Immune-Mediated Damage Completes the Parabola: Cryptococcus neoformans Pathogenesis Can Reflect the Outcome of a Weak or Strong Immune Response

Abstract

Cryptococcosis occurs most frequently in immunocompromised individuals. This has led to the prevailing view that this disease is the result of weak immune responses that cannot control the fungus. However, increasingly, clinical and experimental studies have revealed that the host immune response can contribute to cryptococcal pathogenesis, including the recent study of L. M. Neal et al. (mBio 8:e01415-17, 2017, https://doi.org/10.1128/mBio.01415-17) that reports that CD4⁺ T cells mediate tissue damage in experimental murine cryptococcosis. This finding has fundamental implications for our understanding of the pathogenesis of cryptococcal disease; it helps explain why immunotherapy has been largely unsuccessful in treatment and provides insight into the paradoxical observation that HIV-associated cryptococcosis may have a better prognosis than cryptococcosis in those with no known immune impairment. The demonstration that host-mediated damage can drive cryptococcal disease provides proof of concept that the parabola put forth in the damage-response framework has the flexibility to depict complex and changing outcomes of host-microbe interaction.

Keywords: fungi; pathogenesis; virulence.

FIG 1

Outcomes of host-Cryptococcus neoformans interaction depicted by the basic parabola of the damage-response framework. The left side of the parabola, shaded in green and labeled weak, depicts the original circa 1999 concept that C. neoformans was a class 2 pathogen that caused damage in the setting of a weak or normal immune response. Here, the immune response fails to limit fungal growth, which results in host damage. The right side of the parabola, shaded in red and labeled strong, depicts information that has emerged since 1999, which has revealed that C. neoformans can elicit strong immune responses that produce host damage stemming from inflammation. The portion of the parabola that rises above the black dotted line represents the threshold for clinical disease. The portion of the parabola that lies below the black dotted line represents the state of C. neoformans latency, which is not associated with clinically evident host damage. Proposed therapeutic interventions, based on counteracting the main source of host damage are depicted by red (to enhance weak response) or green (to reduce strong response) arrows. Some factors that contribute to weak and strong immune responses are shown along the y axis for each type of response, though immunity is likely multifactorial, and additional factors are also likely to contribute (16, 29–35).