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1.
Cell ; 186(19): 4003-4004, 2023 09 14.
Article in English | MEDLINE | ID: mdl-37714131

ABSTRACT

Avian influenza viruses continue to cross the species barrier and infect mammals. In this issue of Cell, Sun and colleagues demonstrate that viruses obtained from humans infected with an emergent avian H3N8 viruses exhibit increasing accumulation of mutations that promote respiratory droplet transmission and disease in mammals.


Subject(s)
Influenza A Virus, H3N8 Subtype , Influenza A virus , Animals , Humans , Influenza A virus/genetics , Mutation , Mammals
2.
Nat Immunol ; 23(5): 781-790, 2022 05.
Article in English | MEDLINE | ID: mdl-35383307

ABSTRACT

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Humans , Phenotype , Receptors, Antigen, T-Cell/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Synthetic , mRNA Vaccines
3.
Nature ; 628(8009): 835-843, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38600381

ABSTRACT

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.


Subject(s)
Lung Injury , Necroptosis , Orthomyxoviridae Infections , Protein Kinase Inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases , Animals , Female , Humans , Male , Mice , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Alveolar Epithelial Cells/metabolism , Influenza A virus/classification , Influenza A virus/drug effects , Influenza A virus/immunology , Influenza A virus/pathogenicity , Lung Injury/complications , Lung Injury/pathology , Lung Injury/prevention & control , Lung Injury/virology , Mice, Inbred C57BL , Necroptosis/drug effects , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , Orthomyxoviridae Infections/virology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , Respiratory Distress Syndrome/virology
4.
Nature ; 587(7834): 466-471, 2020 11.
Article in English | MEDLINE | ID: mdl-33116313

ABSTRACT

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.


Subject(s)
ADAMTS4 Protein/metabolism , Fibroblasts/enzymology , Fibroblasts/pathology , Influenza A virus/pathogenicity , Lung/pathology , Lung/physiopathology , ADAMTS4 Protein/antagonists & inhibitors , Animals , Birds/virology , Extracellular Matrix/enzymology , Gene Expression Profiling , Humans , Influenza in Birds/virology , Influenza, Human/pathology , Influenza, Human/therapy , Influenza, Human/virology , Interferons/immunology , Interferons/metabolism , Leukocyte Common Antigens/metabolism , Lung/enzymology , Lung/virology , Mice , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/virology , Seasons , Single-Cell Analysis , Stromal Cells/metabolism
6.
J Virol ; 98(6): e0177823, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38785423

ABSTRACT

Obesity is well established as a risk factor for many noncommunicable diseases; however, its consequences for infectious disease are poorly understood. Here, we investigated the impact of host obesity on influenza A virus (IAV) genetic variation using a diet-induced obesity ferret model and the A/Hong Kong/1073/1999 (H9N2) strain. Using a co-caging study design, we investigated the maintenance, generation, and transmission of intrahost IAV genetic variation by sequencing viral genomic RNA obtained from nasal wash samples over multiple days of infection. We found evidence for an enhanced role of positive selection acting on de novo mutations in obese hosts that led to nonsynonymous changes that rose to high frequency. In addition, we identified numerous cases of mutations throughout the genome that were specific to obese hosts and that were preserved during transmission between hosts. Despite detection of obese-specific variants, the overall viral genetic diversity did not differ significantly between obese and lean hosts. This is likely due to the high supply rate of de novo variation and common evolutionary adaptations to the ferret host regardless of obesity status, which we show are mediated by variation in the hemagglutinin and polymerase genes (PB2 and PB1). We also identified defective viral genomes (DVGs) that were found uniquely in either obese or lean hosts, but the overall DVG diversity and dynamics did not differ between the two groups. Our study suggests that obesity may result in a unique selective environment impacting intrahost IAV evolution, highlighting the need for additional genetic and functional studies to confirm these effects.IMPORTANCEObesity is a chronic health condition characterized by excess adiposity leading to a systemic increase in inflammation and dysregulation of metabolic hormones and immune cell populations. Influenza A virus (IAV) is a highly infectious pathogen responsible for seasonal and pandemic influenza. Host risk factors, including compromised immunity and pre-existing health conditions, can contribute to increased infection susceptibility and disease severity. During viral replication in a host, the negative-sense single-stranded RNA genome of IAV accumulates genetic diversity that may have important consequences for viral evolution and transmission. Our study provides the first insight into the consequences of host obesity on viral genetic diversity and adaptation, suggesting that host factors associated with obesity alter the selective environment experienced by a viral population, thereby impacting the spectrum of genetic variation.


Subject(s)
Ferrets , Genetic Variation , Genome, Viral , Influenza A virus , Obesity , Orthomyxoviridae Infections , Animals , Humans , Male , Disease Models, Animal , Evolution, Molecular , Ferrets/virology , Genetic Variation/genetics , Genome, Viral/genetics , Host Microbial Interactions , Influenza A virus/genetics , Mutation , Obesity/virology , Orthomyxoviridae Infections/virology , RNA, Viral/genetics , Thinness/virology
7.
J Virol ; 98(8): e0078124, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39078191

ABSTRACT

Influenza remains a worldwide public health threat. Although seasonal influenza vaccines are currently the best means of preventing severe disease, the standard-of-care vaccines require frequent updating due to antigenic drift and can have low efficacy, particularly in vulnerable populations. Here, we demonstrate that a single administration of a recombinant adenovirus-associated virus (rAAV) vector expressing a computationally optimized broadly reactive antigen (COBRA)-derived influenza H1 hemagglutinin (HA) induces strongly neutralizing and broadly protective antibodies in naïve mice and ferrets with pre-existing influenza immunity. Following a lethal viral challenge, the rAAV-COBRA vaccine allowed for significantly reduced viral loads in the upper and lower respiratory tracts and complete protection from morbidity and mortality that lasted for at least 5 months post-vaccination. We observed no signs of antibody waning during this study. CpG motif enrichment of the antigen can act as an internal adjuvant to further enhance the immune responses to allow for lower vaccine dosages with the induction of unique interferon-producing CD4+ and CD8+ T cells specific to HA head and stem peptide sequences. Our studies highlight the utility of rAAV as an effective platform to improve seasonal influenza vaccines. IMPORTANCE: Developing an improved seasonal influenza vaccine remains an ambitious goal of researchers and clinicians alike. With influenza routinely causing severe epidemics with the potential to rise to pandemic levels, it is critical to create an effective, broadly protective, and durable vaccine to improve public health worldwide. As a potential solution, we created a rAAV viral vector expressing a COBRA-optimized influenza hemagglutinin antigen with modestly enriched CpG motifs to evoke a robust and long-lasting immune response after a single intramuscular dose without needing boosts or adjuvants. Importantly, the rAAV vaccine boosted antibody breadth to future strains in ferrets with pre-existing influenza immunity. Together, our data support further investigation into the utility of viral vectors as a potential avenue to improve our seasonal influenza vaccines.


Subject(s)
Adaptive Immunity , Antibodies, Viral , Dependovirus , Ferrets , Hemagglutinin Glycoproteins, Influenza Virus , Influenza Vaccines , Orthomyxoviridae Infections , Animals , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Mice , Antibodies, Viral/immunology , Antibodies, Viral/blood , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/immunology , Dependovirus/genetics , Dependovirus/immunology , Antibodies, Neutralizing/immunology , Humans , Female , Genetic Vectors , Mice, Inbred BALB C , Vaccination , Influenza, Human/prevention & control , Influenza, Human/immunology , CD8-Positive T-Lymphocytes/immunology
8.
J Virol ; 97(6): e0049323, 2023 06 29.
Article in English | MEDLINE | ID: mdl-37255439

ABSTRACT

Influenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent viruses and induce antiviral immunity. However, the mechanisms underlying DI-mediated antiviral immunity have not been extensively explored. Here, we demonstrated the interferon (IFN)-independent protection conferred by the influenza DI virus against homologous virus infection in mice deficient in type I and III IFN signaling. We identified unique host signatures responding to DI coinfection by integrating transcriptional and posttranscriptional regulatory data. DI-treated mice exhibited reduced viral transcription, less intense inflammatory and innate immune responses, and primed multiciliated cell differentiation in their lungs at an early stage of infection, even in the absence of type I or III IFNs. This increased multiciliogenesis could also be detected at the protein level via the immunofluorescence staining of lung tissue from DI-treated mice. Overall, our study provides mechanistic insight into the protection mediated by DIs, implying a unifying theme involving inflammation and multiciliogenesis in maintaining respiratory homeostasis and revealing their IFN-independent antiviral activity. IMPORTANCE During replication, the influenza virus generates genetically defective viruses. These are found in natural infections as part of the virus population within the infected host. Some versions of these defective viruses are thought to have protective effects through their interference with replication-competent viruses and induction of antiviral immunity. To better determine the mechanisms underlying the protective effects of these defective interfering (DI) viruses, we tested a DI that we previously identified in vitro with mice. Mice that were infected with a mix of wild-type influenza and DI viruses had less intense inflammatory and innate immune responses than did mice that were infected with the wild-type virus only, even when type I or III interferons, which are cytokines that play a prominent role in defending the respiratory epithelial barrier, were absent. More interestingly, the DI-infected mice had primed multiciliated cell differentiation in their lungs, indicating the potential promotion of epithelial repair by DIs.


Subject(s)
Cell Differentiation , Defective Interfering Viruses , Orthomyxoviridae Infections , Animals , Mice , Interferons , Virus Replication , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Orthomyxoviridae
9.
J Virol ; 97(9): e0102523, 2023 09 28.
Article in English | MEDLINE | ID: mdl-37668367

ABSTRACT

Human astrovirus is a positive-sense, single-stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive-strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double-membrane vesicles (DMVs). Here, we show that astrovirus infection leads to an increase in DMV formation through a replication-dependent mechanism that requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Both chemical and genetic inhibition of the PI3K complex lead to significant reduction in DMVs, as well as viral replication. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients. IMPORTANCE These studies provide critical new evidence that astrovirus replication requires formation of double-membrane vesicles, which utilize class III phosphatidylinositol 3-kinase (PI3K), but not LC3 conjugation autophagy machinery, for biogenesis. These results are consistent with replication mechanisms for other positive-sense RNA viruses suggesting that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive-sense RNA virus infections.


Subject(s)
Mamastrovirus , Phosphatidylinositol 3-Kinase , Virus Replication , Humans , Autophagy , Class III Phosphatidylinositol 3-Kinases/metabolism , Intracellular Membranes/metabolism , Organelles , Phosphatidylinositol 3-Kinase/metabolism , RNA Viruses , Mamastrovirus/physiology , Signal Transduction
10.
J Virol ; 97(5): e0054423, 2023 05 31.
Article in English | MEDLINE | ID: mdl-37166327

ABSTRACT

The interface between humans and wildlife is changing and, with it, the potential for pathogen introduction into humans has increased. Avian influenza is a prominent example, with an ongoing outbreak showing the unprecedented expansion of both geographic and host ranges. Research in the field is essential to understand this and other zoonotic threats. Only by monitoring dynamic viral populations and defining their biology in situ can we gather the information needed to ensure effective pandemic preparation.


Subject(s)
Influenza in Birds , Influenza, Human , Zoonoses , Animals , Humans , Animals, Wild , Disease Outbreaks , Host Specificity , Influenza in Birds/epidemiology , Influenza, Human/epidemiology , Influenza, Human/prevention & control , Pandemics , Zoonoses/epidemiology , Zoonoses/prevention & control
11.
PLoS Pathog ; 18(4): e1009716, 2022 04.
Article in English | MEDLINE | ID: mdl-35452499

ABSTRACT

Human astroviruses (HAstV), positive sense single-stranded RNA viruses, are one of the leading causes of diarrhea worldwide. Despite their high prevalence, the cellular mechanisms of astrovirus pathogenesis remain ill-defined. Previous studies showed HAstV increased epithelial barrier permeability by causing a re-localization of the tight junction protein, occludin. In these studies, we demonstrate that HAstV replication induces epithelial-mesenchymal transition (EMT), by upregulating the transcription of EMT-related genes within 8 hours post-infection (hpi), followed by the loss of cell-cell contacts and disruption of polarity by 24 hpi. While multiple classical HAstV serotypes, including clinical isolates, induce EMT, the non-classical genotype HAstV-VA1 and two strains of reovirus are incapable of inducing EMT. Unlike the re-localization of tight junction proteins, HAstV-induced EMT requires productive replication and is dependent transforming growth factor-ß (TGF-ß) activity. Finally, inhibiting TGF-ß signaling and EMT reduces viral replication, highlighting its importance in the viral life cycle. This finding puts classical strains of HAstV-1 in an exclusive group of non-oncogenic viruses triggering EMT.


Subject(s)
Astroviridae Infections , Mamastrovirus , Epithelial-Mesenchymal Transition , Humans , Mamastrovirus/genetics , Transforming Growth Factor beta , Virus Replication
12.
J Infect Dis ; 225(2): 341-351, 2022 01 18.
Article in English | MEDLINE | ID: mdl-34197595

ABSTRACT

BACKGROUND: Influenza immunization during pregnancy provides protection to the mother and the infant. Studies in adults and children with inactivated influenza vaccine have identified changes in immune gene expression that were correlated with antibody responses. The current study was performed to define baseline blood transcriptional profiles and changes induced by inactivated influenza vaccine in pregnant women and to identify correlates with antibody responses. METHODS: Pregnant women were immunized with inactivated influenza vaccine during the 2013-2014 and 2014-2015 seasons. Blood samples were collected on day 0 (before vaccination) and on days 1 and 7 after vaccination for transcriptional profile analyses, and on days 0 and 30, along with delivery and cord blood samples, to measure antibody titers. RESULTS: Transcriptional analysis demonstrated overexpression of interferon-stimulated genes (ISGs) on day 1 and of plasma cell genes on day 7. Prevaccination ISG expression and ISGs overexpressed on day 1 were significantly correlated with increased H3N2, B Yamagata, and B Victoria antibody titers. Plasma cell gene expression on day 7 was correlated with increased B Yamagata and B Victoria antibody titers. Compared with women who were vaccinated during the previous influenza season, those who were not showed more frequent significant correlations between ISGs and antibody titers. CONCLUSIONS: Influenza vaccination in pregnant women resulted in enhanced expression of ISGs and plasma cell genes correlated with antibody responses. Brief summary: This study identified gene expression profiles of interferon-stimulated genes and plasma cells before vaccination and early after vaccination that were correlated with antibody responses in pregnant women vaccinated for influenza.


Subject(s)
Antibodies, Viral/blood , Blood Group Antigens , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Interferons/genetics , Antibody Formation , Antiviral Agents/therapeutic use , Female , Gene Expression Profiling , Humans , Influenza A Virus, H3N2 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/immunology , Pregnancy , Pregnant Women , Transcriptome , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/immunology
13.
Clin Infect Dis ; 75(1): e705-e714, 2022 08 24.
Article in English | MEDLINE | ID: mdl-34891165

ABSTRACT

BACKGROUND: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Aged , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Immunoglobulin G , Middle Aged , Prospective Studies , Spike Glycoprotein, Coronavirus , Vaccination
14.
J Virol ; 95(15): e0069221, 2021 07 12.
Article in English | MEDLINE | ID: mdl-33980596

ABSTRACT

Swine influenza virus (SIV) can cause respiratory illness in swine. Swine contribute to influenza virus reassortment, as avian, human, and/or swine influenza viruses can infect swine and reassort, and new viruses can emerge. Thus, it is important to determine the host antiviral responses that affect SIV replication. In this study, we examined the innate antiviral cytokine response to SIV by swine respiratory epithelial cells, focusing on the expression of interferon (IFN) and interferon-stimulated genes (ISGs). Both primary and transformed swine nasal and tracheal respiratory epithelial cells were examined following infection with field isolates. The results show that IFN and ISG expression is maximal at 12 h postinfection (hpi) and is dependent on cell type and virus genotype. IMPORTANCE Swine are considered intermediate hosts that have facilitated influenza virus reassortment events that have given rise pandemics or genetically related viruses have become established in swine. In this study, we examine the innate antiviral response to swine influenza virus in primary and immortalized swine nasal and tracheal epithelial cells, and show virus strain- and host cell type-dependent differential expression of key interferons and interferon-stimulated genes.


Subject(s)
Cytokines/metabolism , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N2 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Respiratory Mucosa/immunology , Animals , Cell Line , Cytokines/immunology , Dogs , Epithelial Cells/virology , Host-Pathogen Interactions/immunology , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N2 Subtype/growth & development , Influenza A Virus, H3N2 Subtype/growth & development , Interferons/immunology , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/immunology , Respiratory Mucosa/cytology , Swine , Virus Replication/physiology
15.
J Infect Dis ; 223(12 Suppl 2): S201-S208, 2021 06 16.
Article in English | MEDLINE | ID: mdl-33330907

ABSTRACT

The bacterial, fungal, and helminthic species that comprise the microbiome of the mammalian host have profound effects on health and disease. Pathogenic viruses must contend with the microbiome during infection and likely have evolved to exploit or evade the microbiome. Both direct interactions between the virions and the microbiota and immunomodulation and tissue remodeling caused by the microbiome alter viral pathogenesis in either host- or virus-beneficial ways. Recent insights from in vitro and murine models of viral pathogenesis have highlighted synergistic and antagonistic, direct and indirect interactions between the microbiome and pathogenic viruses. This review will focus on the transkingdom interactions between human gastrointestinal and respiratory viruses and the constituent microbiome of those tissues.


Subject(s)
Microbiota/physiology , Viruses/pathogenicity , Animals , Bacterial Physiological Phenomena , Bacteriophages/physiology , Fungi/physiology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/parasitology , Gastrointestinal Tract/virology , Helminths/physiology , Humans , Lung/immunology , Lung/microbiology , Lung/parasitology , Lung/virology , Viruses/classification
16.
J Infect Dis ; 224(5): 821-830, 2021 09 01.
Article in English | MEDLINE | ID: mdl-33395484

ABSTRACT

BACKGROUND: Human spillovers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to dogs and the emergence of a highly contagious avian-origin H3N2 canine influenza virus have raised concerns on the role of dogs in the spread of SARS-CoV-2 and their susceptibility to existing human and avian influenza viruses, which might result in further reassortment. METHODS: We systematically studied the replication kinetics of SARS-CoV-2, SARS-CoV, influenza A viruses of H1, H3, H5, H7, and H9 subtypes, and influenza B viruses of Yamagata-like and Victoria-like lineages in ex vivo canine nasal cavity, soft palate, trachea, and lung tissue explant cultures and examined ACE2 and sialic acid (SA) receptor distribution in these tissues. RESULTS: There was limited productive replication of SARS-CoV-2 in canine nasal cavity and SARS-CoV in canine nasal cavity, soft palate, and lung, with unexpectedly high ACE2 levels in canine nasal cavity and soft palate. Canine tissues were susceptible to a wide range of human and avian influenza viruses, which matched with the abundance of both human and avian SA receptors. CONCLUSIONS: Existence of suitable receptors and tropism for the same tissue foster virus adaptation and reassortment. Continuous surveillance in dog populations should be conducted given the many chances for spillover during outbreaks.


Subject(s)
COVID-19/virology , Influenza A virus/physiology , Lung/virology , Nasal Cavity/virology , SARS-CoV-2/physiology , Trachea/virology , Viral Tropism/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Dogs , Humans , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Nasal Cavity/metabolism , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Trachea/metabolism
17.
J Virol ; 94(18)2020 08 31.
Article in English | MEDLINE | ID: mdl-32661141

ABSTRACT

Metabolic syndrome increases the risk of severe disease due to viral infection. Yet few studies have assessed the pathogenesis of respiratory viruses in high-risk populations. Here, we summarize how metabolic dysregulation impairs immune responses, and we define the role of metabolism during influenza virus and coronavirus infections. We also discuss the use of various in vitro, in vivo, and ex vivo models to elucidate the contributions of host factors to viral susceptibility, immunity, and disease severity.


Subject(s)
Coronavirus Infections/complications , Disease Susceptibility , Influenza, Human/complications , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , Animals , Biomarkers , Coronavirus Infections/virology , Disease Models, Animal , Humans , Influenza, Human/virology , Metabolic Syndrome/diagnosis
18.
J Virol ; 94(5)2020 02 14.
Article in English | MEDLINE | ID: mdl-31776285

ABSTRACT

Astroviruses (AstV) are a leading cause of diarrhea, especially in the very young, the elderly, and immunocompromised populations. Despite their significant impact on public health, no drug therapies for astrovirus have been identified. In this study, we fill this gap in knowledge and demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication in vitro with a 50% effective concentration (EC50) of approximately 1.47 µM. It can be administered up to 8 h postinfection and is effective against multiple human astrovirus serotypes, including clinical isolates. Most importantly, NTZ reduces viral shedding in vivo, exhibiting its potential as a future clinical therapeutic.IMPORTANCE Human astroviruses (HAstV) are thought to cause between 2 and 9% of acute, nonbacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants, where the virus has been associated with necrotizing enterocolitis and severe and persistent diarrhea, as well as rare instances of systemic and fatal disease. And yet, no antivirals have been identified to treat astrovirus infection. Our study provides the first evidence that nitazoxanide may be an effective therapeutic strategy against astrovirus disease.


Subject(s)
Astroviridae Infections/drug therapy , Mamastrovirus/drug effects , Thiazoles/antagonists & inhibitors , Virus Replication/drug effects , Animals , Astroviridae Infections/virology , Caco-2 Cells , Cell Survival/drug effects , Diarrhea/virology , Enterocolitis, Necrotizing/drug therapy , Enterocolitis, Necrotizing/virology , Humans , Mamastrovirus/immunology , Nitro Compounds , Poultry , Virus Replication/physiology
19.
J Virol ; 94(24)2020 11 23.
Article in English | MEDLINE | ID: mdl-32967961

ABSTRACT

Influenza virus isolation from clinical samples is critical for the identification and characterization of circulating and emerging viruses. Yet efficient isolation can be difficult. In these studies, we isolated primary swine nasal and tracheal respiratory epithelial cells and immortalized swine nasal epithelial cells (siNEC) and tracheal epithelial cells (siTEC) that retained the abilities to form tight junctions and cilia and to differentiate at the air-liquid interface like primary cells. Critically, both human and swine influenza viruses replicated in the immortalized cells, which generally yielded higher-titer viral isolates from human and swine nasal swabs, supported the replication of isolates that failed to grow in Madin-Darby canine kidney (MDCK) cells, and resulted in fewer dominating mutations during viral passaging than MDCK cells.IMPORTANCE Robust in vitro culture systems for influenza virus are critically needed. MDCK cells, the most widely used cell line for influenza isolation and propagation, do not adequately model the respiratory tract. Therefore, many clinical isolates, both animal and human, are unable to be isolated and characterized, limiting our understanding of currently circulating influenza viruses. We have developed immortalized swine respiratory epithelial cells that retain the ability to differentiate and can support influenza replication and isolation. These cell lines can be used as additional tools to enhance influenza research and vaccine development.


Subject(s)
Epithelial Cells/virology , Influenza A virus/growth & development , Influenza A virus/isolation & purification , Respiratory System/virology , Virus Cultivation/methods , Animals , Cell Line , Dogs , Humans , Influenza A virus/genetics , Kinetics , Madin Darby Canine Kidney Cells , Swine , Trachea , Virus Replication
20.
J Virol ; 94(3)2020 01 17.
Article in English | MEDLINE | ID: mdl-31694942

ABSTRACT

Hemagglutinin (HA) stability, or the pH at which HA is activated to cause membrane fusion, has been associated with the replication, pathogenicity, transmissibility, and interspecies adaptation of influenza A viruses. Here, we investigated the mechanisms by which a destabilizing HA mutation, Y17H (activation pH, 6.0), attenuates virus replication and pathogenicity in DBA/2 mice compared to wild-type (WT) virus (activation pH, 5.5). The extracellular lung pH was measured to be near neutral (pH 6.9 to 7.5). WT and Y17H viruses had similar environmental stability at pH 7.0; thus, extracellular inactivation was unlikely to attenuate the Y17H virus. The Y17H virus had accelerated replication kinetics in MDCK, A549, and RAW 264.7 cells when inoculated at a multiplicity of infection (MOI) of 3 PFU/cell. The destabilizing mutation also increased early infectivity and type I interferon (IFN) responses in mouse bone marrow-derived dendritic cells (DCs). In contrast, the HA-Y17H mutation reduced virus replication in murine airway murine nasal epithelial cell and murine tracheal epithelial cell cultures and attenuated virus replication, virus spread, the severity of infection, and cellular infiltration in the lungs of mice. Normalizing virus infection and weight loss in mice by inoculating them with Y17H virus at a dose 500-fold higher than that of WT virus revealed that the destabilized mutant virus triggered the upregulation of more host genes and increased type I IFN responses and cytokine expression in DBA/2 mouse lungs. Overall, HA destabilization decreased virulence in mice by boosting early infection in DCs, resulting in the greater activation of antiviral responses, including the type I IFN response. These studies reveal that HA stability may regulate pathogenicity by modulating IFN responses.IMPORTANCE Diverse influenza A viruses circulate in wild aquatic birds, occasionally infecting farm animals. Rarely, an avian- or swine-origin influenza virus adapts to humans and starts a pandemic. Seasonal and many universal influenza vaccines target the HA surface protein, which is a key component of pandemic influenza viruses. Understanding the HA properties needed for replication and pathogenicity in mammals may guide response efforts to control influenza. Some antiviral drugs and broadly reactive influenza vaccines that target the HA protein have suffered resistance due to destabilizing HA mutations that do not compromise replicative fitness in cell culture. Here, we show that despite not compromising fitness in standard cell cultures, a destabilizing H1N1 HA stalk mutation greatly diminishes viral replication and pathogenicity in vivo by modulating type I IFN responses. This encourages targeting the HA stalk with antiviral drugs and vaccines as well as reevaluating previous candidates that were susceptible to destabilizing resistance mutations.


Subject(s)
Dendritic Cells/metabolism , Hemagglutinins/metabolism , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Interferon Type I/metabolism , Virus Replication/physiology , Animals , Cell Line , Chemokines/metabolism , Cytokines/metabolism , Female , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Hemagglutinins/genetics , Hemagglutinins/immunology , Humans , Hydrogen-Ion Concentration , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza Vaccines , Influenza, Human/virology , Lung/pathology , Lung/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Orthomyxoviridae Infections/virology , Protein Stability , Viral Fusion Proteins , Virulence
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