Biology subjects

Corry, J.

Publications and source records attributed to Corry, J..

6 recordsLinked to original sources

bioRxiv2026

Productive Mayaro Virus Infection Requires Host Fatty Acid Synthase for nsP1 S-palmitoylation

To date, twenty-seven pathogenic human viruses require host-catalyzed de novo fatty acid biosynthesis for replication. This pathway is driven by fatty acid synthase (FASN), which produces palmitate. Palmitate is a precursor for various functions during viral infection, including lipid droplet formation for assembly, beta-oxidation for ATP generation, and post-translational modification of proteins. Whether Mayaro virus (MAYV), an emerging alphavirus that causes debilitating arthritogenic disease, required FASN for infection was unknown. Using genetic and pharmacological approaches in a human cell line and primary cell model, we found that MAYV requires FASN-dependent palmitate synthesis for virion production. To determine how palmitate contributes to infection, we pharmacologically inhibited pathways downstream of FASN and found that only 2-bromopalmitate (2-BP), a protein palmitoylation inhibitor, led to a 94% reduction in MAYV infection. S-palmitoylation is a post-translational modification in which palmitate is attached to sulfur atoms in cysteine residues. In chikungunya virus, a related alphavirus, FASN-dependent palmitoylation of nonstructural protein 1 (nsP1) is essential for membrane association and replication. Consequently, we hypothesized that MAYV nsP1 is palmitoylated in a FASN-dependent manner. Using an alkyne acetate analog, Alk-4, metabolized by FASN into alkyne palmitate, we observed specific labeling of wild-type nsP1 at conserved cysteine residues (C417-419), but not of a cysteine-to-alanine triple mutant. Treatment with TVB-2640 or 2-BP abrogated Alk-4 labeling of wild-type nsP1 during active infection, reinforcing that MAYV protein palmitoylation is a FASN-dependent process. Our findings reveal a conserved mechanism of FASN-dependent protein palmitoylation in alphaviruses and highlight FASN as a potential anti-viral target. ImportanceMayaro virus (MAYV) is a neglected, mosquito-borne tropical virus that causes debilitating pathologies, such as chronic joint pain that can last from months to years. Currently, MAYV transmissions are endemic in sylvatic and peri-urban regions in Central and South America and the Caribbean. However, MAYV has been detected in urban-adapted mosquitos like Aedes aegypti (Ae. aegypti) and is a concern for potential global spread. Consequently, investigating the mechanisms of MAYV infection is critical to uncover opportunities for antiviral drug development. In this study, we report that MAYV infection requires host fatty acid synthase (FASN) derived palmitate for palmitoylation of the viral non-structural protein 1 (nsP1). In addition, we report that inhibiting FASN with the clinically advanced small molecule TVB-2640 significantly reduced MAYV infection and nsP1 palmitoylation. This study highlights FASN as an essential host factor for MAYV replication and establishes it as a promising therapeutic target for MAYV and related alphaviruses.

microbiology↗

bioRxiv2026

Compartment-specific soluble immune profiles associated with preterm birth, perinatal death, and low birthweight in pregnant individuals living with HIV

BackgroundHuman immunodeficiency virus (HIV) infection in pregnancy is associated with preterm birth (PTB), low birthweight (LBW), and perinatal death (PND). Although antiretroviral therapy (ART) suppresses viral load it does not prevent HIV-associated adverse pregnancy outcomes or resolve inflammation. As circulating maternal immune factors may not fully capture maternal-fetal interface immune dysregulation, this observational cohort study aimed to identify localized and systemic immune factors associated with PTB, LBW and PND in ART-treated pregnant people living with HIV (PPLWH). MethodsWe enrolled 118 PPLWH in Kinshasa, Democratic Republic of the Congo, during the second or third trimester. We collected maternal peripheral plasma (at enrollment, 1-3 days post-delivery, and postpartum) alongside umbilical cord and placental plasma at delivery. Concentrations of 45 immune factors were measured via LegendPlex and ELISAs and associations analyzed using Kruskal-Wallis tests with Dunns correction or Mann-Whitney tests. ResultsPlacental plasma exhibited the highest overall concentrations of immune factors, highlighting a distinct localized microenvironment. Among 118 pregnancies, 35 (30%) resulted in PTB, 10 (9%) in PND, and 9 (8%) in LBW. Compared to term births, PTB was associated with higher levels of the chemokines CCL20, CXCL9, and CXCL10 in cord and/or postdelivery plasma (p<0.01), while placental CCL20 levels were lower (p<0.05). Compared to live births, PND was associated with higher postdelivery CXCL1, cord IL-8, placental MPO and NGAL (p<0.05); higher postdelivery CXCL5 (p<0.01); and higher S100A8/A9 levels in cord and postdelivery plasma (p<0.01 and p<0.001, respectively). Finally, LBW was associated with higher enrollment IL-18 and S100A8/A9 levels (p<0.05 and p<0.01, respectively); as well as higher SAA levels in postdelivery and postpartum plasma (p<0.05). ConclusionsIn ART-treated PPLWH, distinct adverse birth outcomes are driven by time- and compartment-specific immune pathways. PTB is associated with localized T-cell chemokine responses, PND with neutrophil recruitment and activation, and LBW with pro-inflammatory cytokine and acute-phase protein responses. These pathways provide mechanistic insights into pregnancy complications in PPLWH and highlight potential compartment-specific biomarkers for risk stratification.

microbiology↗

bioRxiv2025

The cervicovaginal microbiome of pregnant people living with HIV on antiretroviral therapy in the Democratic Republic of Congo: A Pilot Study and Global Meta-analysis.

Recent studies are revealing that a suboptimal cervicovaginal microbiome (CVMB), including enrichment of anaerobic bacteria associated with multiple female genital disorders, and adverse pregnancy and birth outcomes in pregnant people. Problematically, however, the majority of the available data to date are biased towards highly developed, Global North countries, leaving underrepresented populations like the Democratic Republic of Congo (DRC) poorly characterised. Here, we investigate the CVMB from a cohort of 82 pregnant people living with HIV (PLWH) on antiretroviral therapy (ART) from the DRC. Specifically, we explore the associations between the CVMB via 16S rRNA gene sequencing and maternal peripheral immune factors. Additionally, we compare the CVMB of PLWH-ART from DRC to publicly available CVMB data (5 studies, 1861 samples) in a meta-analysis to elucidate the impact of HIV on the CVMB. Combined, these analyses revealed differences in community structure and predicted function of the microbiota between PLWH-ART and pregnant people without HIV (PWoH). Taxonomically, the CVMB of DRC PLWH-ART were enriched for Lactobacillus iners-dominated CVMBs (53%) or a diverse, polymicrobial CVMB, i.e., bacterial vaginosis (BV) (43%). Functional predictions made from these taxa suggested that protein-coupled receptors, amino sugar and nucleotide sugar metabolism, fatty acid metabolism, and polycyclic aromatic hydrocarbon degradation pathways were differentially abundant between communities. Correlation with host plasma immune factors revealed putative links between some CVMB metrics (e.g., alpha diversity and species abundance) that have been linked to adverse pregnancy and birth outcomes. ImportanceHIV remains prevalent in sub-Saharan Africa, where it has been linked to adverse birth outcomes. . Suboptimal CVMBs have shown similar links. This pilot study fills critical gaps in understanding how HIV interacts with the pregnant CVMB in populations underrepresented in microbiome research, like the Democratic Republic of Congo. We identified maternal systemic immune factors associated with suboptimal CVMBs that have been linked to poor birth outcomes. In a global meta-analysis, we found significant taxonomic and functional difference in the CVMBs between pregnant people living with and without HIV, revealing potential biomarkers that for increased risks for adverse birth outcomes. These findings provide crucial insights into CVMB features that may influence pregnancy health in pregnant people living with HIV, guiding future research and tailored interventions to support safer pregnancies in the DRC and similar populations.

microbiology↗

bioRxiv2022

The Cdc42 effector and non-receptor tyrosine kinase, ACK defines a distinct STAT5 transcription signature in a chronic myeloid leukaemia cell model

Activated Cdc42-associated kinase (ACK) is a Rho family effector that is widely implicated in cancer. Here, we describe new roles for ACK in transcriptional regulation mediated by its relationship with the signal transducer and activators of transcription (STAT) family. We show that ACK can interact with STAT3, STAT5A and STAT5B, and augments phosphorylation at the conserved activation tyrosine on these STAT members. ACK stimulates oncogenic STAT nuclear relocation and transcriptional activation. We also identify endogenous relationships between ACK and STAT family members in haematopoietic disease cell lines. In the K562 chronic myeloid leukaemia cell line, we confirm that ACK contributes to the pool of active, nuclear STAT5. By interrogating ACK knock out cells we describe an ACK-driven STAT5 transcriptional signature in K562s. We propose ACK as a contributor to hyperactivated STAT5 signalling in this CML cell line and reveal a new route for therapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/494364v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1c4973dorg.highwire.dtl.DTLVardef@1a54ba1org.highwire.dtl.DTLVardef@1083bf9org.highwire.dtl.DTLVardef@1997ad0_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant(R)), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection. One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

microbiology↗

bioRxiv2019

Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK

The tyrosine kinase ACK is an oncogene associated with poor prognosis in human cancers. ACK promotes proliferation, in part, by contributing to the activation of Akt, the major PI3-Kinase effector. We show that ACK also regulates PI3-Kinase directly, via interactions with the PI3-Kinase regulatory subunits. ACK interacts with all five regulatory subunit isoforms and directly phosphorylates p85, p85{beta}, p55 and p50 on Tyr607 (or equivalent). Phosphorylation of p85{beta} at this residue promotes cell proliferation but, counterintuitively, ACK does not stimulate PI3-Kinase catalytic activity. We show that ACK stabilizes p85 levels by promoting an interaction between the p85 nSH2 domain and pTyr607, protecting p85 from ubiquitination. We demonstrate that ACK interacts with p85 exclusively in nuclear-enriched cell fractions where the increased levels of the regulatory subunits, together with the nSH2-pTyr607 interaction, promote formation of dimeric p85. We postulate that these novel dimers undertake nuclear functions that contribute to Cdc42-ACK driven oncogenesis. We propose that ACK shapes PI3-Kinase signalling by dampening the PIP3 response, whilst continuing to drive cell proliferation through Akt activation and hereto unexplored but crucial functions of nuclear dimeric p85. These new regulatory subunit dimers represent a previously undescribed mode of regulation for PI3-Kinase and potentially reveal additional avenues for therapeutic intervention.

molecular biology↗