Inbred SJL mice recapitulate human resistance to Cryptococcus infection due to differential immune activation

Abstract

Cryptococcosis remains a significant threat to human health. While the popular C57BL/6J mouse model of cryptococcosis has some advantages, there are some serious shortcomings that limit the ability of researchers to address the disease. Since humans are resistant to environmental cryptococcal infection until rendered immunodeficient while C57BL/6J mice are innately susceptible, we screened 15 inbred mouse strains for resistance to Cryptococcus infection. The SJL/J mouse strain was unusually resistant to several virulent strains of Cryptococcus while the closely related FVB/J strain was susceptible. The infection pathobiology in SJL/J mice and susceptible mice was similar for the first 7–10 days then markedly diverged toward pathogen clearance. Interferon-gamma (IFN-γ) expression was critical for SJL/J resistance while tumor necrosis factor-alpha was also important. Both CD4 and CD8 T cells produced IFN-γ and were collectively critical. While IL-17 and associated cytokines were expressed in SJL/J mice, IL-17 inhibition did not affect the outcome of infection. Unlike the C57BL/6J, infected SJL/J mice failed to express Th2/atopy-type cytokines even when rendered susceptible by IFN-γ blockade or infection with an alternative fatal cryptococcal strain virulent in SJL/J. These data suggest that the atopic-type response typically associated with the C57BL/6J model is not critical for susceptibility. The productive immune response in SJL/J mice resulted in immune memory that protected mice from reinfection. The SJL/J cryptococcal resistance phenotype was associated with a strong genetic linkage from regions located in chromosomes 2 and 11 suggesting strain-specific modifiers contribute to disease severity. Thus, SJL/J mice are an exciting alternative animal model for cryptococcal pathobiology. IMPORTANCE Cryptococcosis studies often utilize the common C57BL/6J mouse model. Unfortunately, infection in these mice fails to replicate the basic course of human disease, particularly hampering immunological studies. This work demonstrates that SJL/J mice can recapitulate human infection better than other mouse strains. The immunological response to Cryptococcus infection in SJL/J mice was markedly different from C57BL/6J and much more productive in combating this infection. Characterization of infected mice demonstrated strain-specific genetic linkage and differential regulation of multiple important immune-relevant genes in response to Cryptococcus infection. While our results validate many of the previously identified immunological features of cryptococcosis, we also demonstrate limitations from previous mouse models as they may be less translatable to human disease. We concluded that SJL/J mice more faithfully recapitulate human cryptococcosis serving as an exciting new animal model for immunological and genetic studies.

Preclinical Models for Cryptococcosis of the CNS and Their Characterization Using In Vivo Imaging Techniques

“…Additional advantages are the relatively low maintenance costs, the ease of handling mice, and the availability of many inbred and transgenic mouse strains [48]. Past studies have shown differences between inbred strains in survival rates, inoculum doses (even when administered via the same route), yielding differences in susceptibility, and disease progression [93][94][95]. C57BL/6, A/J, CBA/J, DBA/J, and BALB/c mouse strains are most often used to study experimental Cryptococcus infection models [96][97][98].…”

“…C57BL/6, A/J, CBA/J, DBA/J, and BALB/c mouse strains are most often used to study experimental Cryptococcus infection models [96][97][98]. A study by Davis et al indicated discrepancies between the C57BJ/6J, FVB/J, and SJL/J strains observed due to differences in immune response [95]. Another study performed by Zaragoza et al observed immunological differences in the susceptibility of CBA/J and BALB/C strains when injected with IT but not when injected with IV [94].…”

Card9 Broadly Regulates Host Immunity against Experimental Pulmonary Cryptococcus neoformans 52D Infection

“…Integration of these findings into a coherent model is limited by the use of diverse cryptococcal isolates, including a laboratory strain (B3501), an avirulent strain (LW10), or a highly virulent strain (H99). Finally, all of these studies were performed in the naturally susceptible C57BL/6 inbred mice that developed progressive C. neoformans infection in the presence of a functional Card9 gene [ 20 , 21 ]. Thus, to gain further insight into the role of Card9 during the pathogenesis of cryptococcal pneumonia we challenged wild-type and Card9-mutant mice on the Balb/c background with a moderately virulent serotype D strain of C. neoformans (52D) using well-established experimental conditions and analyzed host resistance and immune responses at serial time points up to day 28 post-infection.…”