: Johne's disease (JD) is a chronic enteric infection of cattle caused by Mycobacterium avium subsp. paratuberculosis (MAP). The high economic cost and potential zoonotic threat of JD have driven efforts to develop tools and approaches to effectively manage this disease within livestock herds. Efforts to control JD through traditional animal management practices are complicated by MAP's ability to cause long-term environmental contamination as well as difficulties associated with diagnosis of JD in the pre-clinical stages. As such, there is particular emphasis on the development of an effective vaccine. This is a daunting challenge, in large part due to MAP's ability to subvert protective host immune responses. Accordingly, there is a priority to understand the MAP's interaction with the bovine host: this may inform rationale targets and approaches for therapeutic intervention. Here we review the early host defenses encountered by MAP and the strategies employed by the pathogen to avert or subvert these responses, during the critical period between ingestion and the establishment of persistent infection in macrophages.
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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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    ABSTRACT: The initial interaction between host cell and pathogen sets the stage for the ensuing infection and ultimately determine the course of disease. However, there is limited knowledge of the transcripts utilized by host and pathogen and how they may impact one another during this critical step. The purpose of this study was to create a host-Mycobacterium avium subsp. paratuberculosis (MAP) interactome for early infection in an epithelium-macrophage co-culture system using RNA-seq. Establishment of the host-MAP interactome revealed a novel iron assimilation system for carboxymycobactin. Iron assimilation is linked to nitric oxide synthase-2 production by the host and subsequent nitric oxide buildup. Iron limitation as well as nitric oxide is a prompt for MAP to enter into an iron sequestration program. This new iron sequestration program provides an explanation for mycobactin independence in some MAP strains grown in vitro as well as during infection within the host cell. Utilization of such a pathway is likely to aid MAP establishment and long-term survival within the host. The host-MAP interactome identified a number of metabolic, DNA repair and virulence genes worthy for consideration as novel drug targets as well as future pathogenesis studies. Reported interactome data may also be utilized to conduct focused, hypothesis-driven research. Co-culture of uninfected bovine epithelial cells (MAC-T) and primary bovine macrophages creates a tolerant genotype as demonstrated by downregulation of inflammatory pathways. This co-culture system may serve as a model to investigate other bovine enteric pathogens.
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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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    ABSTRACT: Mycobacterium avium subsp. paratuberculosis causes chronic inflammation of the intestine known as Johne’s disease (JD) in domestic and wild ruminants including primates. MAP has also been associated with inflammatory bowel disease (IBD) so called Crohn’s disease (CD) of human beings, which is incurable even after surgery. By virtue of the pasteurization resistant power, high endemicity of the infection in ani- mals continues to be the permanent source of infection to human population. High bio-burden of MAP in wide range of biotic (animal hosts in- cluding human beings) and abiotic environment in each and every country where it has been investigated, serves a reminder about the sur- vival abilities of the MAP in diverse range of en- vironmental conditions. Ability of the MAP to evade immune system of the host and the tem- poral events during infection of the macro- phages, is an area of major concern and re- search activities as the pattern of distribution are quiet different from those of other patho- genic intracellular organisms. Moreover, the or- ganism can survive over a wide range of envi- ronmental conditions such as high and low en- vironmental temperatures, pasteurization, low pH, and high salt concentration etc. This superior survival efficiency from environmental degrada- tion and dormancy within host allows the path- ogen to be available for causing disease and pathogenicity in animals and human beings, when conditions are favorable. Perusal of lit- erature reveal that, despite the availability of whole genome sequence of MAP, a very little is known about the replication, persistence and survival mechanisms of this pathogen. There- fore, this review tries to address the survival mechanisms of Mycobacterium avium subspe-cies paratuberculosis in the different host spe- cies and adverse environmental conditions in order to allow designing of more rational diag- nostic and control procedures.
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