The pathophysiology and treatment of Candida sepsis

Spellberg, Brad; Edwards, John E.

doi:10.1007/s11908-002-0005-3

Cited by 35 publications

(24 citation statements)

References 119 publications

(80 reference statements)

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“…First, if the majority of the cytokines detected in the whole-organ analysis were of serum origin, similar profiles would have been detected in the kidney and in the highly vascularized spleen. Furthermore, investigators have found that serum levels of inflammatory cytokines are low during lethal disseminated candidiasis (2,33).…”

Section: Discussionmentioning

confidence: 99%

“…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 infection (19).…”

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confidence: 99%

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

Spellberg¹,

Johnston²,

Phan³

et al. 2003

Infect Immun

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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 ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Spellberg¹,

Johnston²,

Phan³

et al. 2003

Infect Immun

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“…Invasive candidiasis, caused mainly by Candida albicans and also by other Candida species, has emerged as a major cause of morbidity and mortality in immunocompromised host, and Candida species represent one of the most common nosocomial bloodstream isolates (Calderone 2002;Spellberg and Edwards 2002). These species are present as commensal organisms, but when the normal host defence is impaired, they act as serious agents of infection, and are considered as opportunistic pathogens of humans.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the usefulness of anti-glyceraldehyde-3-phosphate dehydrogenase antibodies as a treatment for invasive candidiasis in a murine model

Gil

Dagan

Eren

et al. 2006

Antonie Van Leeuwenhoek

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We have evaluated the effect of antibodies against the Candida albicans glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a potential immunotherapeutic treatment for acute invasive candidiasis in a murine model of infection. Three different approaches were assayed: (i) active immunization of mice using recombinant His-tagged GAPDH, (ii) treatment of fungal yeast cells with anti-GAPDH antibodies prior to infection, and (iii) passive transfer of polyclonal anti-GAPDH antibodies. Results showed that all three approaches, although tending to show a slight beneficial effect in some instances, fail to have a relevant and statistically significant effect on the infection course, determined by survival curves and fungal burden in kidneys. This suggests that the cell wall-associated GAPDH of C. albicans, despite its potential role in virulence, does not appear to be a suitable target protein for the development of immunotherapeutic strategies against candidiasis, although further studies may be required to confirm this observation.

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“…The major clinical risk factors for developing disseminated candidiasis have been well described (58). These key risk factors include colonization with the organism, gastrointestinal or cardiac surgery, a prolonged stay in an intensive care unit, burns, and use of central venous catheters, broad-spectrum antibiotics, and parenteral nutrition.…”

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confidence: 99%

Vaccination with Recombinant N-Terminal Domain of Als1p Improves Survival during Murine Disseminated Candidiasis by Enhancing Cell-Mediated, Not Humoral, Immunity

et al. 2005

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Candida spp. are opportunistic fungal pathogens that are among the most common causes of nosocomial bloodstream infections. The mortality attributable to disseminated candidiasis is 40 to 50% despite antifungal therapy. Clearly, new strategies are needed to prevent this life-threatening infection. Because risk factors for disseminated candidiasis are well defined and frequently of limited duration, vaccination is an appealing prophylactic strategy. We have identified a cell surface protein, Als1p, that mediates adherence of Candida albicans to a variety of human substrates and plastic. Here we report that immunizing BALB/c mice with the recombinant N-terminal domain of Als1p (rAls1p-N) improved survival during a subsequent challenge with a lethal inoculum of C. albicans. The protective 20-g dose of rAls1p-N significantly increased Candida stimulation of Th1 splenocytes and increased in vivo delayed-type hypersensitivity. In contrast, antibody titers did not correlate with protection. Finally, the vaccine was not protective in T-cell-deficient mice but was protective in B-cell-deficient mice. These data indicate that the mechanism of action of the rAls1p-N vaccine is stimulation of cell-mediated, rather than humoral, immunity against C. albicans. The majority of efforts to date have focused on the development of passive immunization strategies to prevent or treat disseminated candidiasis. In contrast, our results provide proof of principle for vaccination with an adhesin of C. albicans and emphasize the potential for cell-mediated immune modulation as a prophylactic or therapeutic strategy against disseminated candidiasis.

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The pathophysiology and treatment of Candida sepsis

Cited by 35 publications

References 119 publications

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

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

Evaluation of the usefulness of anti-glyceraldehyde-3-phosphate dehydrogenase antibodies as a treatment for invasive candidiasis in a murine model

Vaccination with Recombinant N-Terminal Domain of Als1p Improves Survival during Murine Disseminated Candidiasis by Enhancing Cell-Mediated, Not Humoral, Immunity

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