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English Wikipedia
CD4(+) T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance
during Cryptococcus neoformans Meningoencephalitis
#MMPMID29162707
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(+) T cells
have demonstrated roles in anticryptococcal defenses, but increasing evidence
suggests that they may contribute to clinical deterioration and pathology in both
HIV-positive (HIV+) 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(+) 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(+)
cells significantly impaired IFN-? production, CD8(+) 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(+) 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 HIV+ and non-HIV patients. Thus, physicians need to
balance efforts to enhance patients' immune responses and promote microbiological
control with anti-inflammatory 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 addresses the urgent need for animal models to investigate the
specific cellular and molecular mechanisms underlying cryptococcal disease in
order to better treat treat patients with CNS infections.
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