Cryptococcal Interactions with the Host Immune System

Opportunistic pathogens have become of increasing medical importance over the last decade due to the AIDS pandemic. Not only is cryptococcosis the fourth-most-common fatal infectious disease in sub-Saharan Africa, but also Cryptococcus is an emerging pathogen of immunocompetent individuals. The interaction between Cryptococcus and the host''s immune system is a major determinant for the outcome of disease. Despite initial infection in early childhood with Cryptococcus neoformans and frequent exposure to C. neoformans within the environment, immunocompetent individuals are generally able to contain the fungus or maintain the yeast in a latent state. However, immune deficiencies lead to disseminating infections that are uniformly fatal without rapid clinical intervention. This review will discuss the innate and adaptive immune responses to Cryptococcus and cryptococcal strategies to evade the host''s defense mechanisms. It will also address the importance of these strategies in pathogenesis and the potential of immunotherapy in cryptococcosis treatment.The basidiomycetous yeast genus Cryptococcus includes the two medically important pathogens C. neoformans and C. gattii. These two species are further divided into C. neoformans serotypes A (C. neoformans var. grubii), D (C. neoformans var. neoformans), and A/D and C. gattii serotypes B and C (formerly C. neoformans var. gattii) based on differential antibody recognition of the polysaccharide capsule (135). The two pathogenic species show different geographical distributions. C. neoformans is globally distributed and has been isolated from various natural sources, with particularly high concentrations occurring in avian guano, rotting vegetables, and soil. In contrast, C. gattii is geographically restricted to tropical and subtropical regions, with the notable exception of British Columbia. In tropical and subtropical regions, it has been found to be associated with the eucalyptus species Eucalyptus camaldulensis, Eucalyptus tereticornis, Eucalyptus rudis, and Eucalyptus gomphocephala (64, 172). C. neoformans causes mainly opportunistic infections in immunocompromised patients with underlying conditions, such as HIV, leukemia, and other cancers, or in those taking corticosteroid medication (135). Serotype A is responsible for the majority of cryptococcosis cases in immunocompromised hosts (135). In contrast, C. gattii affects mainly immunocompetent individuals. The recent and spreading cryptococcosis outbreak in healthy individuals in British Columbia has highlighted the potential of C. gattii to act as an emerging pathogen (84, 85, 121). In addition, other non-C. neoformans/non-C. gattii species, such as Cryptococcus laurentii and Cryptococcus albidus, have recently started to emerge as potential human pathogens (83).Cryptococcal infection can be asymptomatic, chronic, or acute. Typically, an initial pulmonary infection can spread systemically, with a particular predilection for the central nervous system. Pulmonary infections are in most cases asymptomatic. However, they can involve coughing, pleuritic chest pain, fever, dyspnoea, weight loss, and malaise. Pneumonia and acute respiratory distress syndrome have been reported mainly for immunocompromised patients (17, 141). Cryptococcosis of the central nervous system is life threatening and presents as meningitis or meningoencephalitis, with symptoms such as headache, increased intracranial pressure, fever, lethargy, coma, personality changes, and memory loss. Less common are secondary infections of the skin, lungs, prostate, and eye (135). A recent publication estimated 957,900 cases of cryptococcal meningitis resulting in 624,700 deaths globally each year (150). It is the leading cause of death in HIV-infected individuals, with an incidence of 30% and a mortality of 30 to 60%. The mortality rate in transplant patients is even higher (20 to 100%) (Centers for Disease Control and Prevention) (135).The dramatic course of Cryptococcus infections in immunocompromised individuals shows the importance of an intact immune response to the pathogen. This review will consider both the host''s innate and adaptive immune responses to C. neoformans and C. gattii together with the pathogens'' strategy to undermine these defense mechanisms and how current knowledge might be applied to improve anticryptococcal therapy.