Immunocompromised individuals are at high risk of developing severe fungal infections with high mortality rates, while fungal pathogens pose little risk to most healthy people. Poor therapeutic outcomes and growing antifungal resistance pose further challenges for treatments. Identifying specific immunomodulatory mechanisms exploited by fungal pathogens is critical for our understanding of fungal diseases and development of new therapies. A gap currently exists between the large body of literature concerning the innate immune response to fungal infections and the potential manipulation of host immune responses to aid clearance of infection. This review considers the innate immune mechanisms the host deploys to prevent fungal infection and how these mechanisms fail in immunocompromised hosts. Three clinically relevant fungal pathogens (Candida albicans, Cryptococcus spp. and Aspergillus spp.) will be explored. This review will also examine potential mechanisms of targeting the host therapeutically to improve outcomes of fungal infection.

Candida albicans is a human commensal that can cause life-threatening invasive infection in immunocompromised individuals. Human immunity to C. albicans infection is thought to be largely dependent on neutrophil reactive oxygen and nitrogen species (ROS/RNS) generation by neutrophils. Despite this, our understanding of innate immune killing and escape by C. albicans is primarily studied in macrophages, and the precise mechanisms of evasion are unclear in neutrophils. Here, we sought to determine the importance of neutrophil reactive nitrogen species (RNS) production during C. albicans infection in vivo . Using a zebrafish model, we found that C. albicans rapidly downregulated neutrophil RNS below basal levels during the first day post-infection, a time at which neutrophil RNS is upregulated in bacterial infections as an important host-defense mechanism, indicating fungal evasion of host neutrophils. We confirmed the downregulation of RNS in human primary neutrophils and with clinical Candida isolates, including emerging human pathogens Candida auris and Candida glabrata . Inducible nitric oxide synthase (iNOS; Nos2 in zebrafish), the enzyme responsible for RNS production, competes with the arginase enzyme for a shared substrate, L-arginine. Using a zebrafish arginase2 transgenic line and a C. albicans car1 Δ mutant, we showed that both host and fungal arginase contribute to the reduction in neutrophil RNS. Despite pathogen downregulation, upregulation of neutrophil RNS via hypoxia-inducible factor 1α (Hif-1α) stabilization was sufficient to improve host survival following C. albicans infection. Inhibition of Nos2 blocked the host protective effect of Hif-1α stabilization. Finally, restoration of neutrophil RNS via Hif-1α stabilization was additive to clinically relevant antifungal treatment, increasing survival and clearance of C. albicans infections. Together, these data demonstrate that restoration of the neutrophil RNS response in C. albicans infection improves infection outcomes, highlighting the potential of targeting Hif-1α and RNS in host-directed therapies against fungal infections. IMPORTANCE: Candida albicans is a fungus that normally lives harmlessly in the human body but can cause life-threatening infections in people with weakened immune systems. A key part of the body’s defense against this fungus is neutrophils, immune cells that kill microbes using toxic molecules. However, how Candida avoids neutrophil defense is not well understood. Here, we used zebrafish and human immune cells to show that Candida suppresses an important neutrophil defense, reactive nitrogen species (RNS), during infection. Unlike bacteria, which trigger RNS, Candida reduces these protective molecules to below normal levels, helping its survival. This effect was also observed with other disease-causing Candida species. We went on to show that both the host and Candida contribute to this suppression. Importantly, boosting the neutrophil response improved survival and helped clear infection, especially when combined with standard antifungal drugs. These findings suggest new ways to support the immune system alongside existing treatments.

Rett syndrome (RTT) is a rare, genetic, neurodevelopmental disorder that predominantly affects girls. Clinical presentation is defined by regression of acquired motor and communication skills followed by stabilisation or recovery. Other clinical features can include decelerated head growth, breathing difficulties and seizures. Clinicians must therefore balance treatment of multiple comorbidities throughout the management of RTT. Trofinetide is the first drug approved specifically for treatment of neurological symptoms of RTT. While the number of RTT therapy trials has expanded in recent years, positive results have been limited. Additional preclinical and clinical investigations are ongoing.

Agitation and psychosis are common, highly challenging symptoms of Alzheimer’s disease (AD). Although non-pharmacological strategies are the recommended first-line treatment for agitation and psychosis in AD, pharmacological interventions may be necessary if there is severe risk of self-harm or harm to others. Brexpiprazole is approved by the US FDA for treatment of agitation associated with dementia due to AD, while other medications are used off label. Several novel and repurposed drugs are under investigation for use in agitation and psychosis in AD.