Integrated epigenomic exposure signature discovery.

The epigenome influences gene regulation and phenotypes in response to exposures. Epigenome assessment can determine exposure history aiding in diagnosis. Here we developed and implemented a machine learning algorithm, the exposure signature discovery algorithm (ESDA), to identify the most important features present in multiple epigenomic and transcriptomic datasets to produce an integrated exposure signature (ES).

Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk.

Foxp3 acetylation is essential to regulatory T (Treg) cell stability and function, but pharmacologically increasing it remains an unmet challenge. Here, we report that small-molecule compounds that inhibit TIP60, an acetyltransferase known to acetylate Foxp3, unexpectedly increase Foxp3 acetylation and Treg induction. Utilizing a dual experimental/computational approach combined with a newly developed FRET-based methodology compatible with flow cytometry to measure Foxp3 acetylation, we unraveled the mechanism of action of these small-molecule compounds in murine and human Treg induction cell cultures.

A methylation clock model of mild SARS-CoV-2 infection provides insight into immune dysregulation.

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection.

Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection.

We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection.

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females.

Asymptomatic SARS-CoV-2 Infection Is Associated With Higher Levels of Serum IL-17C, Matrix Metalloproteinase 10 and Fibroblast Growth Factors Than Mild Symptomatic COVID-19.

Young adults infected with SARS-CoV-2 are frequently asymptomatic or develop only mild disease. Because capturing representative mild and asymptomatic cases require active surveillance, they are less characterized than moderate or severe cases of COVID-19. However, a better understanding of SARS-CoV-2 asymptomatic infections might shed light into the immune mechanisms associated with the control of symptoms and protection.

Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation.

Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNβ, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNβ mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive.

Antibody Responses to SARS-CoV-2 Following an Outbreak Among Marine Recruits With Asymptomatic or Mild Infection.

We investigated serological responses following a SARS-CoV-2 outbreak in spring 2020 on a US Marine recruit training base. 147 participants that were isolated during an outbreak of respiratory illness were enrolled in this study, with visits approximately 6 and 10 weeks post-outbreak (PO). This cohort is comprised of young healthy adults, ages 18-26, with a high rate of asymptomatic infection or mild symptoms, and therefore differs from previously reported longitudinal studies on humoral responses to SARS-CoV-2, which often focus on more diverse age populations and worse clinical presentation.

Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues.

SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.

Background: Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection.

Methods: This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM).

SARS-CoV-2 Seropositivity among US Marine Recruits Attending Basic Training, United States, Spring-Fall 2020.

In a study of US Marine recruits, seroprevalence of severe acute respiratory syndrome coronavirus 2 IgG was 9.0%. Hispanic and non-Hispanic Black participants and participants from states affected earlier in the pandemic had higher seropositivity rates.

SARS-CoV-2 Transmission among Marine Recruits during Quarantine.

Background: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults.

Methods: We investigated SARS-CoV-2 infections among U.S.

Differential Modulation of Innate Immune Responses in Human Primary Cells by Influenza A Viruses Carrying Human or Avian Nonstructural Protein 1.

The influenza A virus (IAV) nonstructural protein 1 (NS1) contributes to disease pathogenesis through the inhibition of host innate immune responses. Dendritic cells (DCs) release interferons (IFNs) and proinflammatory cytokines and promote adaptive immunity upon viral infection. In order to characterize the strain-specific effects of IAV NS1 on human DC activation, we infected human DCs with a panel of recombinant viruses with the same backbone (A/Puerto Rico/08/1934) expressing different NS1 proteins from human and avian origin.

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1.

Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level.

Pandemic H1N1 influenza A viruses suppress immunogenic RIPK3-driven dendritic cell death.

The risk of emerging pandemic influenza A viruses (IAVs) that approach the devastating 1918 strain motivates finding strain-specific host-pathogen mechanisms. During infection, dendritic cells (DC) mature into antigen-presenting cells that activate T cells, linking innate to adaptive immunity. DC infection with seasonal IAVs, but not with the 1918 and 2009 pandemic strains, induces global RNA degradation.

Comparative analysis of anti-viral transcriptomics reveals novel effects of influenza immune antagonism.

Background: Comparative analysis of genome-wide expression profiles are increasingly being used to study virus-specific host interactions. In order to gain mechanistic insights, gene expression profiles can be combined with information on DNA-binding sites of transcription factors to detect transcription factor activity (by analysis of target gene sets) during viral infections. Here, we apply this approach to study mechanisms of immune antagonism elicited by Influenza A virus (New Caledonia/20/1999) by comparing the transcriptional response with the non-pathogenic Newcastle disease virus (NDV), which lacks human immune antagonism.

Human Dendritic Cell Response Signatures Distinguish 1918, Pandemic, and Seasonal H1N1 Influenza Viruses.

Unlabelled: Influenza viruses continue to present global threats to human health. Antigenic drift and shift, genetic reassortment, and cross-species transmission generate new strains with differences in epidemiology and clinical severity. We compared the temporal transcriptional responses of human dendritic cells (DC) to infection with two pandemic (A/Brevig Mission/1/1918, A/California/4/2009) and two seasonal (A/New Caledonia/20/1999, A/Texas/36/1991) H1N1 influenza viruses.

Combinatorial cytokine code generates anti-viral state in dendritic cells.

The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naïve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an anti-viral state.

Mouse dendritic cell (DC) influenza virus infectivity is much lower than that for human DCs and is hemagglutinin subtype dependent.

We show that influenza A H1N1 virus infection leads to very low infectivity in mouse dendritic cells (DCs) in vitro compared with that in human DCs. This holds when H3 or H5 replaces H1 in recombinant viruses. Viruslike particles confirm the difference between mouse and human, suggesting that reduced virus entry contributes to lower mouse DC infectivity.

Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts.

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha.

Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: effects of statins and farnesyl and geranylgeranyl transferase inhibitors.

Objective: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB.

Methods: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component.

Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation.

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H.

Resolution of inflammation: prostaglandin E2 dissociates nuclear trafficking of individual NF-kappaB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts.

NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay.

Matrix metalloproteinase secretion by gastric epithelial cells is regulated by E prostaglandins and MAPKs.

Because matrix metalloproteinases (MMPs) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in Helicobacter pylori-induced inflammation and/or cyclooxygenase inhibition. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the MAPK Erk and subsequent protein synthesis but was down-regulated by the alternate MAPK, p38.