Murine immune responses to strains of Candida albicans

Hu, Yan. (2005). Murine immune responses to strains of Candida albicans PhD Thesis, School of Dentistry, The University of Queensland.

       
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Author Hu, Yan.
Thesis Title Murine immune responses to strains of Candida albicans
School, Centre or Institute School of Dentistry
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor A/Prof Robert Ashman
A/Prof Neil Savage
Camile S. Farah
Total pages 203
Language eng
Subjects 320800 Dentistry
L
110502 Dental Therapeutics, Pharmacology and Toxicology
Formatted abstract

Candida albicans is a commensal organism in humans, and an important opportunistic fungal pathogen. It can cause either mucocutaneous or systemic infections, both of which are increasing in prevalence, so that C. albicans is now the fourth leading cause of nosocomial bloodstream infections. Candidiasis usually occurs in patients whose immune defenses have been compromised, but the host response in normal individuals is not well understood.                  

 

Innate immunity is recognized as the first line of defense against Candida infection, but cell-mediated immunity is essential for recovery from mucosal infection, and may play a role in the systemic disease. The position of humoral immunity is uncertain, though it may have a protective role against systemic infection. However, little is known of the effect of strain variation in C. albicans on susceptibility to C albicans infection in different strains of inbred mice, or of the effects of different virulence phenotypes on the host response. Therefore, this study focused on an analysis of the following: (1) The effect of infection with different strains of C. albicans on the severity of oral and systemic candidiasis in resistant and susceptible strains of inbred mice; (2) A comparison of phagocytosis and killing of different strains of yeasts by neutrophils and macrophages from these mice; (3) The ability of antibody to protect against infection, and the spectrum of antigenic determinants to which they respond; (4) The role of T-helper cytokines in candidiasis.                    

 

Mouse models of systemic and oral candidiasis were established for assessment of the virulence of different strains of yeasts and susceptibility to infection of inbred mice and cytokine-specific gene knockout mice. Neutrophils and macrophages from bone marrow cultures were used for an analysis of phagocytosis and killing of yeasts, and the effects of opsonisation with normal and immune serum were determined. Western blotting was used for the detection of antibody specificity and isotype.                   

 

Of the three strains of C. albicans tested, SC5314 was most virulent in systemic infection, producing a high fungal burden in the kidney, though it was much less efficient in infecting the brain or oral mucosa. Strains 3630 and 3683 established consistent systemic and oral infections, with the latter, an oral isolate, being more virulent in oral infection. In the absence of opsonisation, killing by neutrophils from mice of both strains was poor, but normal or immune serum dramatically increased killing by BALB/c, but not by CBA/CaH cells. Macrophages from BALB/c mice killed unopsonised yeasts more efficiently than did neutrophils, whereas those from CBA/CaH mice were much less effective, except against 3683, which was killed threefold more efficiently than the other two strains. Opsonisation had no effect on the killing of 3683 by either mouse strain, but increased killing of both 3630 and SC5314, to a greater extent in CBA/CaH than in BALB/c mice. TNF-α, IFN- ƴ and GM-CSF enhanced the ability of macrophages from CBA/CaH mice to kill yeasts, but had little effect on BALB/c macrophages.                

 

CBA/CaH mice demonstrated a stronger humoral response to Candida infection, and displayed recognition of a larger range of antigens of C. albicans by both IgGl and IgG2a, than did BALB/c mice, which produced only IgGl Antigenic profiles tended to be specific for each yeast strain, and this was consistent with a lack of cross-protection after infection in vivo. An assessment in knockout mice of the functional relevance of various cytokines found that susceptibility to infection was affected neither by IFN- ƴ, IL-4, nor EL-10. In contrast, IL-12 knockout mice developed a chronic infection, and macrophages from these mice did not kill yeasts as efficiently as those from control mice.             

 

The results confirm the importance of innate immunity in recovery from primary infection with C. albicans, but demonstrate significant differences in the ways in which phagocytic cells interact with yeasts of different strains. The role of antibodies is highly complex, with a marked degree of yeast strain-specificity. Finally, the effect of cytokines may depend on the genetic context in which the infection occurs. 

Keyword Candida albicans
Candidiasis
Cytokines
Natural immunity

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
 
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Created: Fri, 24 Feb 2012, 15:29:09 EST by Talha Alam on behalf of The University of Queensland Library