Biology subjects

Dey, I.

Publications and source records attributed to Dey, I..

3 recordsLinked to original sources

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↗

bioRxiv2025

An estrogen-independent and IL-1-dependent pathway controls vulvovaginal candidiasis through combined IL-17/IL-22 signaling

Vulvovaginal candidiasis (VVC) affects >75% of women, with considerable morbidity and high medical cost burden. While Type 17 cytokines (IL-17, IL-22) are critical for oral and dermal immunity to C. albicans, their role in VVC has been less clear. Th17 gene signatures are potently upregulated in VVC, yet impairment of individual Th17 components (IL-17A, IL-17R subunits, IL-22) does not worsen disease. Rather, estrogen activity is tightly linked to VVC, leading to a paradigm that hormonal pathways rather than immune defense, dominate susceptibility. Here, we reveal a previously unappreciated role for IL-1/Type 17 in VVC that operates independently of estrogenic hormones. In contrast to mice lacking IL-17A, IL-17RA, IL-22, or IL-22R individually, mice lacking IL-17RA and IL-22RA1 together (Il17raIl22ra1-/-) exhibited high fungal loads and exacerbated tissue damage and inflammation. In human vulvar epithelial cells, IL-17 and IL-22 drive synergistic signaling. IL-1R signaling but surprisingly not IL-23 wa upstream of this response. Il17raIl22ra1-/- mice expressed high IL-1{beta} yet did not control disease, indicating that IL-1 is upstream but not downstream of Type 17 responses. Unexpectedly, Type 17-dependent control occurred in the absence of exogenous estrogen administration and persisted even when estrus was prevented by progesterone treatment. Collectively, these data indicate that susceptibility to VVC is driven not only by estrogen sensitization but through combinatorial loss of IL-17 and IL-22. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/671995v2_ufig1.gif" ALT="Figure 1000"> View larger version (52K): org.highwire.dtl.DTLVardef@19946e9org.highwire.dtl.DTLVardef@1feac71org.highwire.dtl.DTLVardef@eb433aorg.highwire.dtl.DTLVardef@18ab622_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Long-term maintenance of patient-specific characteristics in tumoroids from six cancer indications in a common base culture media system

Tumoroids, also known as cancer organoids, are patient-derived cancer cells grown as 3D, self-organized multicellular structures that maintain key characteristics (e.g., genotype, gene expression levels) of the tumor from which they originated. These models have emerged as valuable tools for studying tumor biology, cytotoxicity, and response of patient-derived cells to cancer therapies. However, the establishment and maintenance of tumoroids has historically been challenging, labor intensive, and highly variable from lab to lab, hindering their widespread use. Here, we characterize the establishment and/or expansion of colorectal, lung, head and neck, breast, pancreas, and endometrial tumoroids using the standardized, serum-free Gibco OncoPro Tumoroid Culture Medium. Newly derived tumoroid lines (n=20) were analyzed by targeted genomic profiling and RNA sequencing and were representative of tumor tissue samples. Tumoroid lines were stable for over 250 days in culture and freeze-thaw competent. Previously established tumoroid lines were also transitioned to OncoPro medium and exhibited, on average, similar growth rates and conserved donor-specific characteristics when compared to original media systems. Additionally, OncoPro medium was compatible with both embedded culture in extracellular matrix and growth in a suspension format for facile culture and scale up. An example application of these models for assessing the cytotoxicity of a natural killer cell line and primary natural killer cells over time and at various doses demonstrated the compatibility of these models with assays used in compound and cell therapy development. We anticipate that the standardization and versatility of this approach will have important benefits for basic cancer research, drug discovery, and personalized medicine and help make tumoroid models more accessible to the cancer research community.

cancer biology↗