title: Characterisation of Candida albicans infections of haematogenous and mucosal origin in mice lacking the interferon gamma receptor protein.
abstract: Mice harbouring a null deletion mutation in the IFNgamma receptor gene were used to study the role of IFNgamma responsiveness during experimental systemic candidiasis of mucosal or haematogenous origin. After intravenous (i.v.) or intranasal (i.n.) challenge with Candida albicans the progression of infection and concomitant cellular and antibody anti-C. albicans immune responses were analysed. During the week following i.v. challenge, the rate of C. albicans multiplication in kidneys, liver and spleen was faster in IFNgammaR (-/-) than IFNgammaR (+/+) mice. As a result, IFNgammaR (-/-) mice perished earlier than IFNgammaR (+/+) mice when challenged with equal numbers of live yeast cells. However, the overall susceptibility of the two mouse strains, in terms of survival against different C. albicans challenge doses over a 60-day period, was similar. No differences were found in the cellular anti-C. albicans response generated by i.v. challenge in both mouse strains. In contrast the kinetics and strength of the serum anti-C. albicans antibody responses were markedly different. Significantly stronger, predominantly IgG2a antibody responses accompanied the eventual control of C. albicans infection in IFNgammaR (-/-) mice. Following intranasal challenge, there was no difference in the rate of C. albicans clearance from the lungs of IFNgammaR (-/-) and IFNgammaR (+/+) mice. However, 48 h after challenge, large, conspicuous abscesses appeared in the lungs, liver, kidneys and spleen of IFNgammaR (-/-) mice. These abscesses were characterised by the presence of C. albicans and abundant neutrophilic infiltrates, but very few macrophages. No such abscesses developed in i.n. challenged IFNgammaR (+/+) mice. In both mouse strains, i.n. challenge induced strong systemic anti-C. albicans cellular responses, but relatively low titre systemic antibody responses. Mucosal anti-C. albicans antibody responses were detected in IFNgammaR (+/+), but not IFNgammaR (-/-) mice. Splenic adherent macrophages obtained from IFNgammaR (-/-) mice exhibited a significantly lower candidacidal activity than those of IFNgammaR (+/+) mice, and as expected, were not responsive to IFNgamma. In summary, these data suggest that IFNgamma has a role in limiting C. albicans multiplication during the early stages of infection, as well as in preventing the development of C. albicans-associated abscesses. Activation of macrophages by IFNgamma might be pivotal in mediating this role.
authors.affiliation: Biochemistry Department, Imperial College of Science, Technology and Medicine, Exhibition Road, London, UK.
authors.forename: L P
authors.initials: LP
authors.lastname: Londono
authors.forename: H B
authors.initials: HB
authors.lastname: Jones
authors.forename: A T
authors.initials: AT
authors.lastname: Vie
authors.forename: W L
authors.initials: WL
authors.lastname: McPheat
authors.forename: G
authors.initials: G
authors.lastname: Booth
authors.forename: X M
authors.initials: XM
authors.lastname: Gao
authors.forename: G
authors.initials: G
authors.lastname: Dougan
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000097:blood; D002176:Candida albicans / Q000254:growth & development / Q000276:immunology* / Q000302:isolation & purification; D002177:Candidiasis / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D018928:Immunity, Mucosal; D007071:Immunoglobulin A, Secretory / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000382:microbiology; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D000908:Antibodies, Fungal; D016207:Cytokines; D007071:Immunoglobulin A, Secretory; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor