CD4 ⁺ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

Abstract

Cryptococcus neoformans is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4 ϩ T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIVpositive (HIVϩ) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45 hi leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-␥)-producing CD4 ϩ T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4 ϩ cells significantly impaired IFN-␥ production, CD8 ϩ T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4 ϩ T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections.IMPORTANCE CNS infection with the fungal pathogen Cryptococcus neoformans often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIVϩ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with antiinflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

“…Another important variable affecting patient outcomes may be immune dysregulations that could either reduce microbial clearance or result in inflammatory syndromes, similar to cryptococcal immune reconstitution inflammatory syndrome (cIRIS) after antiretroviral therapy (ART) in HIV-related disease or a postinfectious inflammatory syndrome in non-HIV patients (15,29,30) which is also present during murine infections (31). In the present study, CAmB treatment in the presence of CM resulted in small but significant elevations in IL-1␤, the proinflammatory cytokine that had previously been reported to be elevated after exposure to conventional AmB (14,32).…”

ATGGenes Influence the Virulence of Cryptococcus neoformans through Contributions beyond Core Autophagy Functions

“…Also, a clinical study showed that HIV-positive patients with cryptococcal infection developed immune reconstitution inflammatory syndrome after antiretroviral therapy (67). A recent study using a mouse model explicitly demonstrated that CD4 ϩ T cells act as a "double-edged sword" in both killing fungal cells and causing significant immunopathology and mortality to the host during cryptococcal central nervous system infection (68,69).…”

MiR-4792 regulates inflammatory responses in Cryptococcus neoformans infected microglia

“…Microglia are key effector cells in the host defenses to microbial infections and act as antigen presenting cells that can produce active substances that promote in ammatory cell death [39,40]. Following C. neoformans exposure, microglia produce TNF-α, IL-1β and IL-6 to upregulate MHC Class II and CD11c [41,42]. Moreover, microglia can phagocytose C. neoformans and upregulate iNOS with anti-fungal effects which is dependent on GPR43 expression [43][44][45][46].…”