Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

f Candida tropicalis, a species closely related to Candida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. Like C. albicans and Candida dubliniensis, C. tropicalis is able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear in C. tropicalis. Recently, echinocandinand azole-resistant C. tropicalis isolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of the C. tropicalis genes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis in C. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions in C. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance in C. tropicalis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Human fungal infections have significantly increased in recent years due to the emergence of immunocompromised patients with AIDS and cancer. Among them, Candida species are frequently isolated and associated with high mortality if not appropriately treated. Current antifungal drugs (azoles, echinocandins and polyenes) are not sufficient to combat Candida species particularly those that are drug resistant. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is an attractive antifungal drug target, and its inhibitor (FK506 or cyclosporin A) can be combined with azoles or echinocandins for use against multidrug-resistant Candida species. The role of calcineurin in the hyphal growth of Candida albicans is controversial, but its roles in C. dubliniensis, C. tropicalis and C. lusitaniae can be demonstrated. In addition, calcineurin is required for virulence of Candida species in murine systemic, ocular or urinary infection models. However, the requirement for calcineurin substrate Crz1 in these infection models varies in Candida species, suggesting that Crz1 has diverse functions in different Candida species. Besides being critical for growth in serum of Candida species, calcineurin is critical for plasma membrane integrity and growth at body temperature (37°C) uniquely in C. glabrata, suggesting that Candida calcineurin controls pathogenesis via various novel mechanisms. In this review, we summarize studies of calcineurin signaling and hyphal growth, virulence and its relationship with drug tolerance in Candida species, focusing on the divergent and conserved functions.

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