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

Abstract

Genetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformans are poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformans ATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice following C. neoformans pulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN ؋ CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele at Cnes4 and a susceptibility allele at Cnes5. These studies reveal additional genetic complexity of the host response to C. neoformans that is associated with divergent patterns of pulmonary inflammation.

Antifungal activity of topical microemulsion containing a thiophene derivative

“…Cryptococcus neoformans is an encapsulated fungus capable of causing infections in immunocompromised patients (Carroll et al , 2012; Guerra et al , 2012). Inhalation of its basidiospores or cells present in the environment can result in lung infection and its subsequent spread to the central nervous system, causing meningoencephalitis, recognized as one of the most important opportunistic infections in patients with HIV with a worldwide incidence of approximately 957,000 cases per year (Leongson et al , 2013).…”

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

“…Previous studies using a well-established model of intratracheal infection with C. neoformans 52D demonstrated that C57BL/6 mice developed a lung fungal load that was over 1,000 times greater than that in CBA/J mice at day 35 postinfection (44). The wide spectrum of naturally occurring resistance was subsequently demonstrated for a panel of 10 inbred mouse strains (43). Further analysis showed that susceptibility to progressive fungal infection in C57BL/6 mice was associated with lung eosinophilia and a Th2-biased adaptive (E to H) Absolute numbers of neutrophils, eosinophils, ExM, and DC in the lung at 0, 7, 14, 21, and 28 dpi.…”

“…Compared to that of C57BL/6 mice, the immune response of B6.CBA-Cnes2 congenic mice was characterized by a significantly higher expression of type 1 cytokines and greater numbers of lung neutrophils, antigen-presenting cells, and Th1-polarized CD4 ϩ T lymphocytes. Taken together, these data demonstrate that one or more genes within the Cnes2 locus regulate pulmonary host defense through pleiotropic effects on the inflammatory and immune responses following C. neoformans infection (43,47).…”

“…Beyond the well-characterized contribution of spontaneous mutations or specifically engineered defects that alter immunity against C. neoformans, there is emerging evidence that genetic susceptibility to cryptococcal infection in the apparently normal host is a complex trait (42,43). For example, a previous study demonstrated that C57BL/6 mice develop a lung fungal burden that is 1,000-fold higher than that in the CBA/J inbred strain 5 weeks following direct intratracheal infection with moderately virulent C. neoformans 52D (44).…”

Vaccines and Protective Immune Memory against Cryptococcosis

“…Those studies provided new insights into what is termed "innate memory" or "trained immunity," where innate immune cells, including macrophages (Mφ), DCs, and natural killer (NK) cells, exert memory like-responses to antigen reexposure. [23][24][25][26] The immune response and susceptibility to infection often differ in various mouse strains, and different cryptococcal strains show different virulence. Outbred mice such as ICR and Swiss mice were used for early vaccine protection assays, but inbred mice, including C57BL/6, BALB/c, and CBA/J strains, have been widely used in more recent studies.…”