title: Immunomodulation by Candida albicans: crucial role of organ colonization and chronic infection with an attenuated agerminative strain of C. albicans for establishment of anti-infectious protection.
abstract: Intravenous inoculation of an attenuated agerminative strain of Candida albicans (PCA-2) of low virulence, but not of two other species of Candida of low virulence (C. parapsilosis and C. viswanathii) into CD2F1 mice conferred protection against the highly virulent microbes C. albicans CA-6, Staphylococcus aureus and Aspergillus fumigatus. To provide protection, a definite inoculum size (10(6) cells per mouse) resulting in organ colonization and establishment of a long-lasting chronic infection with PCA-2 was needed. An inoculum of 10(5) cells gave rise to transient kidney colonization whereas inocula greater than 10(6) cells led to acute septicaemia and eventual death. Chronic infection of mice following inoculation of 10(6) PCA-2 cells was accompanied by detectable mannoprotein antigen levels in the serum (30-70 ng ml-1) while specific antibodies did not appear until 14 d after inoculation, at which time low antimannan antibody was present (ELISA titre 1:40-1:80). Chronic infection was characterized by the presence in the kidneys of 2-3 x 10(6) c.f.u. of PCA-2 for at least 40 d after inoculation. Pharmacological modulation of the host through administration of either an anti-Candida drug, amphotericin B, or an immunosuppressive agent, cyclophosphamide, strongly supported the premise that the anti-infectious state conferred by PCA-2 'immunization' correlated with the maintenance of a sufficient number of PCA-2 in vivo. Protection was 'switched on' when 2-3 x 10(5) cells were present in the kidneys. It was maximal at a kidney count of 2-3 x 10(6) c.f.u. of PCA-2, and promptly declined when the number of PCA-2 cells in the kidney fell below 2 x 10(5). Mice chronically infected with PCA-2 had splenic macrophages with pronounced candidacidal activity in vitro. Modulation of the growth of PCA-2 in vivo, which determined activation or deactivation of the protective state, was paralleled by a similar modulation in macrophage activation, showing that in all cases resistance to virulent organisms persisted as long as macrophage activation was present. The results demonstrate that a critical in vivo antigenic load is crucial for the occurrence of resistance to infection and suggests that macrophages could be involved in this protection.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vecchiarelli
authors.forename: R
authors.initials: R
authors.lastname: Mazzolla
authors.forename: S
authors.initials: S
authors.lastname: Farinelli
authors.forename: A
authors.initials: A
authors.lastname: Cassone
authors.forename: F
authors.initials: F
authors.lastname: Bistoni
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000666:Amphotericin B / Q000008:administration & dosage; D000818:Animals; D001228:Aspergillosis / Q000517:prevention & control*; D001232:Aspergillus fumigatus; D002176:Candida albicans / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D002177:Candidiasis / Q000276:immunology / Q000517:prevention & control*; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000382:microbiology; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D013154:Spleen / Q000276:immunology; D013203:Staphylococcal Infections / Q000517:prevention & control*; D014774:Virulence
chemical_list: D000276:Adjuvants, Immunologic; D000666:Amphotericin B; D003520:Cyclophosphamide