Immunologic Homeostasis during Infection: Coexistence of Strong Pulmonary Cell-Mediated Immunity to SecondaryCryptococcus neoformansInfection While the Primary Infection Still Persists at Low Levels in the Lungs

Abstract

Maintenance of immunity to persistent pathogens is poorly understood. In this study, we used a murine model of persistent pulmonary fungal infection to study the ongoing cell-mediated immune response. CBA/J mice with low-level persistent Cryptococcus neoformans infection had CD4+ T cells of effector memory phenotype present in their lungs. Although unable to eliminate the primary infection to sterility, these mice displayed hallmarks of immunologic memory in response to rechallenge with C. neoformans: 1) the secondary cryptococcal challenge was controlled much more rapidly, 2) the inflammatory response developed and resolved more rapidly, 3) CD4+ T and CD8+ T cell responses were higher in magnitude, and 4) effector cytokine production by T cells was greatly enhanced. Depletion of CD4+ T cells at the time of secondary challenge adversely affected clearance of C. neoformans from the lungs. These results demonstrate that persistent low-level infection with C. neoformans does not impair the cell-mediated response to the fungus. Although they are relatively free of overt disease, these mice can respond with a rapid secondary immune response if the burden of C. neoformans increases. These data support the concept that immunologically healthy individuals can maintain low numbers of cryptococci that can become a nidus for re-activation disease during immunodeficient states such as AIDS.

Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

“…ϩ , but not CD8 ϩ , T cells at 12 weeks after C. neoformans infection (23). We additionally show that rechallenge of H99␥-immunized mice with fully virulent cryptococci results in a significant increase in the percentage of CD69 ϩ CD8 ϩ T cells.…”

Inheritance of Immune Polarization Patterns Is Linked to Resistance versus Susceptibility toCryptococcus neoformansin a Mouse Model

“…ϩ cells can play a supportive role in generation of a Th1 milieu in the lungs and benefit cryptococcal clearance (1,25,27,37). Thus, the increased numbers of CD8 ϩ cells could contribute to the gradual shift toward a Th1 phenotype in F1 mice and/or contribute to the improved clearance after week 3 postinfection.…”

The Intracellular Life ofCryptococcus neoformans

“…In rats (42), mice (3, 43), and rabbits (44), C. neoformans can be found associated with lung macrophages, in some cases for months, without obvious clinical manifestations. In mice, C. neoformans is rapidly ingested by phagocytes, and in one model of experimental infection, there was a fluctuation in intracellular and extracellular residence during the first 24 h (43).…”

“…The pathogenic yeast can be found worldwide in several environmental niches and has been isolated from soil, trees, and animals, in particular from avian guano (1, 2). Exposure to C. neoformans does not usually lead to overt disease, and epidemiological data led to the accepted view that establishment of an asymptomatic latent state may be the most common outcome of infection (3–5). Even from the early clinical cases described, an association between cryptococcosis and immunosuppression was already inferred (39, 40).…”

“…Various investigators have addressed the immunological mechanism for effective immunization against C. neoformans challenge (3, 27, 34, 35). For example, immunization with capsular mannoproteins was able to prolong mouse survival (34).…”