Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis

Abstract

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.

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

“…1F and G), including the cortex, hippocampus, hypothalamus, pons, and cerebellum. Fungal growth was evident throughout the brains of all infected mice with no discernible predilection for specific areas and appeared as larger areas with centrally abundant fungi, resembling characteristic mucoid pseudocysts (32,43). Notably, the timing of cellular inflammation was synchronized with the onset of mortality and neurological deficits we measured in animals between days 21 and 35 postinfection (Fig.…”

“…Clinical evidence increasingly suggests that the host inflammatory response, rather than pathogen burden, may lead to the development of pathology, neuronal injury, and deteriorating status, especially in IRIS and PIIRS patients (28,30,32,33,(36)(37)(38)(39)(40). Thus, our next goal was to evaluate CNS pathology during the progression of C. neoformans infection and to determine a possible link to the accumulation of a cellular inflammatory response within the CNS.…”

“…T cell inflammatory response in the CNS during cryptococcal meningoencephalitis is highly Th1 polarized, and nearly all CD4 ؉ and CD8 ؉ T cells produce IFN-␥. The subsets of patients with paradoxical inflammatory responses to cryptococcal infection (IRIS and PIIRS) display dominant Th1 T cell polarization with elevated levels of IFN-␥ in the serum and CSF (32,33,(36)(37)(38)(39)(40). Thus, we sought to determine whether murine brain-infiltrating T cells would mimic this phenotype by analyzing T cell cytokine production and expression of polarizing Th-associated transcription factors in the C. neoformans-infected CNS.…”

“…These results support the paradigm that regulation of T cell responses within the CNS needs to be considered part of the therapeutic strategy to prevent CNS damage in certain patients with cryptococcal CNS infection. The treatment of cryptococcal CNS infections presents many challenges due to the need to balance microbial control with a patient's own potentially paradoxical responses during therapy (26,27,29,30,32). In these patients, treatment strategies must strike a balance between activation of antifungal T cell responses and limiting CNS damage due to inflammation.…”

Human fungal pathogens: Why should we learn?

“…neoformans is a basidiomycete fungal human pathogen which causes life-threatening fungal pneumonia and meningitis in immunocompromised patients. Another related species, Cryptococcus gattii, infects immunocompetent individuals in tropical areas; however, there is evidence that C. neoformans also infects immunocompetent hosts (Panackal et al, 2015). C. neoformans is unique among human fungal pathogens as it is encapsulated by polysaccharides.…”