Biology subjects

Uberoi, A.

Publications and source records attributed to Uberoi, A..

6 recordsLinked to original sources

bioRxiv2026

Microbiota-derived butyrate promotes dermal collagen production through epidermal-dermal crosstalk

The commensal microbiota actively shapes skin homeostasis by regulating immune responses and barrier function, yet interactions with the dermis and dermal fibroblasts remain poorly defined. Here, we show that the commensal microbiota regulates dermal collagen homeostasis through epidermal-mediated signaling. Transcriptomic analysis revealed enrichment of extracellular matrix (ECM)-associated gene programs in the dermis of conventionally raised (CR) mice compared with germ-free (GF) counterparts. CR skin exhibited increased collagen content, a thicker dermis, and thicker collagen fibers, indicative of a structurally robust dermal ECM. Similar microbiota-dependent collagen regulation was observed in additional tissues and during embryonic skin development, suggesting contributions from microbiota-derived signals beyond directly colonized sites. Mechanistically, short chain fatty acid butyrate robustly induced epidermal platelet-derived growth factor B (PDGFB) expression in vitro through a histone acetylation-dependent transcriptional program. Conditioned media from butyrate-treated human epidermal equivalents promoted collagen production in primary human dermal fibroblasts, an effect that was attenuated by inhibition of PDGF receptor signaling or histone acetyltransferase activity. Moreover, topical butyrate treatment of explants derived from aged human skin induced epidermal PDGFB and dermal collagen expression. Together, these findings identify a microbiota-epidermis-dermis signaling axis in which the commensal microbiota regulates dermal collagen through metabolite-enhanced epidermal signaling, highlighting a previously underappreciated role for the microbiota in maintaining dermal homeostasis.

Cell Biology↗

bioRxiv2023

Wound microbiota-mediated correction of matrix metalloproteinase expression promotes re-epithelialization of diabetic wounds

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused on Alcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

microbiology↗

bioRxiv2022

Staphyloxanthin production by Staphylococcus aureus promotes resistance to oxidative stress to delay diabetic wound healing

Diabetic foot ulcers (DFU) are a serious complication of diabetes mellitus that burden patients and health care systems. Staphylococcus aureus is prevalent and abundant in the DFU microbiome, and strain-level differences in S. aureus may drive clinical outcomes. To identify mechanisms underlying strain-specific outcomes in DFU with S. aureus, we performed high-throughput phenotyping screens on a collection of 221 S. aureus cultured isolates from clinically uninfected DFU. Of the 4 phenotypes examined (in vitro biofilm formation and production of staphylokinase, staphyloxanthin, and siderophores), we discovered that isolates from non-healing wounds produced more staphyloxanthin, a carotenoid cell membrane pigment. In a murine diabetic wound healing model, staphyloxanthin-producing isolates delayed wound closure significantly compared to staphyloxanthin-deficient isolates. Staphyloxanthin promoted resistance to oxidative stress in vitro and enhanced bacterial survival in human neutrophils. Comparative genomic and transcriptomic analysis of genetically similar clinical isolates with disparate staphyloxanthin phenotypes revealed a mutation in the Sigma B regulatory pathway that resulted in marked differences in stress response gene expression. Our findings suggest that staphyloxanthin production delays wound healing by protecting S. aureus from neutrophil-mediated oxidative stress, and may provide a target for therapeutic intervention in S. aureus-positive wounds.

microbiology↗

bioRxiv2022

Harnessing diversity and antagonism within the pig skin microbiota to identify novel mediators of colonization resistance to methicillin-resistant Staphylococcus aureus

The microbiota mediates multiple aspects of skin barrier function, including colonization resistance to pathogens such as Staphylococcus aureus. The endogenous skin microbiota limits S. aureus colonization via competition and direct inhibition. Novel mechanisms of colonization resistance are promising therapeutic targets for drug-resistant infections, such as those caused by methicillin-resistant S. aureus (MRSA). Here, we developed and characterized a swine model of topical microbiome perturbation and MRSA colonization. As in other model systems, topical antimicrobial treatment had little discernable effect on community diversity though the overall microbial load was sensitive to any type of intervention, including swabbing. In parallel, we established a porcine skin culture collection and screened 7,700 isolates for MRSA inhibition. Inhibitory isolates were represented across all major phyla of the pig skin microbiota and did not have a strong preference for inhibiting closely related species, suggesting that relatedness is not a condition of antagonism. Using genomic and phenotypic criteria, we curated 3 isolates to investigate whether prophylactic colonization would inhibit MRSA colonization in vivo. The 3-member consortium together, but not individually, provided protection against MRSA colonization, suggesting cooperation and/or synergy among the strains. These findings reveal the porcine skin as an underexplored reservoir of skin commensal species with the potential to prevent MRSA colonization and infection.

microbiology↗

bioRxiv2021

The Mus musculus papillomavirus type 1 E7 protein binds to the retinoblastoma tumor suppressor - implications for viral pathogenesis

The species specificity of papillomaviruses has been a significant roadblock for performing in vivo pathogenesis studies in common model organisms. The Mus musculus papillomavirus type 1 (MmuPV1) causes cutaneous papillomas that can progress to squamous cell carcinomas in laboratory mice. The papillomavirus E6 and E7 genes encode proteins that establish and maintain a cellular milieu that allows for viral genome synthesis and viral progeny synthesis in growth-arrested, terminally differentiated keratinocytes. The E6 and E7 proteins provide this activity by binding to and functionally reprogramming key cellular regulatory proteins. The MmuPV1 E7 protein lacks the canonical LXCXE motif that mediates the binding of multiple viral oncoproteins to the cellular retinoblastoma tumor suppressor protein, RB1. Our proteomic experiments, however, revealed that MmuPV1 E7 still interacts specifically with RB1. We show that MmuPV1 E7 interacts through its C-terminus with the C-terminal domain of RB1. Binding of MmuPV1 E7 to RB1 did not cause significant activation of E2F-regulated cellular genes. MmuPV1 E7 expression was shown to be essential for papilloma formation. Experimental infection of mice with MmuPV1 virus expressing an E7 mutant that is defective for binding to RB1 caused delayed onset, lower incidence, and smaller sizes of papillomas. Our results demonstrate that the MmuPV1 E7 gene is essential and that targeting non-canonical activities of RB1, which are independent of RB1s ability to modulate the expression of E2F-regulated genes, contribute to papillomavirus-mediated pathogenesis. ImportancePapillomavirus infections cause a variety of epithelial hyperplastic lesions, warts. While most warts are benign, some papillomaviruses cause lesions that can progress to squamous cell carcinomas and approximately 5% of all human cancers are caused by human papillomavirus (HPV) infections. The papillomavirus E6 and E7 proteins are thought to function to reprogram host epithelial cells to enable viral genome replication in terminally differentiated, normally growth-arrested cells. E6 and E7 lack enzymatic activities and function by interacting and functionally altering host cell regulatory proteins. Many cellular proteins that can interact with E6 and E7 have been identified, but the biological relevance of these interactions for viral pathogenesis has not been determined. This is because papillomaviruses are species-specific and do not infect heterologous hosts. Here we use a recently established mouse papillomavirus (MmuPV1) model to investigate the role of the E7 protein in viral pathogenesis. We show that MmuPV1 E7 is necessary for papilloma formation. The retinoblastoma tumor suppressor protein (RB1) is targeted by many papillomaviral E7 proteins, including cancer-associated HPVs. We show that MmuPV1 E7 can bind RB1 and that infection with a mutant MmuPV1 virus that expresses an RB1 binding defective E7 mutant caused smaller and fewer papillomas that arise with delayed kinetics.

molecular biology↗

bioRxiv2020

Commensal Microbiota Regulates Skin Barrier Function And Repair Via Signaling Through The Aryl Hydrocarbon Receptor

The epidermis forms a barrier that defends the body from desiccation and entry of harmful substances, while sensing and integrating environmental signals. The tightly orchestrated cellular changes required for the proper formation and maintenance of this epidermal barrier occur in the context of the skin microbiome. Using germ free mice, we demonstrate the microbiota is necessary for proper differentiation and repair of the epidermal barrier. These effects were mediated by the aryl hydrocarbon receptor (AHR) in keratinocytes, a xenobiotic receptor also implicated in epidermal differentiation. Murine skin lacking keratinocyte AHR was more susceptible to barrier damage and infection, during steady state and epicutaneous sensitization. Colonization with a defined consortium of human skin isolates restored barrier competence in an AHR-dependent manner. We reveal a fundamental mechanism whereby the microbiota regulates skin barrier formation and repair, with far-reaching implications for the numerous skin disorders characterized by epidermal barrier dysfunction.

microbiology↗