Project description:Viral respiratory infections are an important public health concern, due to their prevalence, transmissibility, and potential to cause serious disease. Disease severity is the product of several factors beyond the presence of the infectious agent, including specific host immune responses, host genetic makeup and bacterial co-infections. To understand these interactions within natural infections we designed a longitudinal cohort study actively surveilling 18 different respiratory viruses over the course of 19 months (2016-2018) in Manhattan, New York City. The cohort includes individuals related to daycare facilities, high school students and health care workers. We retrieved weekly epidemiological and clinical data and collected over 4,000 nasal swabs for molecular characterization from 214 participants. Transcriptomic data enabled the characterization of specific markers of immune response, the identification of signatures associated with symptom severity and bacterial co-infections. We created a computational resource to facilitate access to the data and visualization of analytical results.
Project description:MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Herein, we observe that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provided protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogated the protection conferred by MV130 against Influenza A virus respiratory infection. MV130 induced reprogramming of mouse bone marrow progenitor cells and human monocytes, promoting an enhanced cytokine production that relied on metabolic and epigenetic shifts. Our results unveil that the mucosal a dministration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity. This SuperSeries is composed of the SubSeries listed below.
Project description:BACKGROUND: 50% to 80% of asthma exacerbations are precipitated by viral upper respiratory tract infections (RTI), yet the influence of viral pathogen diversity on asthma outcomes is poorly understood due to the limited scope and throughput of conventional viral detection methods. METHODS: We investigated the capability of the Virochip, a DNA microarray-based viral detection platform, to characterize the viral diversity in RTIs in asthmatic and non-asthmatic adults. RESULTS: The Virochip detected viruses in a higher proportion of samples (65%) than culture isolation (17%), while exhibiting high concordance (98%), sensitivity (97%) and specificity (98%) with pathogen-specific PCR. A similar spectrum of viruses was identified in the RTIs from each patient subgroup; however, unexpected diversity among the coronaviruses (HCoVs) and HRVs was revealed. All but one of the HCoVs corresponded to the newly-recognized HCoV-NL63 and HCoV-HKU1 viruses, and over 20 different serotypes of HRVs were detected, including a set of 5 divergent isolates that form a distinct genetic subgroup. CONCLUSIONS: The Virochip can detect both known and novel variants of viral pathogens present in RTIs. Given the diversity detected here, larger scale studies will be necessary to determine if particular substrains of viruses confer an elevated risk of asthma exacerbation This SuperSeries is composed of the SubSeries listed below.
Project description:Background: Distinguishing between bacterial and viral lower respiratory tract infections (LRTI) in hospitalized patients remains challenging. Transcriptional profiling is a promising tool for improving diagnosis in LRTI. Methods: We performed whole blood transcriptional analysis in a cohort of 118 adult patients (median [IQR] age, 61 [50-76] years) hospitalized with bacterial, viral or viral-bacterial LRTI, and 40 age-matched healthy controls (60 [46-70] years). We applied class comparisons, modular analysis and class prediction algorithms to identify distinct biosignatures for bacterial and viral LRTI, which were validated in an independent group of patients. Results: Patients were classified as bacterial (B, n=22), viral (V, n=71) and bacterial-viral LRTI (BV, n=25) based on comprehensive microbiologic testing. Compared with healthy controls statistical group comparisons (p<0.01; with multiple test corrections) identified 3,376 differentially expressed genes in patients with B-LRTI; 2,391 in V-LRTI, and 2,628 in BV-LRTI. Independent of etiologic pathogen, patients with LRTI demonstrated overexpression of innate immunity and underexpression of adaptive immunity genes. Patients with B-LRTI showed significant overexpression of inflammation (B>BV>V) and neutrophils (B>BV>V) while those with V-LRTI displayed significantly greater overexpression of interferon genes (V>BV>B). The K-Nearest Neighbors (K-NN) algorithm identified 10 classifier genes that discriminated patients with bacterial vs viral LRTI with 97% [95%CI: 84-100] sensitivity and 92% [77-98] specificity. In comparison, procalcitonin classified bacterial vs viral LRTI with 38% [18-62] sensitivity and 91% [76-98] specificity. Conclusions: Transcriptional profiling can be used as a helpful tool for the diagnosis of adults hospitalized with LRTI. 158 samples, no replicates; bacterial LRTI n=22, viral LRTI n=71, bacterial-viral coinfections n=25, and healthy controls n=40
Project description:<p>The overall purpose of this study is to investigate the host genetic factors in response to influenza virus infection, with the focus on influenza vaccination in the first substudy "Adult Influenza Vaccine Genetics" and with the focus on influenza natural infection and other acute respiratory infections (ARIs) in the second substudy "Acute Viral Respiratory Infection Genetics". In the first substudy, healthy adults were enrolled in 2008 (male cohort) and 2010 (female cohort) and immunized with seasonal influenza vaccine. In the second substudy, healthy adults were invited to enroll to be followed for acute respiratory illness through two consecutive influenza seasons 2009-2010 and 2010-2011. Peripheral blood genomic DNA samples were collected from all the subjects, and time-series RNA and serum samples were obtained pre- and post- immunization/infection. Genotyping was carried out on peripheral blood genomic DNA samples using Illumina HumanOmniExpress-12 v1 arrays. Peripheral blood RNA samples obtained at each visit were analyzed using Illumina Human HT-12 (for all the samples) and HiSeq 2000 (for 130 samples in the "Acute Viral Respiratory Infection Genetics" study). Serum specimens were tested using hemagglutination-inhibition (HAI) antibody assay for Influenza H1N1, H3N2, and Influenza B strains.</p> <p>A detailed description of each substudy is provided under their own pages below and via the grouping tool in the right-hand box: <ul> <li><a href="./study.cgi?study_id=phs000635">phs000635</a> Adult Influenza Vaccine Genetics</li> <li><a href="./study.cgi?study_id=phs001031">phs001031</a> Acute Viral Respiratory Infection Genetics</li> </ul> </p>
Project description:Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated after in vitro influenza infection across multiple human epithelial cell lines and influenza A virus subtypes. VILMIR was also upregulated after SARS-CoV-2 and RSV infections in vitro. We experimentally confirmed the response of VILMIR to influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression of VILMIR was robustly induced by IFN-β treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered that VILMIR was upregulated across various cell types including at least five immune cells. The upregulation of VILMIR in immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown of VILMIR expression reduced the magnitude of host transcriptional responses to IFN-β treatment in A549 cells. Together, our results show that VILMIR is a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.
Project description:A pressing clinical challenge is identifying the etiologic basis of acute respiratory illness. Without reliable diagnostics, the uncertainty associated with this clinical entity leads to a significant, inappropriate use of antibacterials. Use of host peripheral blood gene expression data to classify individuals with bacterial infection, viral infection, or non-infection represents a complementary diagnostic approach. Patients with respiratory tract infection along with ill, non-infected controls were enrolled through the emergency department or undergraduate student health services. Whole blood was obtained to generate gene expression profiles. These profiles were then used to generate signatures of bacterial acute respiratory infection, viral acute respiratory infection, and non-infectious illness. 273 subjects were ascertained for this analysis. This included 88 patients with non-infectious illness, 115 with viral acute respiratory infection, and 70 with bacterial acute respiratory infection. Samples were obtained at the time of enrollment, which was at initial clinical presentation. Total RNA was extracted from human blood using the PAXgene Blood RNA Kit. Microarray data were generated using the GeneChip Human Genome U133A 2.0 Array. Microarrays were generated in two microarray batches with seven overlapping samples giving rise to 280 total microarray experiments.