IAI Accepts, published online ahead of print on 19 October 2009

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Infect. Immun. doi:10.1128/IAI.00816-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mycobacterium leprae Actively Modulates the Cytokine Response in Naïve Human Monocytes.

Daniel Sinsimer, Dorothy Fallows, Blas Peixoto, James Krahenbuhl, Gilla Kaplan^*, and Claudia Manca

Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey 225 Warren St. Newark, NJ 07103 USA; Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, 225 Warren St. Newark, NJ 07103 USA; National Hansen's Disease Programs Laboratory Research Branch, Louisiana State University, Baton Rouge, LA 70803 USA

^* To whom correspondence should be addressed. Email: kaplangi{at}umdnj.edu.

Leprosy is a chronic, but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae. Host immunity to M. leprae determines the diversity of clinical manifestations seen in patients, from tuberculoid leprosy with robust production of TH1-type cytokines to lepromatous disease, characterized by elevated levels of Th2-type cytokines and a suboptimal proinflammatory response. Previous reports have indicated that M. leprae is a poor activator of macrophages and dendritic cells in vitro. To understand whether M. leprae fails to elicit an optimal Th1 immune response or actively interferes with its induction, we have examined the early interactions between M. leprae and monocytes from healthy human donors. We found that, in naïve monocytes, M. leprae induced high levels of the negative regulatory molecules MCP-1 and IL-1Ra, while suppressing IL-6 production, through phosphoinositide-3 kinase (PI3K)-dependent mechanisms. In addition, low levels of proinflammatory cytokines were observed in association with reduced activation of nuclear factor-B (NF-B) and delayed activation of IL-1 converting enzyme, ICE (caspase-1) in monocytes stimulated with M. leprae, as compared with M. bovis BCG stimulation. Interestingly, although in itself a weak stimulator of cytokines, M. leprae primed the cells for increased production of TNF- and IL-10 in response to a strongly inducing secondary stimulus. Taken together, our results suggest that M. leprae plays an active role to control the release of cytokines from monocytes by providing both positive and negative regulatory signals via multiple signaling pathways, involving PI3K, NF-B, and caspase-1.