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Review
. 2016 Sep 19;84(10):2724-39.
doi: 10.1128/IAI.00469-16. Print 2016 Oct.

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

Mary Ann Jabra-Rizk  1 , Eric F Kong  2 , Christina Tsui  3 , M Hong Nguyen  4 , Cornelius J Clancy  5 , Paul L Fidel Jr  6 , Mairi Noverr  6
Affiliations
Review

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

Mary Ann Jabra-Rizk et al. Infect Immun. .

Abstract

Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of Candida albicans, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably, C. albicans infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses.

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Figures

FIG 1
FIG 1
Anatomical defenses and host damage associated with the various manifestations of candidiasis. The illustration shows the diverse and site-specific diseases caused by C. albicans, highlighting the disease pathogenesis in each case and site-specific host immune responses.
FIG 2
FIG 2
Damage response framework curves. Individual graphs are included for each class, with an associated Candida infection. (A) Class 1, pathogens that cause damage only in situations of weak immune responses (e.g., oral candidiasis). (B) Class 2, pathogens that cause damage either in hosts with weak immune responses or in the setting of normal immune responses (e.g., invasive candidiasis). (C) Class 3, pathogens that cause damage in the setting of appropriate immune responses and produce damage at both ends of the continuum of immune responses (e.g., intra-abdominal candidiasis). (D) Class 4, pathogens that cause damage primarily at the extremes of both weak and strong immune responses (e.g., gastrointestinal candidiasis). (E) Class 5, pathogens that cause damage across the spectrum of immune responses, but damage can be enhanced by strong immune responses (e.g., denture stomatitis). (F) Class 6, microorganisms that can cause damage only under conditions of strong immune responses (e.g., vaginal candidiasis). (Adapted from reference with permission.)
FIG 3
FIG 3
Clinical manifestations of oral candidiasis. (A) Pseudomembranous candidiasis is characterized by white plaques formed on the tongue and the buccal mucosa. (B) Erythematous candidiasis example, showing the subtle red lesions on the tongue, which can also occur on the palate.
FIG 4
FIG 4
Mouse model of oral candidiasis. (A) An infected mouse exhibiting clinical signs of advanced candidiasis on the surface of the tongue 4 days post-sublingual infection with C. albicans. (B) Histopathology of an infected tongue tissue section, demonstrating the extensive presence of C. albicans around the periphery of the tongue. Hyphae can be seen penetrating the subepithelial tissue, along with a marked presence of host inflammatory cells. (C) Magnified image of tongue tissue, revealing the depth of hyphal invasion into the subepithelium (arrows). Bar, 20 μm. (D) Scanning electron micrograph of excised tongue showing the thick biofilm formed on the outer epithelial surface consisting of C. albicans hyphae invading the subepithelium. (E) Higher-magnification image of the outer surface of the tongue showing the epithelium spiny layer with hyphae penetrating through the surface. (F) Significant gap in the tissue caused by hyphae invading from the sublingual area as it emerges through the tongue surface. (Reprinted from reference .)
FIG 5
FIG 5
Clinical manifestations of denture stomatitis. (A) Red inflammatory lesions formed on the denture-associated palatal tissue in a patient with a partial denture. (B) Inflammation of the gingival tissue in a patient with a full denture.
FIG 6
FIG 6
Rat model of Candida-associated denture stomatitis. Individual impressions were made for each rat, using vinyl polysiloxane impression material. Molds were made from the impressions, which were then used to construct the fixed and removable portions of the denture system. (B) Scanning electron and confocal fluorescence microscopy analysis images of a C. albicans biofilm formed in vivo on the denture and palate of rats 4 and 8 weeks postinfection with C. albicans. (Reprinted from reference .)
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