Biology subjects

McCoy, K. D.

Publications and source records attributed to McCoy, K. D..

14 recordsLinked to original sources

bioRxiv2026

Brown and Lesser noddies as epidemiological reservoirs and sentinels of avian influenza virus in the South-western Indian Ocean

Avian influenza virus (AIV) epidemiology is well-documented in temperate regions but remains poorly understood in isolated ecosystems like tropical oceanic islands. On these islands, seabirds nest in dense interspecific colonies where the role of different species as reservoirs and dispersers of AIV may vary greatly. Here, we examine the role of noddies (Anous spp.) as potential reservoirs for low pathogenic AIV and evaluate their potential as sentinel species for highly pathogenic AIV introduction on tropical oceanic islands. We analyzed blood samples from 11 seabird species across eight islands in the southwestern Indian Ocean (2015-2020). Noddies exhibited high, stable seroprevalence (30-45%), comparable to reservoir host species in temperate regions. The detection of two N7-positive noddies, sampled the same year on two distinct islands, provided direct molecular evidence that AIV actively circulates on these island colonies. While most other species showed low exposure, Bridled Terns (Onychoprion anaethetus) had exceptionally high seroprevalence (80%), though their reservoir status requires further investigation due to limited sampling. Given noddies consistent exposure and regional distribution, we recommend prioritizing islands with large noddy populations for AIV surveillance. Continued investigation of viral dynamics within and among islands is now called for to elucidate the ecological drivers of AIV maintenance and transmission.

ecology↗

bioRxiv2024

The gut microbiota is a determinant of sexual dimorphism in ALS-linked TDP43 mice

The mechanisms underlying the earlier onset and male predominance of amyotrophic lateral sclerosis (ALS), the most common form of human motoneuron disease, are poorly understood. Here we show that the gut microbiota protects against TDP43 toxicity and contributes to the sexual dimorphism in mice expressing a mutant form of TDP43 (A315T) linked to ALS. TDP43 mice raised under germ-free conditions, or treated with antibiotics to deplete the gut microbiota, develop motoneuron disease earlier and show no sex differences in onset and lifespan. Behavioral and histopathological analyses confirm the exacerbation in neurodegeneration caused by the absence of gut microbiota. Castration did not alter disease course of male TDP43 mice, suggesting that male sex hormones do not interact with the gut microbiota to confer disease phenotype. Future identification of gut bacteria species and their mechanisms of action offers a unique opportunity to understand sexual dimorphism in ALS, with the ultimate goal to develop non-invasive and sex-specific treatments for ALS.

physiology↗

bioRxiv2024

Perceived and observed biases within scientific communities: a case study in movement ecology

Who conducts biological research, where, and how the results are disseminated varies among geographies and identities. Identifying and documenting these forms of bias by research communities is a critical first step towards addressing them. We documented perceived and observed biases in movement ecology. Movement ecology is a rapidly expanding sub-discipline of biology, which is strongly underpinned by fieldwork and technology use. First, we surveyed attendees of an international conference, and discussed the results at the conference (comparing uninformed vs informed perceived bias). Although most researchers identified as bias-aware, only a subset of biases were discussed in conversation. Next, by considering author affiliations from publications in the journal Movement Ecology, we found among-country discrepancies between the country of the authors affiliation and study site location related to national economics. At the within-country scale, we found that race-gender identities of postgraduate biology researchers in the USA differed from national demographics. We discuss the role of potential specific causes for the emergence of bias in the sub-discipline, e.g. parachute-science or accessibility to fieldwork. Undertaking data-driven analysis of bias within research sub-disciplines can help identify specific barriers and first steps towards the inclusion of a greater diversity of participants in the scientific process.

ecology↗

bioRxiv2024

Innate immune system signaling and CD11b+CD11c+CD103+ cell migration to the brain underlie changes in mouse behavior after microbial colonization.

Background and AimsAccumulating evidence suggests the microbiota is a key factor in disorders of gut-brain interaction (DGBI), by affecting host immune and neural systems. However, the underlying mechanisms remain elusive due to their complexity and clinical heterogeneity of patients with DGBIs. We aimed to identify neuroimmune pathways that are critical in microbiota-gut-brain communication during de novo gut colonization. MethodsWe employed a combination of gnotobiotic and state-of-the-art microbial tools, behavioral analysis, immune and pharmacological approaches. Germ-free wild type, MyD88-/- Ticam1-/- and SCID mice were studied before and after colonization with specific pathogen-free microbiota, Altered Schaedler Flora, E. coli or S. typhimurium (permanent or transient colonizers). TLR agonists and antagonists, CCR7 antagonist or immunomodulators were used to study immune pathways. We assessed brain c-Fos, brain-derived neurotrophic factor, and dendritic and glial cells by immunofluorescence, expression of neuroimmune genes by NanoString and performed brain proteomics. ResultsBacterial monocolonization, conventionalization or administration of microbial products to germ-free mice altered mouse behavior similarly, acting through Toll-like receptor or nucleotide-binding oligomerization domain signaling. The process required CD11b+CD11c+CD103+ cell activation and migration into the brain. The change in behavior did not require the continued presence of bacteria and was associated with activation of multiple neuro-immune networks in the gut and the brain. ConclusionsChanges in neural plasticity occur rapidly upon initial gut microbial colonization and involve innate immune signaling to the brain, mediated by CD11b+CD11c+CD103+ cell migration. The results identify a new target with therapeutic potential for DGBIs developing in context of increased gut and blood-brain barrier permeability. HighlightsO_LIMicrobiota impairment is a key factor in disorders of gut-brain interaction (DGBI) C_LIO_LIMicrobial colonization induces changes in brain and behavior via innate immunity C_LIO_LIMicrobial colonization activates multiple neuro-immune networks in gut and brain C_LIO_LIBehavioral change is mediated by CD11b+CD11c+CD103+ cells migration to the brain C_LI

animal behavior and cognition↗

bioRxiv2024

Low abundant intestinal commensals modulate immune control of chronic myeloid leukemia stem cells

Leukemia stem cells (LSCs) are resistant to therapy and immune control. The reason for their resistance to elimination by cytotoxic T cells (CTLs) remains unclear. This study shows that specific low abundant Gram-negative intestinal commensals of the genus Sutterella suppress the anti-leukemia immune response in chronic myeloid leukemia (CML). We found that germ-free and specific opportunistic pathogen-free (SOPF) mice are protected from CML development and that colonization of SOPF mice with Sutterella wadsworthensis, but not other related and unrelated bacterial strains, rescues CML development. A higher prevalence of this microbe resulted in Myd88/TRIF-mediated CTL exhaustion in SPF compared to SOPF CML mice as evidenced by higher surface expression of exhaustion markers on CTLs, a reduced capacity to produce interferon-gamma and granzyme B and to kill LSCs in vitro. These findings provide new insights into the immune control of LSCs and identify Sutterella species as regulators of anti-leukemic immunity in CML.

cancer biology↗

bioRxiv2024

Mining for microbial metabolites associated with disease progression in an age-dependent model of experimental autoimmune encephalomyelitis

Age is a risk factor for the neurological decline and physical disability that characterize progressive multiple sclerosis (MS). The intestinal microbiota and the bioactive compounds it produces can influence aging, immunity, and the central nervous system (CNS). Here, we use an experimental autoimmune encephalomyelitis (EAE) model that mimics features of progressive MS in aged, but not young, mice to address the intersection of age and the microbiota on EAE outcomes. Although the microbiota of SJL/J mice aged under controlled laboratory conditions does not promote an aged non-remitting EAE phenotype, young mice harboring heterochronic human fecal microbiota transplants (hFMT) developed a range of EAE phenotypes. Metabolomic profiling of mice colonized with an aged hFMT that promoted non-remitting EAE indicated a severe reduction in circulating levels of the microbiota-derived tryptophan metabolite indole 3-propionic acid (IPA). IPA-supplementation enforced remission in mice colonized with the non-remitting hFMT, demonstrating the utility of this in vivo pipeline for discovering metabolites associated with progressive MS-like disease. SummaryThe microbiota is a critical determinant of disease susceptibility in mouse models of MS. Here, Pu & Fettig et al. demonstrate that disease outcomes (remitting or non-remitting) are microbiota-responsive, and describe an in vivo pipeline that can be mined for microbial metabolites with therapeutic potential for progressive MS.

immunology↗

bioRxiv2024

T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota.

The gut microbiota and immune system maintain intestinal homeostasis and regulate gut physiology in concert with the enteric nervous system (ENS). However, the underlying mechanisms remain incompletely understood. Using wildtype and T-cell deficient germ-free mice colonized with segmented filamentous bacteria (SFB) or specific pathogen-free (SPF) microbiota, we studied immune regulation of the ENS and intestinal motility. Colonization markedly increased Th17 cells and Treg expressing ROR{gamma}+T cells in both the ileum and colon of wildtype mice. T cells were necessary for the normalization of intestinal motility after colonization by SPF microbiota, and for SFB to restore neuronal density in the ENS of the ileum of germ-free mice. T cells were also required for neurogenic responses in myenteric neurons of the ileum, but not the colon, and for regulating the levels of nestin expression. The cytokines IL-1{beta} and IL-17A mediate the enteric neurogenic response to an SPF microbiota but were not involved in the regulation of intestinal motility. Together, our findings provide new insights into the microbiota-neuroimmune dialogue that regulates intestinal physiology.

physiology↗

bioRxiv2024

Antibiotic-induced Malassezia spp. expansion in infants promotes early-life immune dysregulation and airway inflammation in mice

Antibiotics have deleterious consequences for the gut microbiome and can increase the risk of childhood asthma. While the effects of antibiotics on the bacterial microbiome and asthma risk are well characterized, their impact on the fungal microbiome (mycobiome) remains vastly unexplored. We investigated the effect of antibiotic use on the gut mycobiome in an observational, prospective clinical study of young infants. Antibiotic treatment resulted in increased fungal abundance and expansion of the yeast Malassezia spp. Based on these findings, germ-free mouse pups were colonized with a defined consortium of mouse-derived bacteria (Oligo-MM12) with or without Malassezia restricta. Colonization with this yeast increased myeloid and lymphoid intestinal immune responses deemed critical in atopy development, and elevated airway inflammation in house-dust mite (HDM)-challenged mice. Further evaluation in eosinophil-deficient mice revealed that the observed immune response is partially dependent on this cell type. This translational work demonstrates that fungal overgrowth and expansion of Malassezia spp. are previously overlooked collateral effects of infant antibiotic use, which may offer a potential strategy to prevent or mitigate pediatric asthma and related conditions. One Sentence Summary: Antibiotic-induced Malassezia spp. expansion in infants promotes early-life immune dysregulation and airway inflammation in gnotobiotic mice.

immunology↗

bioRxiv2023

The distribution, phenology, host range and pathogen prevalence of Ixodes ricinus in France: a systematic map and narrative review

The tick Ixodes ricinus is the most important vector species of infectious diseases in European France. Understanding its distribution, phenology, and host species use, along with the distribution and prevalence of associated pathogens at national scales is essential for developing prevention strategies. The aim of this paper is to provide a systematic map and narrative review of the existing knowledge on the eco-epidemiology of I. ricinus in France. Using literature published up to 2020, the present paper provides a distribution map for the species and a summary of environmental factors explaining observed geographical differences in phenology and temporal differences in abundance. The diversity of vertebrate host species used by this tick, along with their degree of infestation when available, are presented and discussed with respect to their potential contribution to the population dynamics of I. ricinus and the circulation of tick-borne zoonotic pathogens. Prevalence data of detected pathogens are summarised in different maps. Results from 187 identified references show that the species is present in most departments, but scarce under Mediterranean climate and in coastal habitats. Its phenology is generally bimodal with variations depending on climate. Abundance seems positively influenced by forest cover and host abundance. Rodents and ruminants are the most studied species groups, but the diversity of sampling protocols (e.g., location, season, exhaustivity of inspection) precluded direct comparisons between species groups. Data on pathogens are patchy, with most studies conducted near research units. Among pathogens, Borrelia burgdorferi sensu lato is the most searched for in ticks and seems more prevalent in north-eastern and central France. The review carried out here has made it possible to highlight the gaps in our knowledge of tick-host-pathogen interactions, their ecology and their distribution, and the need to address these gaps in order to optimize tick and tick-borne diseases prevention and control strategies.

ecology↗

bioRxiv2022

Genomic Changes During the Evolution of the Coxiella Genus Along the Parasitism-Mutualism Continuum.

The Coxiellaceae family is composed of five genera showing lifestyles ranging from free-living to symbiosis. Among them, Coxiella burnetii is a well-known pathogen causing Q fever in humans. This bacterium presents both intracellular (parasitic) and environmental (resistant) forms. Recently, several environmental Coxiella genomes have been reported, among which several have come from intracellular mutualistic symbionts of ticks, termed Coxiella-like endosymbionts. We sequenced two new Coxiella-LE genomes from Dermacentor marginatus (CLEDm) and Ornithodoros maritimus (CLEOmar) ticks, the latter belonging to the C. burnetii lineage. Using these newly sequenced Coxiella-LEs and 43 Coxiellaceae genomes, we conducted comparative genomic and phylogenomic analyses to increase our knowledge of C. burnetii pathogenicity and the emergence of Coxiella-LEs. Results highlight the probably parasitic nature of the common ancestor of the Coxiellaceae. Indeed, the virulence factor Dot/Icm T4 Secretion System is present in most, but not all, Coxiellaceae. Whereas it is part of a putative pathogenic island in C. burnetii, it has been entirely lost or inactivated in Coxiella-LEs, suggesting its importance in pathogenesis. Additionally, we found that a Sha/Mrp antiporter was laterally acquired in the C. burnetii lineage. This antiporter might be involved in alkali resistance and the development of the resistant form that is able to persist in the environment for long periods of time. The Sha operon is eroded or absent in Coxiella-LEs. Finally, we found that all Coxiella representatives produce B vitamins and co-factors indicating a pre-adaptation of Coxiella to mutualism with hematophagous arthropods. Accordingly, the ancestor of C. burnetii and Coxiella-LEs was likely a parasitic bacterium able to manipulate its host cell and to produce vitamins and co-factors for its own use.

microbiology↗

bioRxiv2021

Small Intestinal Resident Eosinophils Maintain Gut Homeostasis Following Microbial Colonisation

Intestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil recruitment to this organ has long remained enigmatic. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine. HIGHLIGHTSO_LIThe microbiota is a critical regulator of eosinophil activation and turnover C_LIO_LIEosinophils uphold intestinal barrier integrity following microbial colonization C_LIO_LILoss of eosinophils at steady-state results in increased villous blunting and altered intestinal motility C_LI

immunology↗

bioRxiv2019

Contribution of fungal microbiome to intestinal physiology, early-life immune development and mucosal inflammation in mice

Gut microbiomes make major contributions to the physiological and immunological development of the host, but the relative importance of their bacterial and fungal components, and how they interact, remain largely unknown. We applied carefully controlled experiments in gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis and airway inflammation. Our results revealed that fungal colonization alone was insufficient to promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, and had limited impact on the fecal metabolome. However, fungal colonization promoted major shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive immune development in young mice. Fungi further exacerbated some aspects of the inflammatory effects of the bacterial community during OVA-induced airway inflammation by promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor shaping the assembly of the bacterial community and a direct capacity to impact immune system and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for the inclusion of fungi in human microbiome studies.

microbiology↗

bioRxiv2017

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute for 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naive and foreign antigen-experienced memory T cells are incompletely understood. By analyzing TCR repertoires and using retrogenic monoclonal T-cell populations, we show that virtual memory T cells originate exclusively from strongly self-reactive T cells. Moreover, we show that the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T-cell clones. We propose a so far unappreciated peripheral T-cell fate decision checkpoint that eventually leads to the differentiation of highly self-reactive T cells into virtual memory T cells. This underlines the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they do not show higher capacity to induce autoimmune diabetes than naive T cells. Thus, virtual memory T cells are not generally more responsive than naive T cells, because their activity highly depends on the immunological context.\n\nSummaryWe conclude that virtual memory T cells are formed from self-reactive CD8+ T cells in a process regulated by CD8-Lck stoichiometry. Despite their self-reactivity and partial memory differentiation program, virtual memory T cells did not show a strong autoimmune potential.

immunology↗

bioRxiv2017

Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response

Although the mammalian microbiota is well-contained within the intestine and on other body surfaces, it profoundly shapes development and metabolism of almost every host organ, presumably through pervasive microbial metabolite penetration. The challenge is that most metabolites can be of both host and microbial origin. We developed a model to distinguish between microbial and host metabolites by stable isotope tracing using fully 13C-labelled live non-replicating Escherichia coli, differentiating 12C and 13C isotopes with high-resolution mass spectrometry. Hundreds of microbial compounds penetrated across 23 host tissues and fluids after intestinal exposure: subsequent 12C host metabolome signatures included lipidemia, reduced glycolysis and inflammation. Mucosal barrier maturation with transient microbial exposure increased early clearance of penetrant bacterial metabolites from the small intestine into the urine, independently of antibody induction. Induced antibodies curtailed microbial metabolite exposure at the intestinal surface, by accelerating intestinal bacterial transit into the colon where metabolite transport mechanisms are limiting.

immunology↗