Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

Abstract

Cryptococcal meningitis (CM) is the leading cause of central nervous system (CNS) fungal infections in humans, with the majority of cases reported from the African continent. This is partly due to the high burden of HIV infection in the region and reduced access to standard-of-care including optimal sterilising antifungal drug treatments. As such, CM is responsible for 10-15% of all HIV-related mortality, with a large proportion being preventable. Immunity to the causative agent of CM, Cryptococcus neoformans, is only partially understood. IFNγ producing CD4⁺ T-cells are required for the activation of myeloid cells, especially macrophages, to enable fungal killing and clearance. However, macrophages may also act as a reservoir of the fungal yeast cells, shielding them from host immune detection thus promoting latent infection or persistent chronic inflammation. In this chapter, we review the epidemiology and pathogenesis of CNS fungal infections in Africa, with a major focus on CM, and the antifungal immune pathways operating to protect against C. neoformans infection. We also highlight the areas of research and policy that require prioritisation to help reduce the burden of CNS fungal diseases in Africa.

Keywords: HAART; astrocyte; cryptococcal meningitis; fungal infection; microglia.

Figure 1

Pathogenesis of cryptococcal meningitis immune reconstitution inflammatory response syndrome (CM-IRIS). Th1 immune responses are required for better clearance of Cryptococcus. This reduces the risk of CM-IRIS and results in improved survival. However, there is an imbalance as the far as the Th1-Th2 paradigm is concerned with extreme HIV-associated CD4 depletion. A predominantly Th2 response is associated with M2 macrophages and poor pathogen clearance. Initiation of HAART restores CD4⁺ T cell counts. In a setting of poor pathogen clearance, the residual cryptococcal antigen induces an expansion of predominantly Th1 CD4⁺ T cells with secretion of IFNγ. This polarizes macrophages to an M1 phenotype which secretes pro-inflammatory cytokines and chemokines that recruit more innate immune cells. This predominantly Th1 immune response generates a dysregulated and exaggerated CNS inflammation that presents as paradoxical CM-IRIS. CNS, central nervous system; CM-IRIS, Cryptococcal meningitis immune reconstitution inflammatory response syndrome; HAART, highly active antiretroviral therapy.

Figure 2

Neuroimmunology of C. neoformans infection. (Left panel) In the brain parenchyma, C. neoformans mostly interacts with brain-resident microglia and astrocytes, which differentiate into distinct functional states depending on the inflammatory context and infiltrating immune cells (e.g. T-cells). For example, astrocytes can develop into pro-inflammatory A1 or tissue-healing A2 subsets, but whether this occurs during CM is unknown. (Right panel) In the meninges, C. neoformans mostly localises to the sub-arachnoid space where it will encounter meningeal macrophages (MMΩs) and a variety of resident lymphocytes including B-cells (deriving from skull bone marrow and connecting channels) and T-cells. Image created with Biorender.com.