Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins

Kozel, Thomas R.; Wilson, Michael A.; Pfrommer, G. S. T.; Schlageter, Annette

doi:10.1128/iai.57.7.1922-1927.1989

Cited by 64 publications

(37 citation statements)

References 20 publications

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“…Incubation of encapsulated cryptococci in normal human serum leads to activation of the alternative complement system and deposition of potentially opsonic fragments of C3 at the capsular surface and in the capsule interior (Kozel et al ., 1988; 1989). In an effort to assess the extent to which C3 penetrates to the capsule interior, encapsulated cryptococci were incubated for 30 min in 40% NHS, washed with PBS, and the sites of C3 binding were determined by immunofluorescence using fluorescein isothiocyanate (FITC)‐labelled Fab fragments of polyclonal C3 antibody.…”

Section: Resultsmentioning

confidence: 77%

Molecular architecture of the Cryptococcus neoformans capsule

Gates¹,

Thorkildson²,

Kozel³

2004

Molecular Microbiology

115

136

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SummaryMany microbes are surrounded by phagocytosisinhibiting capsules. We took advantage of the large size of the polysaccharide capsule of the pathogenic yeast Cryptococcus neoformans to examine capsular architecture and the relationship between molecular architecture and the interaction of the capsule with potentially opsonic serum proteins. Our experimental design used complementary approaches in which (i) assessment of permeability to macromolecules of different Stokes radii; (ii) determination of the binding of Fab fragments of anticapsular antibodies as a measure of matrix density; (iii) capsular deconstruction by treatment with dimethyl sulphoxide; and (iv) evaluation of capsule plasticity, were used to probe the molecular structure of the capsule. The results showed that the capsule is a matrix with a variable porosity that increases with distance from the cell wall. A high density of the matrix at the capsule interior prevents penetration of large macromolecules to sites near the cell wall. In contrast, the capsular edge that is the interface with phagocytes presents capsular polysaccharide in a very low density that exhibits considerable plasticity and permeability to macromolecules. Notably, the capsule of yeast cells harvested from infected tissue showed a greater matrix density than yeast cells grown in vitro under capsule induction conditions.

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Section: Resultsmentioning

confidence: 77%

Molecular architecture of the Cryptococcus neoformans capsule

Gates¹,

Thorkildson²,

Kozel³

2004

Molecular Microbiology

115

136

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“…Encapsulated and acapsular strains of C. neoformans are powerful activators of the complement system via the alternative and classical pathways, respectively (20,21,40). Incorporation of anti-C3a and anti-C5 into the incubation medium was used to assess the contribution of C3a and C5a to IL-8 induction by PMN exposed to encapsulated or acapsular strains of C. neoformans.…”

Section: Resultsmentioning

confidence: 99%

Involvement of C3a and C5a in Interleukin-8 Secretion by Human Polymorphonuclear Cells in Response to Capsular Material ofCryptococcus neoformans

et al. 1998

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In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflammatory cytokines in response to Cryptococcus neoformans or its major capsular component, glucuronoxylomannan (GXM). The hypothesis that activation of the complement system could be responsible for the observed phenomenon is supported by the fact that encapsulated and acapsular C. neoformans isolates are activators of the complement system and, in particular, large encapsulated isolates are powerful activators. In the present study we demonstrate that (i) interleukin-8 (IL-8) release in response to acapsular or encapsulated strains of C. neoformans is significantly reduced in the presence of heatinactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) GXMinduced IL-8 release is strictly dependent on the presence of NHS, is inhibited by specific antibodies to either C3a and C5 complement components, and is completely abrogated by the combined use of these antibodies; (iii) the addition of purified C3a and C5a directly stimulates IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combination with GXM or encapsulated C. neoformans potentiates IL-8 release by PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for complement in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytokine regulation.

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“…Evidence for an absence of classical pathway initiation comes from two lines of study. First, incubation of encapsulated cells in an alternative pathway reconstituted from purified factors B, D, H, I, and C3 and properdin leads to activation and binding of C3 fragments to the capsule in a manner that is qualitatively and quantitatively indistinguishable from the pattern of activation and binding that occurs with normal serum (59). Second, the kinetics for activa-tion and binding of C3 to encapsulated C. neoformans is characterized by a lag of 4 to 6 min before readily detectable amounts of C3 accumulate on the yeast cells ( Fig.…”

Section: Initiation and Regulation Of The Complement Cascade By Encapmentioning

confidence: 99%

Activation of the complement system by pathogenic fungi

Kozel

1996

Clin Microbiol Rev

Self Cite

122

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Fungi have been studied as prototype activators of the complement cascade since the early 1900s. More recently, attention has focused on the role of the complement system in the pathogenesis of fungal infections. The interactions of Cryptococcus neoformans and Candida albicans with the complement system are the most widely characterized; however, all pathogenic fungi examined to date have the ability to initiate the complement cascade. The molecular mechanisms for initiation and regulation of the complement cascade differ from one fungus to another, most likely reflecting differences in the structure of the outer layers of the cell wall. The molecular bases for such differences remain to be identified. Studies of mycoses in experimental animals with induced or congenital deficiencies in the complement system demonstrate that complement is an important innate system for control of fungal infection. Contributions to host resistance include opsonization and generation of inflammatory mediators. Inflammation induced by chemotactic products of the complement system may contribute to the pathogenesis of some fungal infections.

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Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins

Cited by 64 publications

References 20 publications

Molecular architecture of the Cryptococcus neoformans capsule

Molecular architecture of the Cryptococcus neoformans capsule

Involvement of C3a and C5a in Interleukin-8 Secretion by Human Polymorphonuclear Cells in Response to Capsular Material ofCryptococcus neoformans

Activation of the complement system by pathogenic fungi

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