The potential impact of antifungal drug resistance mechanisms on the host immune response to Candida

Figures & data

Figure 1. Pathogenesis and host immune response to invasive candidiasis. This figure was recreated in a different format from the review by Gow et al.⁸

Table 1. Acquired Candida resistance mechanisms and potential impact on host pathogen interaction

Resistance mechanism	Drugs affected	Genotypic or phenotypic changes associated with resistance that may alter host immune response
Alterations in the ergosterol biosynthetic pathway (i.e., loss of function in ERG3)	Triazoles Amphotericin B	Impaired yeast to hyphal transition; impaired biofilm formation Alterations in membrane cell wall protein localization and function
Alterations in drug target binding (i.e., ERG11 mutation)	Triazoles	Changes in cell wall mannoproteins, decreased β-1,2-linked mannose residues and side chain structure
Mitochondrial dysfunction	Triazoles	Enhanced cell wall remodeling, increased biofilm formation
Drug efflux (i.e., CDR1 and CDR2), MDR1	Triazoles	Possible decreased lysozomal acidification inside macrophages, increased biofilm formation?
Alterations in glucan synthases (i.e., FKS1 and FKS2 mutations)	Echinocandins	Impaired yeast to hyphal transition, increased cell wall remodeling; increased cell wall chitin, alterations in biofilm matrix

Figure 2. Illustrative hypothetical scenarios for the risk of breakthrough infection with resistant Candida species. In (A), expression of a new resistance mechanisms in the presence of antifungal therapy does not alter host immune detection/elimination, but diminishes pathogen fitness. Therefore, the probability of breakthrough infection is low at the current clinical status of the host. In (B), the expression of the resistance mechanism is not associated with a significant fitness cost but does impact immune evasion strategies, therefore the emergence of the resistant subpopulation in held in check by the immune response. In (C), expression of the resistance mechanism is not associated with significant costs in terms of pathogen fitness or host immune evasion, therefore the resistant subpopulation “emerges” in the presence of antifungal therapy. In (D), the isolate does not express resistance mechanisms in the presence of drug, but the high virulence and strong induction of immune responses lead to sepsis (SIRS). The concept for this figure was derived from review by James Anderson.⁸⁰

Gow NA, van de Veerdonk FL, Brown AJ, Netea MG. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 2012; 10:112 - 22; http://dx.doi.org/10.1038/nrmicro2711; PMID: 22158429

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Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol 2005; 3:547 - 56; http://dx.doi.org/10.1038/nrmicro1179; PMID: 15953931

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