Biology subjects

Kovats, S.

Publications and source records attributed to Kovats, S..

6 recordsLinked to original sources

bioRxiv2025

Persistent CD4+ T cell functional deficits during recovery from prolonged symptomatic SARS-CoV-2 infection

Symptoms of acute SARS-CoV-2 infection often resolve quickly but are sometimes associated with persistent immune dysfunction. The factors that predispose individuals to compromised immune function have not been well defined. We investigated CD4+ T cell phenotype and function in a small cohort of individuals who recovered from mild to moderate SARS-CoV-2 infection without hospitalization and were divided into short or prolonged symptom duration groups. Five individuals with prolonged symptom duration showed marked downregulation of CD4 on CD3+CD8- T cells (CD4low group) and a poor response to TCR stimulation with the superantigen Staphylococcal enterotoxin B (SEB), as shown by weak upregulation of the activation markers CD134 and CD69. CD4 surface intensities recovered to normal levels in four of these individuals within 3-12 months. Selected cytokines (IL-1RA, IL-7, and VEGF) were elevated in individuals with low CD4, but plasma levels of anti-S1 IgG did not correlate with CD4 defects. Bulk RNA sequencing of unstimulated and SEB-treated CD3+CD8- T cells revealed a >50% reduction in the number of differentially expressed genes in the CD4low group compared to the same individuals after CD4 levels were recovered and a healthy control group. Upstream regulator analysis of differentially expressed genes in unstimulated CD4low cells suggested a response to IFN, while SEB-stimulated CD4low cells showed reduced functionality of IL-2, CD28, and SATB1 regulated pathways. In summary, prolonged symptomatic recovery from SARS-CoV-2 infection was associated with a global CD4+ T cell response defect, defined by low surface CD4 expression, evidence of IFN signaling, and defective T cell activation.

immunology↗

bioRxiv2025

ANDROGENS PROTECT ILC2S FROM FUNCTIONAL SUPPRESSION DURING INFLUENZA VIRUS INFECTION

Biological sex differences in morbidity upon influenza A virus (IAV) infection are linked to stronger IFN-centered immune responses in females, yet the regulatory role of sex hormone receptors in immune cell subsets is incompletely understood. Lung-resident group 2 innate lymphoid cells (ILC2s) express notably high levels of androgen receptors (AR). In IAV infection, ILC2s produce type 2 cytokines and facilitate tissue repair, but they also may be functionally suppressed by type 1 cytokines. Here we report sex differences in the magnitude of lung ILC2 functional suppression at the peak of sublethal IAV infection. Relative to males, ILC2s in females show attenuated proliferation, decreased propensity for IL-5 and amphiregulin production and reduced expression of GATA3 and IL-33R, features supported by divergent transcriptomes. Equivalent inflammatory cytokine levels and viral load suggested sex differences in ILC2-intrinsic factors. Indeed, naive female ILC2s showed elevated IFNGR expression and higher phospho-STAT1 levels following IFN{gamma} stimulation, and lymphocyte-restricted STAT1 deficiency reversed IAV-induced suppression of female ILC2s. Lymphocyte-restricted AR deficiency or loss of androgens via orchiectomy led to increased IFNGR expression and suppression of male ILC2s. These data support the hypothesis that intrinsic AR activity regulates IFNGR-STAT1 signaling pathways to preserve canonical ILC2 function in males during IAV infection.

immunology↗

bioRxiv2023

A single-cell atlas of the aging murine ovary

Ovarian aging leads to diminished fertility, dysregulated endocrine signaling, and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Around 35 years old, women experience a sharp decline in fertility, corresponding to declines in oocyte quality. Despite a growing body of work, the field lacks a comprehensive cellular map of the transcriptomic changes in the aging ovary to identify early drivers of ovarian decline. To fill this gap, we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with lymphocyte proportions increasing the most, which was confirmed by flow cytometry. We also found an age-related downregulation of collagenase pathways in stromal fibroblasts, which corresponds to rises in ovarian fibrosis. Follicular cells displayed stress response, immunogenic, and fibrotic signaling pathway inductions with aging. This report raises provides critical insights into mechanisms responsible for ovarian aging phenotypes.

cell biology↗

bioRxiv2023

Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge

BackgroundDuring infectious diseases, pro-inflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury. MethodsCytokine-dependent ubiquitination and proteasomal degradation of ERG was analyzed in cultured Human Umbilical Vein ECs (HUVECs). Systemic administration of TNF or the bacterial cell wall component lipopolysaccharide (LPS) was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine Erg deletion was genetically induced in ECs (Ergfl/fl;Cdh5(PAC)CreERT2), and multiple organs were analyzed by histology, immunostaining, and electron microscopy. ResultsIn vitro, TNF promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNF or LPS resulted in a rapid and substantial degradation of ERG within lung ECs, but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection. Ergfl/fl;Cdh5(PAC)-CreERT2 mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of Tek, a gene target of ERG previously implicated in maintaining pulmonary vascular stability during inflammation. ConclusionsCollectively, our data highlight a unique role for ERG in pulmonary vascular function. We propose that cytokine-induced ERG degradation and subsequent transcriptional changes in lung ECs play critical roles in the destabilization of pulmonary blood vessels during infectious diseases.

cell biology↗

bioRxiv2022

DIETARY PROTECTION AGAINST THE VISUAL AND MOTOR DEFICITS INDUCED BY EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE). This model of autoimmune-mediated demyelination induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS). Here, we report that limiting dietary carbohydrates by feeding mice a ketogenic diet (KD) enriched in medium chain triglycerides, -linolenic acid, and fiber is effective at mitigating EAE-induced optic neuritis and motor deficits. The KD was efficacious when fed as a preventive regimen prior to EAE immunization as well as when initiated as an interventional regimen following the onset of EAE symptoms. The KD minimally impacted body weight during the experimental time course, increased circulating ketones, prevented motor and ocular deficits, preserved myelination of the optic nerve, and reduced infiltration of immune cells to optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with EAE-mediated pathological inflammation. In light of ongoing clinical trials using dietary strategies to treat people with MS, these findings support that a KD promotes a systemic anti-inflammatory milieu and ameliorates autoimmune-induced demyelinating visual and motor deficits.

immunology↗

bioRxiv2021

Peptide Aggregation Induced Immunogenic Rupture (PAIIR)

Under the influence of stress and membrane damage, cells undergo immunogenic cell death (ICD), which involves the release of damage associated molecular patterns (DAMPs), natural adjuvants for enhancing an immune response. In the presence of an antigen, released DAMPs can determine the type and magnitude of the immune response, and therefore the longevity and efficacy of an antigen-specific immunity. In the last decade, the immune response effect of ICD has been shown, yet there is no tool that can induce controlled ICD with predictable results, regardless of the cell type. We designed a peptide-based tool, called [II], for controlled damage to cell membrane to induce ICD and DAMPs release. Herein we describe a series of experiments that determine that the mechanism of action of [II] includes a caspase-dependent ICD and subsequent release of immune stimulating DAMPs, on various cell types. Moreover, we tested the hypothesis that controlled DAMP release via [II] in vivo was associated with enhancement of antigen-specific adaptive immunity with influenza hemagglutinin (HA) subunit vaccine. HA and [II] showed significantly higher HA specific IgG1 and IgG2a antibodies, compared to HA-only immunized mice, while the peptide itself did not elicit antibodies. In this paper, we demonstrate the first peptide-aggregation induced immunogenic rupture (PAIIR) approach as vaccine adjuvants for increasing both humoral and cellular immunity. In consideration of its ability to enhance IgG2a responses that are associated with heterosubtypic influenza virus protection, PAIIR is a promising adjuvant to promote universal protection upon influenza HA vaccination.

bioengineering↗