Fungal antioxidant pathways promote survival against neutrophils during infection

Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 06/2012; 122(7):2482-98. DOI: 10.1172/JCI63239
Source: PubMed


Filamentous fungi are a common cause of blindness and visual impairment worldwide. Using both murine model systems and in vitro human neutrophils, we found that NADPH oxidase produced by neutrophils was essential to control the growth of Aspergillus and Fusarium fungi in the cornea. We demonstrated that neutrophil oxidant production and antifungal activity are dependent on CD18, but not on the β-glucan receptor dectin-1. We used mutant A. fumigatus strains to show that the reactive oxygen species-sensing transcription factor Yap1, superoxide dismutases, and the Yap1-regulated thioredoxin antioxidant pathway are each required for protection against neutrophil-mediated oxidation of hyphae as well as optimal survival of fungal hyphae in vivo. We also demonstrated that thioredoxin inhibition using the anticancer drug PX-12 increased the sensitivity of fungal hyphae to both H2O2- and neutrophil-mediated killing in vitro. Additionally, topical application of PX-12 significantly enhanced neutrophil-mediated fungal killing in infected mouse corneas. Cumulatively, our data reveal critical host oxidative and fungal anti-oxidative mediators that regulate hyphal survival during infection. Further, these findings also indicate that targeting fungal anti-oxidative defenses via PX-12 may represent an efficacious strategy for treating fungal infections.

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    • "For example, histones H2A, H2B, and H4, given the adhesive nature of histones, serve to physically sequester pathogens such as bacteria. Upon sequestration, microbial killing can be executed through antimicrobial proteins, such as MPO, which generate cytotoxic reactive oxygen species (ROS) (HOCl), or through nutritional immunity involving pathogen starvation of divalent cations mediated by S100 proteins (2, 8). S100A8 and S100A9 starve Candida albicans via creating local environments with low divalent ion concentrations, as divalent ion presence is required for Candida albicans growth. "
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    ABSTRACT: Significant advances in our understanding of neutrophil biology were made in the past several years. The exciting discovery that neutrophils deploy neutrophil extracellular traps (NETs) to catch pathogens paved the way for a series of additional studies to define the molecular mechanisms of NET generation and the biological significance of NETosis in acute and chronic pathologic conditions. This review highlights the latest knowledge regarding NET structures, deployment, and function, with an emphasis on current understanding of NET proteomes, their conservation, and significance in the context of cystic fibrosis (CF), a condition characterized by excessive extracellular DNA/NET presence. We also discuss how our understanding of NETosis yields novel therapeutic approaches and their applicability to CF.
    Frontiers in Immunology 08/2014; 5:378. DOI:10.3389/fimmu.2014.00378
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    • "For example, in fungi, following activation by H 2 O 2 -induced oxidation of specific cysteines, AP-1-like transcription factors promote expression of ROS defense and repair enzymes (reviewed in Veal et al., 2007). In pathogenic fungi, this is a vital response to ROS generated by host immune cells (Guo et al., 2011; Leal et al., 2012). As well as the activation of ROS defenses, H 2 O 2 signals also regulate fundamental processes, including cell division, differentiation, migration, and death. "
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    ABSTRACT: H2O2 can cause oxidative damage associated with age-related diseases such as diabetes and cancer but is also used to initiate diverse responses, including increased antioxidant gene expression. Despite significant interest, H2O2-signaling mechanisms remain poorly understood. Here, we present a mechanism for the propagation of an H2O2 signal that is vital for the adaptation of the model yeast, Schizosaccharomyces pombe, to oxidative stress. Peroxiredoxins are abundant peroxidases with conserved antiaging and anticancer activities. Remarkably, we find that the only essential function for the thioredoxin peroxidase activity of the Prx Tpx1(hPrx1/2) in resistance to H2O2 is to inhibit a conserved thioredoxin family protein Txl1(hTxnl1/TRP32). Thioredoxins regulate many enzymes and signaling proteins. Thus, our discovery that a Prx amplifies an H2O2 signal by driving the oxidation of a thioredoxin-like protein has important implications, both for Prx function in oxidative stress resistance and for responses to H2O2.
    Cell Reports 11/2013; 5(5). DOI:10.1016/j.celrep.2013.10.036 · 8.36 Impact Factor
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    • "Defense against mold infections is closely linked to innate immunity mediated by neutrophils and macrophages. Neutrophils are the most critical element in fighting Fusarium infections because they are able to destroy fungal hyphae by producing NADPH oxidase; macrophages block germination of conidia [7]. Allogeneic HLA-mismatched Hematologic Stem Cell Transplant (HSCT) recipients have a high incidence of fatal Fusarium infection due to T-cell deficiency associated with graft-versus-host-disease and high dose corticosteroid therapy [6, 8, 9]. "
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    ABSTRACT: Systemic mycotic infections have been increasing in incidence in immunocompromised patients. Although yeasts are most often isolated, opportunistic fungal infections may also be caused by filamentous fungi, including Aspergillus and Fusarium. Like Aspergillus, Fusarium is angioinvasive with an ability to disseminate widely. Disseminated fusariosis is most commonly linked to prolonged neutropenia. Disseminated infections due to Fusarium are rare in Human Immunodeficiency Virus (HIV) positive patients but have been reported in HIV positive patients with neutropenia and lymphoma. We describe an HIV positive patient without neutropenia, skin lesions, or concomitant malignancy, who developed fatal disseminated infection with possible endocarditis due to Fusarium solani. Early identification of Fusarium is important because of its high level of resistance to several antifungal drugs, with response often requiring combination therapy.
    05/2013; 2013:379320. DOI:10.1155/2013/379320
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