ABSTRACT
M. tuberculosis accesses the terminal lung and is phagocytosed by alveolar macrophages. Utilizing a mouse intratracheal challenge model, we demonstrate that M. tuberculosis rapidly enters through M cells as well. From there, bacilli are deposited within associated intraepithelial leukocytes and subsequently conveyed to the draining lymph nodes early after infection. Osteopetrotic (Csfm(op)/Csfm(op)) mice, null mutants for macrophage colony-stimulating factor, possess diminished numbers of circulating monocytes and tissue macrophages. Csfm(op)/Csfm(op) mice were highly susceptible to challenge with M. tuberculosis. In contrast to controls, tubercle bacilli were not conveyed to draining lymph nodes early after infection but were instead retained within the mucosa. These results indicate that M cells represent an alternate portal of entry for M. tuberculosis, which may contribute to the rapid development of protective lung immune responses.
Subject(s)
Mycobacterium tuberculosis/pathogenicity , Tuberculosis/pathology , Animals , Bronchi/microbiology , Epithelial Cells/microbiology , Epithelial Cells/ultrastructure , Female , Genetic Predisposition to Disease/microbiology , Lung/microbiology , Lymph Nodes/microbiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mucous Membrane/microbiology , Mycobacterium tuberculosis/ultrastructure , Osteopetrosis/genetics , Osteopetrosis/microbiology , Time Factors , Tuberculosis/microbiology , Tuberculosis/mortalityABSTRACT
IL-12 is both required and prognostic for Th1 development in mice with Candida albicans infection. To delineate further the physiologic role of IL-12 in antifungal immunity, mice deficient for this cytokine were assessed for susceptibility to C. albicans infections, and for parameters of innate and adaptive immunity. IL-12-deficient mice were highly susceptible to gastrointestinal infection or to reinfection and showed elevated production of Candida-specific IgE and IL-4 and defective production of IFN-gamma. The failure to mount protective Th1 responses occurred despite the presence of an unimpaired innate antifungal immune response, which correlated with unaltered IFN-gamma production, but defective production of, and responsiveness to, inhibitory IL-10. IL-10 or IL-12 neutralization increased the innate antifungal resistance in wild-type mice. However, in IL-12-deficient mice, treatment with exogenous IL-12 or IL-10 impaired IL-4 production and increased resistance to infection, through a negative effect on the CTLA-4/B7-2 costimulatory pathway. These results confirm the obligatory role of IL-12 in the induction of anticandidal Th1 responses, and indicate the existence of a positive regulatory loop between IL-12 and IL-10 that may adversely affect the innate antifungal response, but is required for optimal costimulation of IL-12-dependent CD4+ Th1 cells.
Subject(s)
Candidiasis/immunology , Immunoconjugates , Interleukin-10/physiology , Interleukin-12/deficiency , Interleukin-12/genetics , Th1 Cells/metabolism , Abatacept , Animals , Antigens, CD/biosynthesis , Antigens, CD/physiology , Antigens, Differentiation/physiology , B7-2 Antigen , CTLA-4 Antigen , Candidiasis/genetics , Candidiasis/microbiology , Candidiasis/prevention & control , Female , Genetic Predisposition to Disease/immunology , Genetic Predisposition to Disease/microbiology , Immunity, Innate , Interleukin-10/biosynthesis , Interleukin-10/pharmacology , Interleukin-4/biosynthesis , Male , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/physiology , Mice , Mice, Inbred BALB C , Mice, Knockout , Phagocytes/immunology , Phagocytes/microbiology , Th1 Cells/immunology , Up-Regulation/drug effects , Up-Regulation/immunologyABSTRACT
The possible association between susceptibility to infection with Cryptococcus neoformans var. gattii and HLA phenotype was examined in a group of Papua New Guinean patients. There was no evidence for a statistically significant association between susceptibility to infection and HLA class I and HLA class II phenotypes, although analysis of data which had not been subjected to the appropriate Bonferroni correction factor suggested a trend for susceptibility linked to HLA B*5601.
