Enhanced Innate Immune Responsiveness to PulmonaryCryptococcus neoformansInfection Is Associated with Resistance to Progressive Infection

Abstract

Genetically regulated mechanisms of host defense against Cryptococcus neoformans infection are not well understood. In this study, pulmonary infection with the moderately virulent C. neoformans strain 24067 was used to compare the host resistance phenotype of C57BL/6J with that of inbred mouse strain SJL/J. At 7 days or later after infection, C57BL/6J mice exhibited a significantly greater fungal burden in the lungs than SJL/J mice. Characterization of the pulmonary innate immune response at 3 h after cryptococcal infection revealed that resistant SJL/J mice exhibited significantly higher neutrophilia, with elevated levels of inflammatory cytokine tumor necrosis factor alpha (TNF-␣) and keratinocyte-derived chemokine (KC)/CXCL1 in the airways, as well as increased whole-lung mRNA expression of chemokines KC/CXCL1, MIP-1␣/CCL3, MIP-1␤/CCL4, MIP-2/CXCL2, and MCP-1/CCL2 and cytokines interleukin 1␤ (IL-1␤) and IL-1Ra. At 7 and 14 days after infection, SJL/J mice maintained significantly higher levels of TNF-␣ and KC/CXCL1 in the airways and exhibited a Th1 response characterized by elevated levels of lung gamma interferon (IFN-␥) and IL-12/IL-23p40, while C57BL/6J mice exhibited Th2 immunity as defined by eosinophilia and IL-4 production. Alveolar and resident peritoneal macrophages from SJL/J mice also secreted significantly greater amounts of TNF-␣ and KC/CXCL1 following in vitro stimulation with C. neoformans. Intracellular signaling analysis demonstrated that TNF-␣ and KC/CXCL1 production was regulated by NF-B and phosphatidylinositol 3 kinase in both strains; however, SJL/J macrophages exhibited heightened and prolonged activation in response to C. neoformans infection compared to that of C57BL/6J. Taken together, these data demonstrate that an enhanced innate immune response against pulmonary C. neoformans infection in SJL/J mice is associated with natural resistance to progressive infection.

Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

“…Preserved production of other CCR2 agonists, such as MCP-2 and MCP-3, may have compensated for the defective production of MCP-1. Because dendritic cells and alveolar macrophages play a critical role in the early innate protective host response against C. neoformans (71) and are associated with natural resistance to progressive infection (62), it is likely that functional defects of these cell populations also contributed to the increased susceptibility of the Tg mice to C. neoformans infection. Blood monocytes and alveolar macrophages from HIV-infected patients have impaired fungistatic activity against C. neoformans (72)(73)(74)(75)(76).…”

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

“…The lung lobes were inflated under constant pressure (25 cm H 2 O) with 10% neutral buffered formalin (Sigma-Aldrich), excised, and embedded in paraffin for histopathology. In the second experiment, mouse tracheas were cannulated, and four volumes of 0.5-ml cold sterile saline were instilled through the tracheal cannula, withdrawn, and pooled to recover bronchoalveolar lavage fluids (BALF), as previously described (38). In the third experiment, lungs were perfused with cold saline, flash frozen, and stored at 280˚C until processing for viral titer determination or RNA isolation.…”

Susceptibility to Progressive Cryptococcus neoformans Pulmonary Infection Is Regulated by Loci on Mouse Chromosomes 1 and 9

“…The most notable finding from the phenotypic survey was that C5-sufficient C3H/HeN mice were highly susceptible to C. neoformans infection, with a lung fungal burden that was similar to that of C57BL/6J mice (mean lung burden, 6.49 Ϯ 0.10 log 10 CFU versus 6.94 Ϯ 0.16 log 10 CFU) (22). The marked susceptibility of C3H/HeN mice compared to that of resistant CBA/J mice (mean lung burden, 4.27 Ϯ 0.27 log 10 CFU) was particularly striking since these strains are closely related and share the H-2 k/k haplo-type that mediates antigen presentation by the immune system (17,18). C3H/HeN is susceptible to progressive C. neoformans infection.…”

“…At day 14 after C. neoformans infection, C3H/HeN mice also developed significantly higher airway and lung tissue eosinophilia, while CBA/J mice mounted a neutrophilic response. Pulmonary eosinophilia is a marker of a Th2 response and has been associated with chronic or progressive cryptococcal infection (21), while airway and lung tissue neutrophilia is characteristic of resistant inbred strains such as SJL/J and CBA/J (17). Despite these associations, the role of these inflammatory cell subsets in host defense against C. neoformans is complex.…”

“…Data from mice that harbor natural or genetically engineered immune defects have identified a role for several components of the innate immune system as well as the complexity of antibody (Ab)-and cell-mediated anticryptococcal responses that generate protective immunity (55). Interestingly, immunocompetent inbred mouse strains also show remarkable variation in their susceptibility to experimental C. neoformans lung infection (10,17,21,43,57). As a consequence of the evolutionary origins and distinct breeding histories (4,41), inbred strains carry extensive genomic sequence diversity and can serve as a valuable resource for identification of underlying susceptibility loci, genes, and biochemical pathways through complex trait analysis (25).…”