Infectious diseases have re-emerged as a major health problem in North America, in part due to the widespread emergence of antibiotics resistance. The mechanisms of defense against intracellular parasites, and the bacterial strategies underlying survival and replication in host phagocytes remain poorly understood. A better understanding of host defenses against such infections may suggest new strategies for intervention in these diseases. Using a genetic approach, we have identified a new component (Nramp1) of antimicrobial defenses of phagocytes. Mutations at Nramp1 in mice cause susceptibility to several intracellular infections, and polymorphic variants at human NRAMP1 are also associated with susceptibility to Mycobacterial infections in areas of endemic disease. Nramp1 is expressed at the membrane of bacterial phagosomes formed in macrophages and neutrophils, where it functions as an efflux pump to remove from the phagosomal space divalent metals essential for microbial replication. The current proposal describes a series of experiments aimed at better understanding the mechanism of Nramp1 transport, including the identification of the preferred substrate at the phagosomal membrane. We also wish to identify the metal dependent biochemical pathways and proteins in Mycobacterium species that are essential for survival in macrophages and that are inhibited by Nramp1 action. Finally, we have recently mapped 2 new loci (Trl-3, Trl-4) that control, in an Nramp1-independent fashion, the pulmonary replication of Mycobacterium tuberculosis in mice. We propose to characterize in congenic mouse lines the physiological responses, cell populations, and biochemical pathways of the host that are regulated by Trl-3 and Trl-4. The positional cloning of the underlying genes is also proposed. These combined studies may suggest new avenues and provide novel targets for intervention in infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035237-12
Application #
7188631
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Sizemore, Christine F
Project Start
1993-09-30
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
12
Fiscal Year
2007
Total Cost
$179,207
Indirect Cost
Name
Mcgill University
Department
Type
DUNS #
205667090
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 0-G4
Kong, Xiao-Fei; Martinez-Barricarte, Ruben; Kennedy, James et al. (2018) Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol 19:973-985
Fodil, Nassima; Langlais, David; Gros, Philippe (2016) Primary Immunodeficiencies and Inflammatory Disease: A Growing Genetic Intersection. Trends Immunol 37:126-140
Langlais, David; Barreiro, Luis B; Gros, Philippe (2016) The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J Exp Med 213:585-603
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Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice et al. (2015) Human intracellular ISG15 prevents interferon-?/? over-amplification and auto-inflammation. Nature 517:89-93
Kennedy, James M; Fodil, Nassima; Torre, Sabrina et al. (2014) CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation. J Exp Med 211:2519-35
Salem, Sandra; Langlais, David; Lefebvre, François et al. (2014) Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation. Blood 124:1894-904
Salem, Sandra; Gao, Chan; Li, Ailian et al. (2014) A novel role for interferon regulatory factor 1 (IRF1) in regulation of bone metabolism. J Cell Mol Med 18:1588-98
Fodil, Nassima; Langlais, David; Moussa, Peter et al. (2014) Specific dysregulation of IFN? production by natural killer cells confers susceptibility to viral infection. PLoS Pathog 10:e1004511
Dauphinee, S M; Richer, E; Eva, M M et al. (2014) Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections. Genes Immun 15:282-92

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