Molecular Immunopathogenesis of Innate Host Defense against Chronic Disseminated (Hepatosplenic) Candidiasis

Abstract

Chronic disseminated candidiasis presents a paradox of innate host defense; i.e., hematogenous candidiasis ensues during neutropenia, and despite recovery from neutropenia, deep tissue disease becomes clinically apparent and progressive in severity. It was found that IL-10 also suppresses the host response of monocytes (MNCs) and polymorphonuclear leukocytes (PMNs) to C. albicans, as evidenced by decreased fungicidal activity against serum-opsonized blastoconidia, reduced capacity to damage unopsonized hyphae, and suppressed O2 - production. The authors hypothesized that a switch from Th1 to a Th2 cytokine profile may contribute to this refractoriness. It was found that human peripheral blood MNCs incubated with C. albicans in vitro also released large amounts of biologically active TGF- β1. These results further correlated with the immunolocalization of TGF-β observed in livers from the rabbit model of chronic disseminated (hepatosplenic) candidiasis. It was also found that IL-15 directly up-regulates the oxidative and microbicidal activity of human MNCs against C. albicans. To better understand the immunopathogenesis of disseminated candidiasis, the authors compared the antifungal activities of macrophages residing in the spleen, liver, and lungs of rabbits against blastoconidia and hyphae of C. albicans. The authors found that splenic macrophages, Kupffer cells, and pulmonary alveolar macrophages were similar in their phagocytic capacity but differed in their capacity to damage Candida hyphae, in the order splenic macrophages, Kupffer cells, pulmonary alveolar macrophages. The laboratory findings described collectively support the concept that chronic disseminated candidiasis is a disease of Th1/Th2 dysimmunoregulation.