Parenchymal Organ, and Not Splenic, Immunity Correlates with Host Survival during Disseminated Candidiasis

Abstract

We examined the relationship between host survival and renal and splenic immune responses in a murine model of hematogenously disseminated candidiasis. Male BALB/c mice were infected via tail vein injection with wild-type C. albicans or with an isogenic, ⌬efg1/⌬efg1 hypha-deficient mutant. Host survival, organ fungal burden, intracellular cytokine content of splenic and kidney lymphocytes, and whole-organ cytokine profiles were determined. Wild-type C. albicans induced type 2 splenocyte responses with both nonfatal and fatal inocula. In the kidney, conversely, wild-type inocula causing no or low mortality induced type 1 responses and 100% fatal inocula induced type 2 or interleukin-10 (IL-10)-dominant responses. Hypha-deficient mutant C. albicans caused no or low mortality while inducing type 1 responses in both the spleen and kidney. To our knowledge, this is the first demonstration that host survival during systemic infection correlates with the type of immune response engendered in a nonlymphoid, parenchymal organ and not with the response in the spleen. Furthermore, the results provide in vivo confirmation that hyphal formation by C. albicans induces type 2 or IL-10-dominant host responses in tissues.Candida is the fourth most common bloodstream isolate in the nosocomial setting (31), and the cost associated with nosocomial candidemia in the United States approaches one billion dollars per year (18). Furthermore, disseminated candidiasis has an attributable mortality of nearly 40% overall (and Ͼ50% in myeloablated patients) even in the face of modern antifungal therapy (14,21,35). Strategies to potentiate host defense against the fungus are likely to be efficacious for preventing and/or treating this infection; hence, there has been intense interest in elucidating the precise nature of protective host defense mechanisms against Candida.The paradigm of type 1 and/or type 2 immunity integrates cell-mediated and humoral host defense (32). T-helper 1 (Th1) cells, which secrete gamma interferon (IFN-␥) but not interleukin-4 (IL-4), stimulate type 1 immunity characterized by intense phagocytic activity. Conversely, Th2 cells, which secrete IL-4 but not IFN-␥, stimulate type 2 immunity characterized by induction of high antibody titers and suppression of phagocytic activity. It has been suggested that a type 1 immune response is protective against both disseminated and mucocutaneous candidiasis, while a dominant type 2 immune response results in increased susceptibility to disseminated disease (6,10,17,28,30). Furthermore, during Candida sepsis there is a down-regulation of the host response to the fungus (33), suggesting that T-regulatory (Treg) or Th3 cells, which predominantly secrete the immunosuppressive cytokines IL-10 and transforming growth factor beta (TGF-␤) (8, 9, 11), regulate host immunity to high inoculum levels of Candida. This notion is supported by data from Romani's group, who recently reported that C. albicans induces IL-10 ϩ /TGF-␤ ϩ Treg cells that mediate oral tolerance following intragastric ...

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

“…Specifically, the generation of Th2 responses and M2a polarization in Cryptococcus neoformans (24) and Histoplasma capsulatum (26) renders mice more susceptible to infection. Mice that are biased toward Th2 responsiveness are more susceptible to disseminated (56) and mucosal infection (57) with Candida albicans. However, promotion of M2a polarization in gastrointestinal Candida albicans infection has been shown to limit fungal colonization (58).…”

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

“…Splenic Th1 (CD4 + IFN-γ + IL-4 -) and Th2 (CD4 + IFN-γ -IL-4 + ) lymphocyte frequencies were determined as we have previously described (44). In brief, splenic homogenates were passed through 70-μm filters followed by rbc lysis with 0.15 M ammonium chloride.…”

Optimization of a myeloid cell transfusion strategy for infected neutropenic hosts

“…For murine infections, C. albicans SC5314 [24,27], a well-characterized, clinical isolate, which is highly virulent in animal models, was serially passaged three times in yeast peptone dextrose broth (YPD; Difco, Detroit, MI, USA) and washed twice with PBS. Infectious inocula were prepared by counting in a hemacytometer and confirmed by colony counting.…”

“…Neutropenic mice were infected and treated as above; however, on Day 5 postinfection (after three treatment doses, on the day when placebotreated mice were anticipated to begin dying), mice were killed, and their kidneys were homogenized and cultured quantitatively. Kidneys were used, as they are the predominant target organ of infection during murine candidemia [24,27,[32][33][34][35][36]. Treatment with 1-or 3-day-activated, irradiated HL-60 cells resulted in ϳ0.7 log CFU/g reduction in kidney fungal burden (Fig.…”

“…In pilot studies in which peripheral blood leukocytes were manually counted, this treatment regimen resulted in pancytopenia from Days 1 through 7 postcyclophosphamide treatment (Days 0 -6 postinfection given infection on Day 1 postcyclophosphamide), and recovery of cell counts began on Day 8 postcyclophosphamide (Day 7 postinfection). Mice were infected via the tail vein with 0.2 ml PBS containing 5 ϫ 10 4 blastoconidia of C. albicans ϳ32 h after cyclophosphamide injection, as described previously [27].…”