Biology subjects

Gaffen, S. L.

Publications and source records attributed to Gaffen, S. L..

4 recordsLinked to original sources

bioRxiv2026

The IL-1 Family Controls Acute Mucosal Fungal Infection and Mucosal-Systemic Dissemination.

Candida albicans is a major opportunistic pathogen in humans that is capable of breaching mucosal barriers and causing severe systemic infections with high mortality. How the host controls mucosal infection and prevents dissemination remains unclear but is essential for improving disease outcomes. Here, we demonstrate that C. albicans induces specific IL-1 family members, which are critical for initiating mucosal protection by controlling antimicrobial peptides, IL-17, and neutrophil responses. Loss of combined IL-1 family signalling led to severe mucosal C. albicans infection, which was eventually resolved by a potent neutrophil response. However, in neutropenic conditions (a key risk patient factor) abolishing IL-1 family signalling resulted in C. albicans dissemination, predominantly to the liver, mirroring clinical disease and leading to mortality. This study highlights the IL-1 family as a key initiator of mucosal immunity, restricting mucosal invasion and cooperating with neutrophils to prevent life- threatening systemic infections.

microbiology↗

bioRxiv2025

Epitranscriptomic control of host epithelial responses to candidiasis via N6-Methyladenosine (m6A) methylation

Fungal infections represent a major global threat, yet to date there is a paucity of effective antifungal drugs and no licensed vaccines to any pathogenic fungi. The commensal pathobiont Candida albicans can cause severe oropharyngeal and mucocutaneous infections in immunocompromised individuals. The initial point of interaction of C. albicans in the oral mucosa is with superficial oral epithelial cells (OECs). Upon fungal encounter, OECs upregulate a program of anti-fungal defense genes, a process that has been extensively studied at the level of proximal signaling pathways, transcriptional induction, and epigenetic control. However, inflammatory genes are also subject to extensive regulation at the mRNA level, yet little is known about mechanisms that control C. albicans-induced genes post-transcriptionally. The importance of epitranscriptomic gene regulation by mRNA methylation is becoming increasingly appreciated, yet its contribution to host responses during fungal infection remains poorly understood. N6-methyladenosine (m6A) is the most abundant RNA modification and influences numerous transcript fates including mRNA stabilization. Here, we demonstrate that C. albicans-induced genes in human and mouse OECs are widely subject to m6A modification following infection. Silencing of a specific subclass of m6A binding proteins, the YTHDF1/2/3 readers, reprogrammed the OEC response to C. albicans by up- and down-regulating antifungal transcripts. The net effect of blocking the m6A pathway using a first-in-class METTL3 inhibitor was to amplify mRNA expression of antimicrobial peptides that reduce fungal burden. These studies establish a role for the m6A pathway as a modulator of immunity to mucosal candidiasis and suggest a new therapeutic avenue to treating this condition.

microbiology↗

bioRxiv2024

Non-canonical IL-22 receptor signaling remodels the mucosal barrier during fungal immunosurveillance

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.

immunology↗

bioRxiv2021

The globular C1q receptor is required for epidermal growth factor receptor signaling during Candida albicans infection

During oropharyngeal candidiasis, Candida albicans activates the epidermal growth factor receptor (EGFR), which induces oral epithelial cells to both endocytose the fungus and synthesize proinflammatory mediators that orchestrate the host immune response. To elucidate the signaling pathways that are stimulated when C. albicans interacts with EGFR, we analyzed the proteins that associate with EGFR when C. albicans infects human oral epithelial cells. We identified 1214 proteins that were associated with EGFR in C. albicans-infected cells. We investigated the function of seven of these proteins that either showed increased association with EGFR in response to C. albicans or that mediated the interaction of other microbial pathogens with epithelial cells. Among these proteins, EGFR was found to associate with WW domain-binding protein 2, toll-interacting protein, interferon-induced transmembrane protein 3, and the globular C1q receptor (gC1qR) in viable epithelial cells. Each of these proteins was required for maximal endocytosis of C. albicans and they all regulated fungal-induced production of IL-1{beta} and/or IL-8, either positively or negatively. gC1qR functioned as a key coreceptor with EGFR. Interacting with the C. albicans Als3 invasin, gC1qR was required for the fungus to stimulate both EGFR and the ephrin type-A receptor 2. The combination of gC1qR and EGFR was necessary for maximal endocytosis of C. albicans and secretion of IL-1{beta}, IL-8, and GM-CSF. Thus, this work provides an atlas of proteins that associate with EGFR and identifies several that play a central role in the response of human oral epithelial cells to C. albicans infection. IMPORTANCEOral epithelial cells play a key role in the pathogenesis of oropharyngeal candidiasis. In addition to being target host cells for C. albicans adherence and invasion, they secrete proinflammatory cytokines and chemokines that recruit T cells and activated phagocytes to foci of infection. It is known that C. albicans activates EGFR on oral epithelial cells, which induces these cells to endocytose the organism and stimulates them to secrete proinflammatory mediators. To elucidate the EGFR signaling pathways that govern these responses, we analyzed the epithelial cell proteins that associate with EGFR in C. albicans-infected epithelial cells. We identified four proteins that physically associate with EGFR and that regulate different aspects of the epithelial response to C. albicans. One of these is gC1qR, which is required for C. albicans to activate EGFR, induce endocytosis, and stimulate the secretion of proinflammatory mediators, indicating that gC1qR functions as a key co-receptor with EGFR.

microbiology↗