Abstract Up to 25% of SARS-CoV-2 patients exhibit post-acute cognitive sequelae. Although millions of cases of COVID-19-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1, a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of COVID-19 patients. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 beta variant, leads to CNS infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1β and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes post-acute cognitive deficits. Breakthrough infection after vaccination with a low dose of adenoviral vectored Spike protein prevents hippocampal production of IL-1β during breakthrough SARS-CoV-2 infection, loss of neurogenesis, and subsequent memory deficits. Our study identifies IL-1β as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new murine model that is prevented by vaccination.
Background: Bourbon virus (BRBV) is an emerging pathogen that can cause severe and fatal disease in humans. BRBV is vectored by Amblyomma americanum (lone star ticks), which are widely distributed across the central, southern, and eastern United States. Wildlife species are potentially important for the maintenance and transmission of BRBV, but little is known about which species are involved, and what other factors play a role in their exposure to BRBV. Methods: To assess the exposure risk to BRBV among wildlife in the St. Louis, Missouri, area, we collected sera from 98 individuals, representing 6 different mammalian species from two locations in St. Louis County: Tyson Research Center (TRC) and WildCare Park (WCP) from fall 2021 to spring 2023. The sera were used in a BRBV neutralization assay to detect neutralizing antibodies and RT-qPCR for viral RNA analysis. We also sampled and compared the abundance of A. americanum ticks at the two locations and modeled which factors influenced BRBV seropositivity across species. Results: In TRC, we observed a high rate of seropositivity in raccoons (Procyon lotor, 23/25), and white-tailed deer (Odocoileus virginianus, 18/27), but a low rate in opossums (Didelphis virginiana, 1/18). Neutralizing antibodies were also detected in sampled TRC bobcats (Lynx rufus, 4/4), coyotes (Canis latrans, 3/3), and a red fox (Vulpes vulpes, 1/1). The virological analysis did not detect BRBV RNA in any serum samples. In contrast to TRC, all sera screened from WCP were negative for BRBV-specific neutralizing antibodies, and significantly fewer ticks were collected at WCP (31) compared with TRC (2316). Conclusions: Collectively, these findings suggest that BRBV circulates in multiple wildlife species in the St. Louis area and that tick density and host community composition may be important factors in BRBV ecology.
Low-cost biosensors that can rapidly and widely detect viruses are critical for faster diagnosis and treatment decision-making, especially for infections. The commonly used field-effect transistor is sensitive to the biomarker's detection but struggles with precise detection, particularly of nontargets such as ions and proteins. To overcome this limitation, we developed a field-effect transistor biosensor design based on MXene-graphene materials to increase the accuracy and sensitivity of virus detection. Based on the hybridization process between two complementary DNA strands, single-stranded nucleic acids were immobilized on the sensing surface via 3-aminopropyltriethoxysilane and glutaraldehyde to capture the nucleic acids of the target virus. The addition of the MXene layer provides a reduced system capacitance and tuned bandgap compared to that of stand-alone graphene. This tuning can significantly enhance the sensitivity of the developed platform. The SARS-CoV-2 and its Omicron variant were used to validate the developed biosensor. The results showed high accuracy with detection limits as low as 1 × 10–21 and 1 × 10–22 mol/L (60.2 and 6.02 copies/L equivalently), for SARS-CoV-2 and its Omicron variant, respectively. Twenty-four clinical tests were also conducted using the developed ssDNA-MXene-graphene biosensors with patients' nasopharyngeal swab samples. The biosensor's results closely matched those of the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) detection but with a significantly shorter detection time, demonstrating the sensors' real-time, in situ, practical application. This result also demonstrates the promising future of MXene-based biosensors for virus detection using nucleic acid probes.
Airborne transmission via virus-laden aerosols is a dominant route for the transmission of respiratory diseases, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Direct, non-invasive screening of respiratory virus aerosols in patients has been a long-standing technical challenge. Here, we introduce a point-of-care testing platform that directly detects SARS-CoV-2 aerosols in as little as two exhaled breaths of patients and provides results in under 60 s. It integrates a hand-held breath aerosol collector and a llama-derived, SARS-CoV-2 spike-protein specific nanobody bound to an ultrasensitive micro-immunoelectrode biosensor, which detects the oxidation of tyrosine amino acids present in SARS-CoV-2 viral particles. Laboratory and clinical trial results were within 20% of those obtained using standard testing methods. Importantly, the electrochemical biosensor directly detects the virus itself, as opposed to a surrogate or signature of the virus, and is sensitive to as little as 10 viral particles in a sample. Our platform holds the potential to be adapted for multiplexed detection of different respiratory viruses. It provides a rapid and non-invasive alternative to conventional viral diagnostics.
Abstract Please cite this paper as: Evseenko et al. (2011) Genetic composition of contemporary swine influenza viruses in the West Central region of the United States of America. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2010.00189.x. Background Because of continuous circulation in different animal species and humans, influenza viruses have host-specific phenotypic and genetic features. Reassortment of the genome segments can significantly change virus phenotype, potentially generating virus with pandemic potential. In 2009, a new pandemic influenza virus emerged. Objectives In this study, we attempted to find precursor viruses or genes of pandemic H1N1 influenza 2009 among 25 swine influenza viruses, isolated in the West Central region of the United States of America (USA), between 2007 and 2009. The Phylogenetically Similar Triple-Reassortant Internal Genes (PSTRIG) cassette of all the viruses studied here as well as the PSTRIG cassette of pandemic H1N1 viruses have close but equidistant phylogenetic relationships to the early triple-reassortant swine H3N2 influenza A isolated in the USA in 1998. Methods Samples (nasal swabs and lung tissue lavage) were taken from swine with or without clinical signs of respiratory disease via farmer-funded syndromic surveillance. All studied viruses were isolated in Madin–Darby Canine Kidney cell cultures from the above-mentioned samples according to standard protocols recommended for influenza virus isolation. Sequences were obtained using BigDye Terminator v3.1 Cycle Sequencing kit. Phylogenetic trees were built with MEGA 4.0 software using maximum composite likelihood algorithm and neighbor-joining method for tree topology reconstruction. Results Among the 25 viruses studied, we have not found any gene segments of Eurasian origin. Our results suggest that pandemic H1N1 viruses diverged and are not directly descended from swine viruses that have been circulating in USA since 1998.
The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.
Abstract We developed a prospective observational cohort of COVID-19 and influenza patients to assess the quality and magnitude of their immune responses at the cellular and protein levels. Although COVID-19 patients exhibited equivalent lymphocyte counts compared to influenza patients, they had fewer monocytes and lower surface HLA-class II expression on select monocyte populations compared to influenza patients and healthy controls. Decreased HLA-DR on intermediate monocytes was a significant predictor of COVID-19 disease severity. Protein cytokine levels were measured in two distinct COVID-19 cohorts, composed of 73 and 89 patients, revealing multiple inflammatory phenotypes. Only four percent of patients (7 of 162) exhibited a distinct Cytokine Storm Syndrome (CSS) phenotype. Furthermore, COVID-19 patients generally exhibited lower cytokine levels than influenza patients. Upregulation of a few innate inflammatory mediators, including IL-6, GCSF, IL-1RA, and MCP1, predicted death from acute respiratory failure among COVID-19 patients but were not statistically higher than those of influenza patients. Single-cell transcriptional profiling of 2 healthy controls as well as 3 COVID-19 and 3 influenza subjects with respiratory failure was concordant with the profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple cell types. In contrast, COVID-19 cells were enriched for alterations in metabolic, stress, and apoptotic pathways. When considered across the spectrum of peripheral innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct, with COVID-19 patients generally less inflamed than those with influenza.
We have developed a porcine intestine epithelial cell line, designated SD-PJEC for the propagation of influenza viruses. The SD-PJEC cell line is a subclone of the IPEC-J2 cell line, which was originally derived from newborn piglet jejunum. Our results demonstrate that SD-PJEC is a cell line of epithelial origin that preferentially expresses receptors of oligosaccharides with Sia2-6Gal modification. This cell line is permissive to infection with human and swine influenza A viruses and some avian influenza viruses, but poorly support the growth of human-origin influenza B viruses. Propagation of swine-origin influenza viruses in these cells results in a rapid growth rate within the first 24 h post-infection and the titres ranged from 4 to 8 log(10) TCID(50) ml(-1). The SD-PJEC cell line was further tested as a potential alternative cell line to Madin-Darby canine kidney (MDCK) cells in conjunction with 293T cells for rescue of swine-origin influenza viruses using the reverse genetics system. The recombinant viruses A/swine/North Carolina/18161/02 (H1N1) and A/swine/Texas/4199-2/98 (H3N2) were rescued with virus titres of 7 and 8.25 log(10) TCID(50) ml(-1), respectively. The availability of this swine-specific cell line represents a more relevant substrate for studies and growth of swine-origin influenza viruses.
CD137 is a costimulatory receptor expressed on natural killer cells, T cells, and subsets of dendritic cells. An agonistic monoclonal antibody (mAb) against CD137 has been used to reduce tumor burden or reverse autoimmunity in animal models and clinical trials. Here, we show that mice treated with an agonistic anti-CD137 mAb have reduced numbers of germinal center (GC) B cells and follicular dendritic cells (FDCs) in lymphoid tissues, which impair antibody responses to multiple T-cell-dependent antigens, including infectious virus, viral proteins, and conjugated haptens. These effects are not due to enhanced apoptosis or impaired proliferation of B cells but instead correlate with changes in lymphoid follicle structure and GC B cell dispersal and are mediated by CD137 signaling in CD4+ and CD8+ T cells. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may impair long-term antibody and B cell memory responses.
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