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Review
. 2020 Mar 11;6(1):35.
doi: 10.3390/jof6010035.

Applying the Host-Microbe Damage Response Framework to Candida Pathogenesis: Current and Prospective Strategies to Reduce Damage

Paul L Fidel Jr  1 , Junko Yano  1 , Shannon K Esher  2 , Mairi C Noverr  2
Affiliations
Review

Applying the Host-Microbe Damage Response Framework to Candida Pathogenesis: Current and Prospective Strategies to Reduce Damage

Paul L Fidel Jr et al. J Fungi (Basel). .

Abstract

Disease is a complex outcome that can occur as a result of pathogen-mediated damage, host-mediated damage or both. This has led to the revolutionary concept of the damage response framework (DRF) that defines microbial virulence as a function of host immunity. The DRF outlines six scenarios (classes) of host damage or beneficial outcomes, depending on the microbe and the strength of the immune response. Candida albicans is uniquely adapted to its human host and can exist as either a commensal, colonizing various anatomical sites without causing notable damage, or as a pathogen, with the ability to cause a diverse array of diseases, ranging from mucosal to invasive systemic infections that result in varying levels of microbe-mediated and/or host-mediated damage. We recently categorized six different forms of candidiasis (oropharyngeal, hematogenous, intra-abdominal, gastrointestinal, denture stomatitis, and vulvovaginitis) into independent DRF classes, supporting a contemporary view of unique mechanisms of pathogenesis for these Candida infections. In this review, we summarize the evidence for the pathogenesis of these various forms of candidiasis in the context of the DRF with the further intent to provide insights into strategies to achieve a level of host response or outcome otherwise, that limits host damage.

Keywords: Candida albicans; damage response; host; immune response; pathogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Damage-response framework curves for each class and associated Candida infections. (a) Class 1: ‘Opportunists’, or pathogens that cause damage only in the setting of weak host responses; represented by oropharyngeal candidiasis. (b) Class 2: ‘Equal Opportunists’, or pathogens that cause damage in hosts with weakened immune responses or in the setting or normal responses; represented by invasive candidiasis of hematogenous origin. (c) Class 3: ‘Bipolar Pathogens’, or pathogens that cause damage under appropriate immune responses, which is amplified at both ends of the immune spectrum; represented by invasive candidiasis of intra-abdominal origin. (d) Class 4: ‘Immunoreactive Opportunists’, or pathogens that cause damage primarily in the extremes of weak and strong host responses; represented by gastro-intestinal candidiasis. (e) Class 5: ‘Immunoreactive Pathogens’, or pathogens that cause damage across the spectrum of immune responses, with enhanced damage under strong host responses; represented by denture stomatitis. (f) Class 6: ‘Immunoreactive Commensals’, or pathogens that cause damage only under strong host responses; represented by vulvovaginal candidiasis.
Figure 2
Figure 2
Class 1—Strategies to reduce damage. C. albicans as an ‘Opportunist’ during oropharyngeal candidiasis, with damage under weak responses and minimal to no damage under strong responses (black curve). Under conditions of weak immune responses, antifungal drugs (green arrow) reduce the fungal load, thereby reducing the associated host damage and disease-related symptoms. Boosting secondary host defense responses (pink arrow) reduces damage by bringing the host response to a near normal level. Therapeutic vaccines (orange arrow) would reduce damage by boosting the host response towards normal protective responses.
Figure 3
Figure 3
Class 2—Strategies to reduce damage. C. albicans as an ‘Equal Opportunist’ during invasive candidiasis of hematogenous origin, with damage under weak responses and moderate damage remaining under strong responses (black curve). Antifungals (green arrow), or rapid diagnostics leading to more timely antifungal administration, reduce the fungal load, thereby reducing host damage together with symptoms of disease. Of note, some antifungals (i.e., amphotericin B) can also have immunomodulatory properties, which would result in a shift toward a greater host response in some cases. Trained innate immune (TII) strategies (yellow arrow) would boost the innate host response, resulting in reduced fungal load and a reduction in the associated host damage to moderate levels similar to that seen with normal host responses.
Figure 4
Figure 4
Class 3—Strategies to reduce damage. C. albicans as a ‘Bipolar Pathogen’ during invasive candidiasis of intra-abdominal origin, with damage under strong (hyper) and weak (hypo) responses and moderate damage under moderate responses (black curve). Antifungals (green arrows) reduce fungal load, thereby reducing both fungal-associated host damage under conditions of low host responses and host damage caused by hyperimmune reactivity toward the organism. Trained innate immunity (TII) (yellow arrow) would boost hypoimmune responses into the normal host response level, while trained tolerogenic immunity (TTI) (dashed yellow arrow) would suppress hyperimmune responses back to the normal level concomitant with minimal host damage.
Figure 5
Figure 5
Class 4—Strategies to reduce damage. C. albicans as an ‘Immunoreactive Opportunist’ in gastro-intestinal candidiasis, with mucosal damage occurring under weak (hypo) or strong (hyper) host responses and minimal damage under moderate responses (black curve). Antifungals and/or probiotics (green arrows) reduce fungal loads and promote healthy levels of GI colonization, thereby reducing host damage associated with Candida overgrowth or hyperimmune activation. Immune stimulatory mediators would boost hypoimmune responses (white arrow), while anti-inflammatory mediators (blue arrow) would suppress hyperimmune responses, both resulting in a return to the homeostatic host response level and minimal host damage.
Figure 6
Figure 6
Class 5—Strategies to reduce damage. C. albicans as an ‘Immunoreactive Pathogen’ in denture stomatitis, with mucosal damage occurring across a spectrum of host responses (black curve). Removal of biofilms from dentures and clearance of palatal colonization reduce immune responses, thereby diminishing host damage. Strategies include antifungal therapies via denture-optimized delivery systems and the use of anti-biofilm agents that inhibit fungal adherence to denture materials (green arrow), all of which would minimize both host and biofilm-mediated damage.
Figure 7
Figure 7
Class 6—Strategies to reduce damage. C. albicans as an ‘Immunoreactive Commensal’ in vulvovaginal candidiasis, with damage occurring from a hyper/aggressive inflammatory response by PMNs versus commensalism, characterized by a weak host response with little to no damage (black curve). Antifungal therapies temporarily eliminate C. albicans burden, thereby diminishing immune responses and related damage to an asymptomatic state (green arrow). Alternatively, anti-inflammatory therapies reduce damage by modulating the PMN response, while C. albicans colonization remains, albeit rather asymptomatically (blue arrow). Conversely, strategies to _target heparan sulfate to enhance PMN antifungal activity during an immunoreactive state will promote C. albicans clearance, followed by timely resolution of inflammation-associated damage (purple arrow). Finally, a vaccine strategy would reduce damage by either eliminating/reducing C. albicans, or possibly through immunomodulation (orange arrow).
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