Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a human fungal pathogen of primarily immunocompromised individuals, resistance toward treatment strategies demands alternative approaches. Given the prevalence of virulence factor production during cryptococcal infection, an emerging and important field of research encompasses the development of novel antivirulence therapies proposed to improve host immune responses and promote fungal clearance. To accomplish this task, information regarding the presence and role of virulence factors, the mechanisms of action within the host, and the ability to influence fungal susceptibility to antifungals is pertinent. Research into mechanisms of antifungal resistance for C. neoformans is limited but extrapolation from successful studies in other fungal species can improve our understanding of mechanisms employed by C. neoformans and suggest targeted strategies to enhance our ability to combat the pathogen. In this Review, we highlight antifungal therapy options against Cryptococcus, explore current knowledge of underlying mechanisms promoting resistance, and present new opportunities for novel and effective strategies to overcome fungal infections and reduce, or possibly even reverse, the effects of resistance evolution.

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.

The landscape of infectious fungal agents includes previously unidentified or rare pathogens with the potential to cause unprecedented casualties in biodiversity, food security, and human health. The influences of human activity, including the crisis of climate change, along with globalized transport, are underlying factors shaping fungal adaptation to increased temperature and expanded geographical regions. Furthermore, the emergence of novel antifungal-resistant strains linked to excessive use of antifungals (in the clinic) and fungicides (in the field) offers an additional challenge to protect major crop staples and control dangerous fungal outbreaks.

The global burden of fungal disease poses a substantial threat to human, animal, and environmental health, endangering both human and livestock populations and creating vulnerabilities to food supplies world‐wide. Antifungal drugs provide essential therapies to humans and animals against infections, while fungicides provide protection in agriculture. However, a limited arsenal of antifungal agents results in cross‐use between agriculture and health, promoting the development of resistance, and drastically reducing our defenses against disease. Critically, antifungal resistant strains found ubiquitously within the natural environment demonstrate resistance to the same classes of antifungals used to treat human and animal infections, hindering effective treatment within the clinic. This interconnectivity supports the need for a One Health approach to combat fungal diseases and overcome antifungal resistance, ensuring that treatment and protection of a defined group does not inadvertently endanger or sacrifice other plants, animals, or humans. In this review, we present sources of antifungal resistance and discuss the integration of environmental and clinical resources to manage disease. Moreover, we explore opportunities for drug synergy and repurposing strategies, highlight fungal targets being investigated to overcome resistance, and propose technologies for the discovery of novel fungal targets.This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology

The prevalence of fungal diseases is increasing on a global scale, ranging from acute to systemic infections caused by commensal or pathogenic microorganisms, often associated with the immune status of the host. Morbidity and mortality rates remain high and our ability to treat fungal infections is challenged by a limited arsenal of antifungal agents and the emergence of drug resistant pathogens. There is a high demand for new approaches to elucidate the fungal mechanisms of pathogenesis and the interplay between host and pathogen to discover novel treatment options. Moreover, the need for improved drug efficacy and reduced host toxicity requires the identification and characterization of antifungal biological targets and molecular mechanisms of action. Mass spectrometry (MS)-based proteomics is a rapidly advancing field capable of addressing these priorities by providing comprehensive information on the dynamics of cellular processes, modifications, and interactions. In this Review, we focus on applications of MS-based proteomics in a diverse array of fungal pathogens and host systems to define and distinguish the molecular details of fungal pathogenesis and host–fungal interactions. We also explore the emerging role of MS-based proteomics in the discovery and development of novel antifungal therapies and provide insight into the future of MS-based proteomics in fungal biology.