Biology subjects

Compton, S.

Publications and source records attributed to Compton, S..

6 recordsLinked to original sources

bioRxiv2026

Route of Adenovirus Type 5-Vectored Influenza Vaccination Shapes Systemic and Mucosal Immunity in a Maternal-Neonatal Pig Model

Influenza A virus can cause severe complications in pregnant women and infants, yet no influenza vaccines are approved for infants younger than six months. To address this, novel maternal vaccination strategies are needed to increase global access and coverage in these vulnerable populations. This study evaluated a hemagglutinin (HA) A/California/2009 (H1N1)-based human adenovirus 5 (huAd5) vector vaccine, adjuvanted with a TLR3 agonist, for its ability to induce influenza-specific passive immunity from pregnant and lactating pigs to their piglets following different immunization routes. Influenza naive pregnant dams were vaccinated via oral, intranasal (IN), or intramuscular (IM) routes three weeks prepartum and boosted four weeks later. Serum, colostrum and milk samples were collected longitudinally to assess HA-specific antibody induced by vaccination. H1N1-Ca/09 neutralizing antibodies were evaluated in serum and IFN{gamma} producing cells were assessed in blood, spleen and lymph node cells. IN and IM routes elicited robust serum HA-specific antibody responses when compared to control animals at one- and four-weeks post-boost, whereas the oral route resulted in poor antibody induction across all samples tested. Piglets nursing from IN and IM vaccinated dams showed a significantly higher level of HA-specific antibodies in serum at 2-3 weeks post-partum compared to control piglets. Notably, IN immunized dams and their piglets showed significantly elevated influenza neutralizing antibodies compared to controls. This work demonstrated that both IN and IM immunization with a huAd5-vectored vaccine robustly induced maternal influenza-specific immunity that supported passive transfer to nursing piglets, with IN immunization resulting in superior transfer of neutralizing antibodies.

immunology↗

bioRxiv2023

The histone lysine demethylase KDM5C fine-tunes gene expression to regulate dendritic cell heterogeneity and function

The functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses that are essential for providing host protection. We found that KDM5C, a histone lysine demethylase of the KDM5 family regulates several aspects of conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Using mice conditionally deficient in KDM5C in DCs, we found that loss of KDM5C results in an increase in Ly6C- pDCs compared to Ly6C+ pDCs. We found that Ly6C- pDCs, compared to Ly6C+ pDCs, have increased expression of cell cycle genes, decreased expression of activation markers and limited ability to produce type I interferon (IFN). Both KDM5C-deficient Ly6C- and Ly6C+ pDCs have increased expression of activation markers, however, are dysfunctional and have limited ability to produce type I IFN. For conventional cDCs, KDM5C deficiency resulted in increased proportions of cDC2Bs (CLEC12A+, ESAM-) and cDC1s, which was partly dependent on type I IFN and pDCs. Using ATAC-seq, RNA-seq, and CUT&RUN for histone marks, we found that KDM5C regulates epigenetic programming of cDC1. In the absence of KDM5C, we found an increased expression of inflammatory markers, consistent with our previous results in bone marrow-derived DCs. However, we also found a decrease in mitochondrial metabolism genes and altered expression of cDC lineage-specific genes. In response to Listeria infection, KDM5C-conditionally deficient mice mounted reduced CD8+ T cell responses, indicating that KDM5C expression in DCs is necessary for their function. Thus, KDM5C is a key regulator of DC heterogeneity by modulating the balance of DC subsets and serves as a critical driver of the epigenetic programming and functional properties of DCs.

immunology↗

bioRxiv2023

Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Pulmonary Alveolar Cell Death Induced by LPS and Coronavirus

Pulmonary inflammation compromises lung barrier function and underlies many lung diseases including acute lung injury and acute respiratory distress syndrome (ARDS). However, mechanisms by which lung cells respond to the damage caused by the inflammatory insults are not completely understood. Here we show that Fzd6-deficiency in Foxj1+ ciliated cells reduces pulmonary permeability, lipid peroxidation, and alveolar cell death accompanied with an increase in alveolar number in lungs insulted by LPS or a mouse coronavirus. Single-cell RNA sequencing of lung cells indicates that the lack of Fzd6, which is expressed in Foxj1+ cells, increases expression of the aldo-keto reductase Akr1b8 in Foxj1+ cells. Intratracheal administration of the Akr1b8 protein phenocopies Fzd6-deficient lung phenotypes. In addition, ferroptosis inhibitors also phenocopy Fzd6-deficient lung phenotypes and exert no further effects in Fzd6-deficient lungs. These results reveal an important mechanism for protection of alveolar cells from ferroptotic death during pulmonary inflammation by Foxj1+ ciliated cells via paracrine action of Akr1b8.

pathology↗

bioRxiv2022

SARS-CoV-2 exposure in Norwegian rats (Rattus norvegicus) from New York City

Millions of Norway rats (Rattus norvegicus)inhabit New York City (NYC), presenting the potential for transmission of SARS-CoV-2 from humans to rats and other wildlife. We evaluated SARS-CoV-2 exposure among 79 rats captured from NYC during the fall of 2021. Results showed that 13 of 79 rats (16.5%) tested IgG or IgM positive, and partial genomes of SARS-CoV-2 were recovered from four rats that were qRT-PCR positive. Using a virus challenge study, we also showed that Alpha, Delta, and Omicron variants can cause robust infections in wild-type Sprague Dawley (SD) rats, including high level replications in the upper and lower respiratory tracts and induction of both innate and adaptive immune responses. Additionally, the Delta variant resulted in the highest infectivity. In summary, our results indicated that rats are susceptible to infection with Alpha, Delta, and Omicron variants, and rats in the NYC municipal sewer systems have been exposed to SARS-CoV-2. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations. ImportanceSince its emergence causing the COVID-19 pandemic, the host tropism expansion of SARS-CoV-2 raises a potential risk for reverse-zoonotic transmission of emerging variants into rodent species, including wild rat species. In this study, we presented both genetic and serological evidence for SARS-CoV-2 exposure in wild rat population from New York City, and these viruses are potentially linked to the viruses during the early stages of the pandemic. We also demonstrated that rats are susceptible to additional variants (i.e., Alpha, Delta, and Omicron) predominant in humans and that the susceptibility to different variants vary. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations.

microbiology↗

bioRxiv2022

Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. However, the metabolic pathways critical for optimal T cell responses remain poorly understood. Here, we identify ketone bodies (KBs) - including {beta}-hydroxybutyrate ({beta}OHB) and acetoacetate (AcAc) - as essential fuels supporting CD8+ T cell metabolism and effector function. Ketolysis is an intrinsic feature of highly functional CD8+ T effector (Teff) cells and {beta}OHB directly increases CD8+ Teff cell IFN-{gamma} production and cytolytic activity. Using metabolic tracers, we establish that CD8+ Teff cells preferentially use KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boost the respiratory capacity of CD8+ T cells and TCA cycle-dependent metabolic pathways that fuel T cell growth. Mechanistically, we find that {beta}OHB is a major substrate for acetyl-CoA production in CD8+ T cells and regulates effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses. One Sentence summaryKetone bodies promote CD8+ T cell metabolism and effector function through regulation of epigenetic programming

immunology↗

bioRxiv2020

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

immunology↗