The Cnes2 locus on mouse chromosome 17 regulates host defense against cryptococcal infection through pleiotropic effects on host immunity

• Published in: Infection and immunity Vol. 83; no. 12; pp. 4541 - 4554
• Main Authors: Shourian, Mitra, Flaczyk, Adam, Angers, Isabelle, Mindt, Barbara C, Fritz, Jörg H, Qureshi, Salman T
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2015
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - microbiology; CD4-Positive T-Lymphocytes - pathology; Chromosomes, Mammalian - chemistry; Chromosomes, Mammalian - immunology; Crosses, Genetic; Cryptococcosis - genetics; Cryptococcosis - immunology; Cryptococcosis - microbiology; Cryptococcosis - pathology; Cryptococcus neoformans - immunology; Dendritic Cells - immunology; Dendritic Cells - microbiology; Dendritic Cells - pathology; Gene Expression; Genetic Loci - immunology; Genetic Predisposition to Disease; Host Response and Inflammation; Host-Pathogen Interactions; Immunity, Innate; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-4 - genetics; Interleukin-4 - immunology; Interleukin-5 - genetics; Interleukin-5 - immunology; Macrophages - immunology; Macrophages - microbiology; Macrophages - pathology; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neutrophils - immunology; Neutrophils - microbiology; Neutrophils - pathology; Phenotype; Spotlight; Th1-Th2 Balance
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00697-15

The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b(+) dendritic cells, and CD4(+) cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.