The Role of Late Complement Components and the Alternate Complement Pathway in Experimental Cryptococcosis

Diamond, Richard D.; May, Joseph E.; Kane, Michael; Frank, Michael M.; Bennett, John E.

doi:10.3181/00379727-144-37580

Cited by 60 publications

(26 citation statements)

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“…(5,14) and that animals deficient in C3 but not C4 have faster disease progression (4). In this report, we have now explored the role of complement in infection with C. gattii, an emerging pathogen in North America.…”

Section: Discussionmentioning

confidence: 89%

Role of Complement in Protection againstCryptococcus gattiiInfection

Mershon¹,

Vasuthasawat²,

Lawson³

et al. 2009

Infect Immun

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Previous studies have shown that the alternative pathway of complement activation plays an important role in protection against infection with Cryptococcus neoformans. Cryptococcus gattii does not activate the alternative pathway as well as C. neoformans in vitro. The role of complement in C. gattii infection in vivo has not been reported. In this study, we used mice deficient in complement components to investigate the role of complement in protection against a C. gattii isolate from an ongoing outbreak in northwestern North America. While factor B-deficient mice showed an enhanced rate of death, complement component C3-deficient mice died even more rapidly, indicating that the alternative pathway was not the only complement pathway contributing to protection against disease. Both C3-and factor B-deficient mice had increased fungal burdens in comparison to wild-type mice. Histopathology revealed an overwhelming fungal burden in the lungs of these complementdeficient mice, which undoubtedly prevented efficient gas exchange, causing death. Following the fate of radiolabeled organisms showed that both factor B-and C3-deficient mice were less effective than wild-type mice in clearing organisms. However, opsonization of C. gattii with complement components was not sufficient to prolong life in mice deficient in complement. Killing of C. gattii by macrophages in vitro was decreased in the presence of serum from factor B-and C3-deficient versus wild-type mice. In conclusion, we have demonstrated that complement activation is crucial for survival in C. gattii infection. Additionally, we have shown that the alternative pathway of complement activation is not the only complement pathway contributing to protection.

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Section: Discussionmentioning

confidence: 89%

Role of Complement in Protection againstCryptococcus gattiiInfection

Mershon¹,

Vasuthasawat²,

Lawson³

et al. 2009

Infect Immun

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“…CVF depletion of C3 makes guinea pigs (8) and DBA/1J, CeH/HeJ, and BALB/c mice more susceptible to cryptococcal infection than complement-sufficient animals (19). Ab that blocks CR3 shortens the life spans of CBA mice infected with C. neoformans (4).…”

Section: Discussionmentioning

confidence: 99%

“…Incubation of cryptococci with serum results in the rapid deposition of iC3b fragments on the polysaccharide capsule (24,25), and complement alone can facilitate the opsonization and phagocytosis of encapsulated C. neoformans in vitro (7). Complement-deficient animals are more susceptible to C. neoformans infection (4,8,19,44). Studies with cells expressing heterologous complement receptors indicate that complement receptor 1 (CR1), CR3, and CR4 are each capable of interacting with C. neoformans opsonized with C3 (32).…”

mentioning

confidence: 99%

Immunoglobulin G Monoclonal Antibodies toCryptococcus neoformansProtect Mice Deficient in Complement Component C3

Shapiro¹,

Beenhouwer²,

Feldmesser³

et al. 2002

Infect Immun

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Passive administration of monoclonal antibodies (MAbs) to the capsular polysaccharide of Cryptococcus neoformans can alter the course of infection in mice. In a murine model of cryptococcal infection, immunoglobulin G1 (IgG1), IgG2a, and IgG2b switch variants of the anti-capsular 3E5 MAb prolong the survival of lethally infected mice, whereas the 3E5 IgG3 MAb does not protect and in some cases enhances infection, shortening the life spans of infected mice. We examined the role of complement component C3 in Ab-mediated protection by determining the efficacy of the four mouse IgG subclasses against C. neoformans in mice genetically deficient in factor C3 as well as mice acutely depleted of C3. Similar to other complement-deficient animal models, C3؊/؊ mice and mice depleted of C3 by cobra venom factor were more susceptible to C. neoformans infection than control mice, providing further evidence that complement is important in the host defense against the fungus. In the absence of C3, all IgG isotypes prolonged the lives of mice infected with C. neoformans, indicating that protection by IgG does not require the complement pathways. Furthermore, we observed protection with IgG3 in the complement-deficient mice, suggesting that complement is involved in the lack of protection observed with IgG3 in other mouse models.

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“…1). The survival time of C. neoformans-infected guinea pigs and mice treated with cobra venom to deplete late complement components (C3 to C9) is shortened and the ability to clear C. neoformans from extraneural sites reduced (37). Mice deficient in C5 are more susceptible to intravenously injected C. neoformans and succumb three times quicker than C5-positive mice due to acute and fatal pneumonia (158,159).…”

Section: Innate Immune Response To Cryptococcusmentioning

confidence: 99%

Cryptococcal Interactions with the Host Immune System

2010

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Opportunistic pathogens have become of increasing medical importance over the last decade due to the AIDS pandemic. Not only is cryptococcosis the fourth-most-common fatal infectious disease in sub-Saharan Africa, but also Cryptococcus is an emerging pathogen of immunocompetent individuals. The interaction between Cryptococcus and the host's immune system is a major determinant for the outcome of disease. Despite initial infection in early childhood with Cryptococcus neoformans and frequent exposure to C. neoformans within the environment, immunocompetent individuals are generally able to contain the fungus or maintain the yeast in a latent state. However, immune deficiencies lead to disseminating infections that are uniformly fatal without rapid clinical intervention. This review will discuss the innate and adaptive immune responses to Cryptococcus and cryptococcal strategies to evade the host's defense mechanisms. It will also address the importance of these strategies in pathogenesis and the potential of immunotherapy in cryptococcosis treatment.

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The Role of Late Complement Components and the Alternate Complement Pathway in Experimental Cryptococcosis

Cited by 60 publications

References 0 publications

Role of Complement in Protection againstCryptococcus gattiiInfection

Role of Complement in Protection againstCryptococcus gattiiInfection

Immunoglobulin G Monoclonal Antibodies toCryptococcus neoformansProtect Mice Deficient in Complement Component C3

Cryptococcal Interactions with the Host Immune System

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