Research Article: Candida and Host Determinants of Susceptibility to Invasive Candidiasis

Date Published: January 3, 2013

Publisher: Public Library of Science

Author(s): Michail S. Lionakis, Mihai G. Netea, Joseph Heitman.


Partial Text

Candida is the most common human fungal pathogen and the cause of invasive candidiasis, the fourth leading cause of nosocomial bloodstream infection in the United States with an estimated annual cost of ∼US$2 billion and mortality that exceeds 40% despite administration of antifungal therapy in modern intensive care unit facilities [1]. Hence, invasive candidiasis is an unmet medical condition for which better understanding of its pathogenesis at the host–pathogen interface is essential to improve patient outcomes. To that end, a mouse model of the infection, which introduces Candida yeast cells intravenously and mimics skin-derived bloodstream human candidiasis, has been successfully employed to study fungal and host factors that regulate susceptibility to the infection [2].

Candida expresses a variety of virulence factors that contribute to its pathogenesis and could be exploited for development of vaccines and targeted therapeutic strategies. Firstly, Candida albicans filaments’ virulence factors, including secreted aspartyl proteases and phospholipases, are thought to be important for Candida invasion in infected organs and, probably, for mediating fungus-induced tissue immunopathology [3]. Secondly, Candida is able to efficiently adhere to and invade epithelial and endothelial cells via induced endocytosis and active penetration; both adhesion and invasion facilitate Candida dissemination [4]. Effective adhesion also enables Candida to form biofilms on implanted medical devices such as central venous catheters, which are a frequent portal of entry for invasive infection in humans [5]. Among the known Candida factors that promote its adhesion and invasion, the agglutinin-like sequence (Als) family has attracted significant attention; Als3 in particular, a C. albicans–specific virulence factor, was recently shown to mediate brain-specific Candida endothelial invasion and tissue penetration [6]. Specifically, increased surface expression of Als3 in the vps51Δ/Δ C. albicans mutant was shown to be responsible for its increased ability to invade brain endothelial cells in vitro and traffic to the brain in vivo via binding to the gp96 heat shock protein, which is expressed specifically on brain endothelium [6]. Als3 has formed the basis for the development of a cell wall protein-based vaccine strategy against candidiasis, which was recently tested safely in humans in a Phase I clinical trial [7]. Studies in mice revealed that IFN-γ and IL-17α produced by Th1 and Th17 lymphocytes were essential for vaccine-induced protection, via Ccl3- and Cxcl1-mediated neutrophil recruitment to sites of infection, which resulted in decreased Candida tissue burden [8].

The first step in mounting an effective anti-Candida immune response is fungal recognition by the innate immune system. Over the past decade there has been an explosion in our understanding of how soluble and membrane-bound pattern recognition receptors (PRRs) recognize various pathogen-associated molecular patterns (PAMPs) of Candida yeast and filamentous forms (Text S1) (reviewed in [11], [12]). In brief, the complement components C3 and C5, the complement receptor 3 (CR3), the Toll-like receptors (TLR)-2 (in interaction with TLR1 and TLR6), TLR4, TLR7, and TLR9, and the C-type lectins (CLRs) dectin-1, dectin-2, mannose receptor, DC-SIGN, and Mincle are among the PRRs shown to recognize different fungal PAMPs including mannan, β-glucan, RNA, and DNA (Figure 1); several of these PRRs are indispensable for host defense in vivo by inducing the secretion of pro-inflammatory cytokines and chemokines and modulating innate and adaptive antifungal immune responses (Text S1) [11], [12]. In fact, synergistic interactions between different PRRs resulting in augmented downstream immune activation have been demonstrated, such as between TLRs and CLRs or C5a and TLRs [11], [12]. Candida also activates the inflammasome; both the Nlrp3/caspase-1 pathway and the non-canonical caspase-8 pathway have been implicated in IL-1β production via dectin-1/syk activation by β-glucans (Figure 1) [12], [13].

Neutrophils are indispensable for host defense against invasive candidiasis, and neutropenia is a well-recognized risk factor for development of and adverse outcome after infection in humans [1]. The protective effects of neutrophils are mediated via oxidative and non-oxidative mechanisms that result in efficient Candida killing [12]. Specifically, Candida ingestion is followed by assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex at the phagosomal membrane and oxidative burst, which leads to generation of candidacidal reactive oxygen species and K+-influx–induced activation of neutrophil candidacidal granular proteases [12]. Neutrophils are the only effector cells able to inhibit Candida yeast-to-hyphae conversion, a process dependent on the oxidative burst [12]. The oxidative burst is also important for generation of neutrophil extracellular traps, which ensnare Candida yeasts and hyphae and appear important for anti-Candida host defense in vivo [18].

Besides neutrophils, monocytes/macrophages are key phagocytic cells for protection against invasive candidiasis, as their depletion in mice leads to increased mortality [22]. Monocytes/macrophages are very effective in Candida phagocytosis and secretion of a variety of pro-inflammatory cytokines and chemokines that orchestrate the antifungal innate immune response [12]. Nevertheless, macrophages are significantly less able to inhibit yeast germination and kill Candida compared to neutrophils; the lack of macrophage myeloperoxidase and extracellular trap formation may, at least in part, account for this deficit [12]. On the other hand, the concomitant release of superoxide and nitric oxide, with the subsequent formation of peroxinitrite, has been suggested to mediate the macrophage anti-Candida effects in mice; yet, the importance of Candida-induced nitric oxide formation in human phagocytes is unclear [12]. Several studies have demonstrated the priming role of Th1 cytokines and the inhibitory role of Th2 cytokines on the macrophage killing capacity, but more research is required to elucidate the molecular mechanisms of macrophage activation and effector function in vivo at the sites of Candida infection. In addition, future studies should aim to shed light on the relative role of recruited versus resident monocytes/macrophages in host defense against invasive candidiasis.

In agreement with the requirement of innate immunity for effective host defense in the mouse model of invasive candidiasis, certain innate immune factors have been associated with protection against the infection in humans [26]. Consistent with the crucial role of the NADPH oxidase in phagocyte killing and the heightened susceptibility of NADPH oxidase-deficient mice to invasive candidiasis [8], [12], patients with chronic granulomatous disease are at increased risk for development of the infection [26]. In addition, in line with the enhanced susceptibility of myeloperoxidase-deficient mice to invasive candidiasis and the impaired anti-Candida killing capacity of human myeloperoxidase-deficient phagocytes, invasive candidiasis occurs in patients with myeloperoxidase deficiency, the most common inherited phagocytic disorder [26]. Yet, the majority of myeloperoxidase-deficient patients are asymptomatic, and invasive candidiasis develops only in patients with autosomal-recessive complete myeloperoxidase deficiency who also have concomitant disorders that adversely affect phagocyte function such as diabetes [26].

Candida is a commensal organism that colonizes 50% of individuals of a population at any given time, but in conditions leading to weakening of host defense mechanisms it can convert to an opportunistic pathogen causing localized mucosal disease or life-threatening invasive infections with high mortality rate despite antifungal therapy. In recent years we have witnessed a surge of studies of Candida pathogenesis at the host–pathogen interface. Dissecting the fungal virulence factors that foster the transition of Candida from a commensal to an opportunistic pathogen, and deepening our understanding of the molecular and cellular basis of effective antifungal immunity should lead to novel risk stratification, prognostication, vaccination, and therapeutic strategies in patients.




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