2  Overview of host immunity during cryptococcosis
In this section we introduce the broad concepts of the immune response and pathogenesis of cryptococcosis before exploring each part in greater detail in the sections below. Pulmonary cryptococcal infection will occur only if fungal cells, environmentally acquired by inhalation, are deposited deep in the lungs. After deposition within the lung, alveolar macrophages (AMs), tissue resident macrophages that will remove microorganisms and other particulates, will be the first cells to encounter the cryptococci and will respond by internalising them through phagocytosis (Goldman et al., 2001). Following phagocytosis AMs will ideally kill the microorganisms and initiate and modulate the appropriate wider immune response. This will include the release of cytokines, activation and recruitment of other immune cells and presentation of antigen.
Due to the resolving sub-clinical or mild nature of the infection in immunocompetent individuals there is limited data on the normal immune response to C. neoformans. Cryptococcal infections are occasionally identified due to medical examination for other symptoms or conditions. In these cases cryptococci are enclosed within granulomas (Haugen and Baker, 1954). Granulomas are a diverse group of immune structures, commonly recognised as macrophage like cell clusters surrounded by lymphocytes. Their primary function is to control and remove infections but are also seen in a number of immune diseases (Rose et al., 2014). Cryptococcal granulomas are compact, with macrophages, multinucleated giant cells (both containing intracellular yeasts) and CD4+ lymphocytes (Shibuya et al., 2005, 2002). These granulomas will typically resolve over a period of weeks or months without clinical intervention. Evidence of childhood infection (cryptococcal antibody profile increasing with age) suggests latent infection, or repeated infection (Goldman et al., 2001). In addition, decline of immune efficiency as a trigger for the reemergence of a dormant cryptococcal infection, potentially suggests that cryptococci are able to escape degradation and remain within an individual for long periods of time (Garcia-Hermoso et al., 1999).
It is clear from both the clinic and experimental models of cryptococcosis that T cell responses are key to the control of cryptococcal infection. The major defect in the patient groups at risk of developing cryptococcal meningitis is in the CD4+ T helper system. Therefore, a very different response in the lung is seen in individuals with AIDS. Loosely aggregated giant cells are seen but cryptococci are typically extracellular and there is significant proliferation in the alveolar spaces (Shibuya et al., 2005, 2002). If cryptococcal infection is not controlled in the lungs then it will disseminate throughout the body, with particular preference for the central nervous system (CNS). Infection of the CNS results in life threatening meningitis and/or meningoencephalitis, with very high mortality without treatment (Bovers et al., 2008; Mitchell and Perfect, 1995). The route and mechanism of spread to the CNS has not been directly demonstrated, however, it is likely through the blood as the lymphatic system has no access to the brain (Liu et al., 2012; Iliff and Nedergaard, 2013).