The Relative Susceptibility of Mouse Strains to PulmonaryCryptococcus neoformansInfection Is Associated with Pleiotropic Differences in the Immune Response

Abstract

CBA/J mice were highly susceptible to intratracheal (i.t.) Cryptococcus neoformans infection relative to BALB/c mice, while both strains were equally susceptible to intravenous (i.v.) infection. Increased susceptibility in i.t. infection was associated with higher brain CFU, lower serum immunoglobulin M (IgM) and IgG responses to glucuronoxylomannan (GXM), lack of IgE regulation during infection, and alveolar macrophage permissiveness to intracellular replication in vitro. In contrast, for BALB/c mice, relative resistance was associated with increased interleukin-12 (IL-12) and decreased IL-10 pulmonary levels. In CBA/J mice, relative susceptibility was associated with a decreased proportion of CD4 ؉ and CD8 ؉ T cells and an increase in macrophage percentage in pulmonary infiltrates. In contrast, no significant differences in these cytokines or cell recruitment were observed in the i.v. model, consistent with no differences in the survival rate. Passive antibody (Ab) protection experiments revealed a prozone effect in the BALB/c mice with i.v. infection, such that Ab efficacy decreased at higher doses. In the i.t. model using CBA/J mice, low Ab doses were disease enhancing and protection was observed only at high doses. Our results show (i) that differences in mouse strain susceptibility are a function of the infection model, (ii) that susceptibility to pulmonary infection was associated with macrophage permissiveness for intracellular replication, and (iii) that the efficacy of passive Ab in pulmonary infection is a function of dose and mouse strain. The results highlight significant differences in the pathogenesis of cryptococcal infection among inbred mice and associate their relative susceptibility with differences in numerous components of the innate and adaptive immune responses.Cryptococcus neoformans is a fungal pathogen for individuals with late-stage human immunodeficiency virus infection. The initial infection is usually controlled and either cleared or contained by immunocompetent hosts into a latent asymptomatic state, and there is evidence that persistent infection might be associated with reactive airway disease (24). However, in immunocompromised individuals dissemination and/or reactivation of latent infection can lead to a life-threatening meningoencephalitis (for a review, see reference 9).C. neoformans has several well-characterized virulence factors, including a polysaccharide capsule, melanin production, phospholipase, urease, and the alpha mating factor, among others (for reviews, see references 9, 42, and 55). A recent study analyzing the relative contribution of each virulence factor showed that the capsular polysaccharide makes the largest contribution to C. neoformans virulence (41). The polysaccharide capsule is composed primarily of glucuronoxylomannan (GXM). The capsule participates in virulence through pleitropic effects on the immune system (9, 71, 72). Furthermore, C. neoformans strains that differ in virulence elicit different immune responses in the host (5, 14).

The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing

“…The capacity for intracellular pathogenesis is an important feature because the outcome of interaction of macrophages with fungal pathogens might determine the susceptibility of the host to the infection (28,32). In this work, we demonstrate that the emerging fungal pathogen Candida krusei can survive and exploit the intracellular macrophage environment for its replication, which may influence the dissemination through the organism.…”

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

“…The host immune response is a major determinant of the outcome of cryptococcal infection; however, the underlying basis for the differences in susceptibility is poorly understood (11,71). To elucidate the mechanisms of host resistance against C. neoformans infection, we have compared the innate and adaptive pulmonary responses using C57BL/6J and SJL/J mice, two strains that have been reported to be susceptible and resistant to experimental pulmonary (26) and systemic (55) cryptococcal infection, respectively.…”

“…In this study, C57BL/6J mice developed an allergic bronchopulmonary mycosis (ABPM) characterized by chronic IL-5-dependent eosinophilia and intracellular, as well as extracellular, deposition of Charcot-Leyden-like crystals. Interestingly, C57BL/6J and CBA/J mice were equally susceptible to highdose (10 6 CFU) intravenous infection with the same cryptococcal isolate, demonstrating that host resistance depends on the dose and route of infection (71). In another report that used an intravenous challenge with 5 ϫ 10 6 CFU of a serotype D C. neoformans isolate, inbred strains lacking the fifth component of complement (C5) had a mean survival time of 4 days, compared to 13 days for C5-sufficient strains (55).…”

“…Infection of inbred mouse strains with C. neoformans has revealed significant variations in host susceptibility that are regulated by genetic factors (11,26,55,71). For example, experimental intratracheal infection with 10 4 CFU of a moderately virulent serotype D isolate of C. neoformans revealed that C57BL/6J mice had natural susceptibility, whereas those of the BALB/c and CBA/J inbred strains did not (26).…”

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

“…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).…”