title: P47phox-/- mice are compromised in expansion and activation of CD8+ T cells and susceptible to Trypanosoma cruzi infection.
abstract: Macrophage activation of NAD(P)H oxidase (NOX2) and reactive oxygen species (ROS) is suggested to kill Trypanosoma cruzi that causes Chagas disease. However, the role of NOX2 in generation of protective immunity and whether these mechanisms are deregulated in the event of NOX2 deficiency are not known, and examined in this study. Our data showed that C57BL/6 p47(phox-/-) mice (lack NOX2 activity), as compared to wild-type (WT) mice, succumbed within 30 days post-infection (pi) to low doses of T. cruzi and exhibited inability to control tissue parasites. P47(phox-/-) bone-marrow and splenic monocytes were not compromised in maturation, phagocytosis and parasite uptake capacity. The deficiency of NOX2 mediated ROS was compensated by higher level of inducible nitric oxide synthase (iNOS) expression, and nitric oxide and inflammatory cytokine (TNF-α, IFN-γ, IL-1β) release by p47(phox-/-) macrophages as compared to that noted in WT controls infected by T. cruzi. Splenic activation of Th1 CD4(+)T cells and tissue infiltration of immune cells in T. cruzi infected p47(phox-/-) mice were comparable to that noted in infected control mice. However, generation and activation of type 1 CD8(+)T cells was severely compromised in p47(phox-/-) mice. In comparison, WT mice exhibited a robust T. cruzi-specific CD8(+)T cell response with type 1 (IFN-γ(+)TNF-α>IL-4+IL-10), cytolytic effector (CD8(+)CD107a(+)IFN-γ(+)) phenotype. We conclude that NOX2/ROS activity in macrophages signals the development of antigen-specific CD8(+)T cell response. In the event of NOX2 deficiency, a compromised CD8(+)T cell response is generated, leading to increased parasite burden, tissue pathogenesis and mortality in chagasic mice.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Monisha
authors.initials: M
authors.lastname: Dhiman
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Department of Pathology, UTMB, Galveston, Texas, United States of America; Institute for Human Infections and Immunity, UTMB, Galveston, Texas, United States of America.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1