Marta Feldmesser¹ and Arturo Casadevall^1,2

1Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology², Albert Einstein College of Medicine, Golding Building Room 701, 1300 Morris Park Ave., Bronx, NY 10461

Received 1/5/98 Accepted 1/9/98

3. OVERVIEW OF PATHOGENESIS AND THE HOST IMMUNE RESPONSE

In the normal host, initial infection is presumably contained in the lung, while in immunocompromised hosts, the infection can disseminate from a primary pulmonary focus (1,7). Dissemination is presumed to occur hematogenously, but the actual route is unknown, and lymphatic and/or cell-associated spread may occur. That cell-mediated immunity is important for cryptococcal infection can be deduced from the finding that most patients with cryptococcosis have defects in T cell immunity, such as lymphoreticular malignancies, immunosuppression following organ transplantation and HIV infection. One variable in the course of infection is the ability of the host to mount an inflammatory response (see below). In autopsy specimens of brains from patients with AIDS with cryptococcal meningoencephalitis, significant inflammatory responses are not seen, while most non-AIDs patients have granulomatous inflammatory responses (8). In vitro lymphocyte function occurs more readily with peripheral blood lymphocytes from patients with positive skin tests than from patients cured of disseminated disease, suggesting that defective lymphocyte transformation may be a factor in the ability of cryptococcal disease to disseminate (9).

C. neoformans may be both an intracellular and an extracellular pathogen, and is found in both locations in tissue. In general, the prevalence of extracellular organisms is inversely proportional to the host inflammatory response. Descriptions of the pathogenesis and pathology of C. neoformans ressemble those of Mycobacterium tuberculosis, a prototypical intracellular organism (10,11). However, in other respects, the pathogenesis of C. neoformans and the Ab response to this organism are similar to those associated with the encapsulated bacteria (recently reviewed in 12). Since the effective host response may require strategies associated with both intra- and extracellular pathogens, C. neoformans may present unique challenges to the host immune system.

In murine models, resistance to infection in dependent on the mouse strain (13,14) and the route of infection (15). The early host response that confines cryptococci within the lungs of normal mice infected intratracheally (i.t.) is T cell dependent, and both CD4⁺ and CD8⁺ cells are required. While both T cell populations are important in initial containment of infection, CD4⁺ cells are particularly important in preventing dissemination to the brain (16). T cell transfer from sensitized mice reduces the number of yeast in tissues of infected mice, while B cell depletion and serum transfer play no role (17). CD4⁺, CD8⁺ and NK cells have fungistatic activity without the requirement for additional opsonins, while B cells do not (18). A role for B cells in immunity to cryptococcal infection has been demonstrated in some models, though the mechanism by which they exert their effect has not been defined (19).

Macrophages play an essential role in nonspecific cell-mediated immunity to murine cryptococcosis (20). The ability of macrophages to phagocytose cryptococci or to mediate fungistasis or killing depends upon the macrophage source, the state of cellular activation and the presence of opsonins and cytokines. Alveolar macrophages are thought to be the first effector cell type to encounter cryptococci in natural infection (21). The histologic response that contains infection is granulomatous inflammation, in which the major cellular component is the macrophage. The formation of multinucleated giant cells is dependent on the presence of CD4⁺ cells (16). The association of the development of delayed type hypersensitivity (DTH) with clearance of organisms (15,22) further underscores the importance of macrophages in the host immune response.