Biology subjects

Moreau, G. B.

Publications and source records attributed to Moreau, G. B..

6 recordsLinked to original sources

bioRxiv2025

The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration

The novel respiratory disease COVID-19 caused by the coronavirus SARS-CoV-2 continues to be a public health emergency worldwide, and there is a need for more effective therapy for patients. The relationship between the extracellular matrix and the host immune response to infection is severely understudied. Deposition of the polysaccharide hyaluronan (HA) into the lungs is associated with more severe COVID-19 disease outcomes. HA is a major component of the extracellular matrix in connective tissues and is abundant in many parts of the body, including cartilage, skin, brain, and vitreous body. CD44 is the primary receptor for HA and is found on almost all immune cells in the lung. Known functions of CD44 include mediation of immune cell migration, activation, and differentiation. We hypothesized that increased HA deposition during COVID-19 increases CD44-mediated immune cell infiltration into lungs and results in more severe pathology. Here, we report that in mice infected with a mouse-adapted strain of SARS-CoV-2, treatment with a combination of two anti-CD44 monoclonal antibodies confers a significant survival benefit and reduces weight loss and clinical score of the mice on Day 4 post infection. We show that anti-CD44 treatment decreases many key cytokines and chemokines in the bronchoalveolar lavage fluid on Day 4. With flow cytometry, we show that anti-CD44 reduces the numbers of neutrophils in infected lungs. We also show through immunofluorescence that treatment with anti-CD44 antibodies reduces colocalization of HA and CD45 in lung sections, indicating that HAs interaction with immune cells contributes to pathology. Our findings demonstrate that disruption of HA-receptor interactions is a way to prevent inflammatory pathology in pulmonary infection.

immunology↗

bioRxiv2024

Enhanced immunogenicity of a Clostridioides difficile TcdB vaccine adjuvanted with a synthetic dual-TLR ligand adjuvant.

We report a comprehensive evaluation of the toxin B (TcdB) vaccine adjuvanted with a dual Toll-like receptor ligand liposome adjuvant for Clostridioides difficile infection (CDI). The vaccine completely protected mice from a lethal infection. Compared to alum adjuvanted TcdB, it generated functionally superior systemic antibodies and supported strong memory B cell and gut IgA responses. This pharmaceutically acceptable adjuvant platform holds promise for developing a next-generation CDI vaccine.

immunology↗

bioRxiv2023

Lactobacillus maintains IFNγ homeostasis to promote behavioral stress resilience.

The gut microbiome consists of the trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, for the first time, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea. Using this novel microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFN{gamma} levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and give novel methods to study potential therapies developed to treat mood disorders.

neuroscience↗

bioRxiv2022

Stress-Induced Mucosal Layer Disruption Drives Gut Dysbiosis and Depressive-like Behaviors

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in the microbiome are associated with disease pathology. In depression, stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is then known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes. Using a model of chronic stress, we show that the mucosal protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a regulator of mucin 13 expression. SummaryIn this paper, authors identified a pathway by which stress induces microbiome shifts. They found that psychological stress selectively alters a key mucosal protein, mucin 13, which in turn modifies the microbial niche to induce changes in bacterial composition.

microbiology↗

bioRxiv2021

Fecal Microbiota Transplantation Drives Colonic Expression of Immune Activation Genes in a Mouse Model of Antibiotic Use

Clostridioides difficile infection (CDI) is the leading hospital acquired infection in North America. While the standard treatment for CDI remains antibiotics, fecal microbiota transplantation (FMT) has gained attention as an effective therapy to prevent relapse. Previous work has focused on colonization resistance mounted against C. difficile by FMT-delivered commensals, but the effects of FMT on the gut mucosal immune response are poorly understood. Better understanding of the molecular mechanisms driven by FMT would allow for more targeted therapy against CDI. To address this important gap in knowledge, microbial community structure and host gene expression were assessed after FMT in a mouse model of antibiotic use. Administration of FMT led to a significant increase in microbial diversity and partial restoration of community structure within 48 hours of treatment. RNA sequencing of cecal tissue identified large changes in gene expression between FMT recipient and vehicle control groups. Strikingly, genes upregulated after FMT treatment were enriched in immune activation pathways, many of which were associated with pro-inflammatory immune responses. FMT also upregulated several genes associated with type 2 immunity while repressing several associated with type 3 immunity, trends that are associated with improved response to CDI. These results highlight the interplay between the intestinal microbiota and host transcriptome and identify pathways of interest for exploring the role of FMT on treatment of recurring CDI.

microbiology↗

bioRxiv2020

Evaluation of K18-hACE2 mice as a model of SARS-CoV-2 infection

Abstract/SummaryMurine models of SARS-CoV-2 infection are critical for elucidating the biological pathways underlying COVID-19 disease. Because human ACE2 is the receptor for SARS-CoV-2, mice expressing the human ACE2 gene have shown promise as a potential model for COVID-19. Five mice from the transgenic mouse strain K18-hACE2 were intranasally inoculated with SARS-CoV-2 Hong Kong/VM20001061/2020. Mice were followed twice daily for five days and scored for weight loss and clinical symptoms. Infected mice did not exhibit any signs of infection until day four, when weight loss, but no other obvious clinical symptoms were observed. By day five all infected mice had lost around 10% of their original body weight, but exhibited variable clinical symptoms. All infected mice showed high viral titers in the lungs as well as altered lung histology associated with proteinaceous debris in the alveolar space, interstitial inflammatory cell infiltration and alveolar septal thickening. Overall, these results show that symptomatic SARS-CoV-2 infection can be established in the K18-hACE2 transgenic background and should be a useful mouse model for COVID-19 disease.

pathology↗