scholarly journals Composition and Dynamics of H1N1 and H7N9 Influenza A Virus Quasispecies in a Co-infected Patient Analyzed by Single Molecule Sequencing Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Lin ◽  
Tao Jin ◽  
Xinfen Yu ◽  
Lifeng Liang ◽  
Guang Liu ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Precision Medicine ◽  
Influenza A Virus ◽  
Single Molecule ◽  
Influenza A ◽  
Viral Infections ◽  
Viral Quasispecies ◽  
Substitution Type ◽  
Serial Samples ◽  
High Diversity

A human co-infected with H1N1 and H7N9 subtypes influenza A virus (IAV) causes a complex infectious disease. The identification of molecular-level variations in composition and dynamics of IAV quasispecies will help to understand the pathogenesis and provide guidance for precision medicine treatment. In this study, using single-molecule real-time sequencing (SMRT) technology, we successfully acquired full-length IAV genomic sequences and quantified their genotypes abundance in serial samples from an 81-year-old male co-infected with H1N1 and H7N9 subtypes IAV. A total of 26 high diversity nucleotide loci was detected, in which the A-G base transversion was the most abundant substitution type (67 and 64%, in H1N1 and H7N9, respectively). Seven significant amino acid variations were detected, such as NA:H275Y and HA: R222K in H1N1 as well as PB2:E627K and NA: K432E in H7N9, which are related to viral drug-resistance or mammalian adaptation. Furtherly, we retrieved 25 H1N1 and 22 H7N9 genomic segment haplotypes from the eight samples based on combining high-diversity nucleotide loci, which provided a more concise overview of viral quasispecies composition and dynamics. Our approach promotes the popularization of viral quasispecies analysis in a complex infectious disease, which will boost the understanding of viral infections, pathogenesis, evolution, and precision medicine.

Quantification of Multivalent Interactions between Sialic Acid and Influenza A Virus Spike Proteins by Single-Molecule Force Spectroscopy

2020 ◽  
Vol 142 (28) ◽  
pp. 12181-12192 ◽  
Author(s):  
Jose Luis Cuellar-Camacho ◽  
Sumati Bhatia ◽  
Valentin Reiter-Scherer ◽  
Daniel Lauster ◽  
Susanne Liese ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Single Molecule ◽  
Influenza A ◽  
Force Spectroscopy ◽  
Single Molecule Force Spectroscopy ◽  
Multivalent Interactions ◽  
Spike Proteins

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

2005 ◽  
Vol 289 (1) ◽  
pp. L111-L124 ◽  
Author(s):  
Sabine Teske ◽  
Andrea A. Bohn ◽  
Jean F. Regal ◽  
Joshua J. Neumiller ◽  
B. Paige Lawrence
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Neutrophil Function ◽  
Aryl Hydrocarbon ◽  
Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

scholarly journals Ataxia-telangiectasia mutated is required for the development of protective immune memory after influenza A virus infection

2019 ◽  
Vol 317 (5) ◽  
pp. L591-L601 ◽  
Author(s):  
Rachel Warren ◽  
William Domm ◽  
Min Yee ◽  
Andrew Campbell ◽  
Jane Malone ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Ataxia Telangiectasia ◽  
Influenza A ◽  
Viral Infections ◽  
Neurodegenerative Disorder ◽  
Immune Memory ◽  
Cell Memory ◽  
Memory Response ◽  
Secondary Infections ◽  
Respiratory Viral Infections

Ataxia-telangiectasia (A-T), caused by mutations in the A-T mutated ( ATM) gene, is a neurodegenerative disorder affecting ∼1 in 40,000–100,000 children. Recurrent respiratory infections are a common and challenging comorbidity, often leading to the development of bronchiectasis in individuals with A-T. The role of ATM in development of immune memory in response to recurrent respiratory viral infections is not well understood. Here, we infect wild-type (WT) and Atm-null mice with influenza A virus (IAV; HKx31, H3N2) and interrogate the immune memory with secondary infections designed to challenge the B cell memory response with homologous infection (HKx31) and the T cell memory response with heterologous infection (PR8, H1N1). Although Atm-null mice survived primary and secondary infections, they lost more weight than WT mice during secondary infections. This enhanced morbidity to secondary infections was not attributed to failure to effectively clear virus during the primary IAV infection. Instead, Atm-null mice developed persistent peribronchial inflammation, characterized in part by clusters of B220+ B cells. Additionally, levels of select serum antibodies to hemagglutinin-specific IAV were significantly lower in Atm-null than WT mice. These findings reveal that Atm is required to mount a proper memory response to a primary IAV infection, implying that vaccination of children with A-T by itself may not be sufficiently protective against respiratory viral infections.

scholarly journals Complement Decay-Accelerating Factor is a modulator of influenza A virus lung immunopathology

2021 ◽  
Author(s):  
Nuno Brito Santos ◽  
Zoé Enderlin Vaz da Silva ◽  
Catarina Gomes ◽  
Celso A. Reis ◽  
Maria João Amorim
Keyword(s):  
Disease Severity ◽  
Influenza A Virus ◽  
Immune Cells ◽  
Complement Activation ◽  
Influenza A ◽  
Viral Infections ◽  
Decay Accelerating Factor ◽  
Viral Loads ◽  
Adaptive Immune ◽  
The Impact

AbstractClearance of viral infections, such as SARS-CoV-2 and influenza A virus (IAV), must be fine-tuned to eliminate the pathogen without causing immunopathology. As such, an aggressive initial innate immune response favors the host in contrast to a detrimental prolonged inflammation. The complement pathway bridges innate and adaptive immune system and contributes to the response by directly clearing pathogens or infected cells, as well as recruiting proinflammatory immune cells and regulating inflammation. However, the impact of modulating complement activation in viral infections is still unclear. In this work, we targeted the complement decay-accelerating factor (DAF/CD55), a surface protein that protects cells from non-specific complement attack, and analyzed its role in IAV infections. We found that DAF modulates IAV infection in vivo, via an interplay with the antigenic viral proteins hemagglutinin (HA) and neuraminidase (NA), in a strain specific manner. Our results reveal that, contrary to what could be expected, DAF potentiates complement activation, increasing the recruitment of neutrophils, monocytes and T cells. We also show that viral NA acts on the heavily sialylated DAF and propose that it exacerbates complement activation, leading to lung immunopathology. Remarkably, this mechanism has no impact on viral loads but rather on the host resilience to infection and may have direct implications in zoonotic influenza transmissions.Author summaryExacerbated complement activation and immune deregulation are at the basis of several pathologies induced by respiratory viruses. Here, we report that complement decay-accelerating factor (DAF), which inhibits complement activation in healthy cells, increases disease severity upon Influenza A virus (IAV) infection. Remarkably, DAF interaction with IAV proteins, hemagglutinin (HA) and neuraminidase (NA), resulted in excessive complement activation and recruitment of innate and adaptive immune cells, without affecting viral loads. Furthermore, we observed that viral NA directly cleaves DAF and promotes complement activation, providing a possible link between IAV-DAF interaction and pathology. Therefore, our results unveil a novel pathway that could modulate disease severity, which may help to understand the increased pathogenicity of zoonotic and pandemic IAV infections.

scholarly journals Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Andres J. Gonzalez ◽  
Emmanuel C. Ijezie ◽  
Onesmo B. Balemba ◽  
Tanya A. Miura
Keyword(s):  
Mouse Model ◽  
Respiratory Tract ◽  
Disease Severity ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Respiratory Viruses ◽  
Viral Pathogen ◽  
Viral Coinfection ◽  
Murine Coronavirus

ABSTRACTInfluenza viruses and rhinoviruses are responsible for a large number of acute respiratory viral infections in human populations and are detected as copathogens within hosts. Clinical and epidemiological studies suggest that coinfection by rhinovirus and influenza virus may reduce disease severity and that they may also interfere with each other’s spread within a host population. To determine how coinfection by these two unrelated respiratory viruses affects pathogenesis, we established a mouse model using a minor serogroup rhinovirus (rhinovirus strain 1B [RV1B]) and mouse-adapted influenza A virus (A/Puerto Rico/8/1934 [PR8]). Infection of mice with RV1B 2 days before PR8 reduced the severity of infection by a low or medium, but not high, dose of PR8. Disease attenuation was associated with an early inflammatory response in the lungs and enhanced clearance of PR8. However, coinfection by RV1B did not reduce PR8 viral loads early in infection or inhibit replication of PR8 within respiratory epithelia orin vitro. Inflammation in coinfected mice remained focal compared to diffuse inflammation and damage in the lungs of mice infected by PR8. The timing of RV1B coinfection was a critical determinant of protection, suggesting that sufficient time is needed to induce this response. Finally, disease attenuation was not unique to RV1B: dose-dependent coinfection by a murine coronavirus (mouse hepatitis virus strain 1 [MHV-1]) also reduced the severity of PR8 infection. Unlike RV1B, coinfection with MHV-1 reduced early PR8 replication, which was associated with upregulation of beta interferon (IFN-β) expression. This model is critical for understanding the mechanisms responsible for influenza disease attenuation during coinfection by unrelated respiratory viruses.IMPORTANCEViral infections in the respiratory tract can cause severe disease and are responsible for a majority of pediatric hospitalizations. Molecular diagnostics have revealed that approximately 20% of these patients are infected by more than one unrelated viral pathogen. To understand how viral coinfection affects disease severity, we inoculated mice with a mild viral pathogen (rhinovirus or murine coronavirus), followed 2 days later by a virulent viral pathogen (influenza A virus). This model demonstrated that rhinovirus can reduce the severity of influenza A virus, which corresponded with an early but controlled inflammatory response in the lungs and early clearance of influenza A virus. We further determined the dose and timing parameters that were important for effective disease attenuation and showed that influenza disease is also reduced by coinfection with a murine coronavirus. These findings demonstrate that coinfecting viruses can alter immune responses and pathogenesis in the respiratory tract.

scholarly journals Innate Immune sensing of Influenza A viral RNA through IFI16 promotes pyroptotic cell death

2021 ◽  
Author(s):  
Shalabh Mishra ◽  
Athira S Raj ◽  
Akhilesh Kumar ◽  
Ashwathi Rajeevan ◽  
Puja Kumari ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Type I ◽  
Cell Death Pathways ◽  
Infected Cells ◽  
Immune Sensing

AbstractProgrammed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus IAV infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for influenza A virus by binding to genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). Whereas, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. These results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

scholarly journals Assessing exhibition swine as potential disseminators of infectious disease through the detection of five respiratory pathogens at agricultural exhibitions

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Sarah E. Lauterbach ◽  
Sarah W. Nelson ◽  
Meghann E. Robinson ◽  
Josh N. Lorbach ◽  
Jacqueline M. Nolting ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Human Health ◽  
Influenza A Virus ◽  
Influenza A ◽  
Respiratory Pathogens ◽  
Swine Population

Abstract Widespread geographic movement and extensive comingling of exhibition swine facilitates the spread and transmission of infectious pathogens. Nasal samples were collected from 2862 pigs at 102 exhibitions and tested for five pathogens. At least one pathogen was molecularly detected in pigs at 63 (61.8%) exhibitions. Influenza A virus was most prevalent and was detected in 498 (17.4%) samples. Influenza D virus was detected in two (0.07%) samples. More than one pathogen was detected in 165 (5.8%) samples. Influenza A virus remains a top threat to animal and human health, but other pathogens may be disseminated through the exhibition swine population.

scholarly journals Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

2017 ◽  
Vol 114 (13) ◽  
pp. 3491-3496 ◽  
Author(s):  
Dimitry N. Krementsov ◽  
Laure K. Case ◽  
Oliver Dienz ◽  
Abbas Raza ◽  
Qian Fang ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Genetic Variation ◽  
Influenza A Virus ◽  
Influenza A ◽  
Disease Burden ◽  
Critical Role ◽  
Γδ T Cells ◽  
Gene Families ◽  
Sex Characteristics ◽  
Chromosome Y

Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17–producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.

scholarly journals Rhesus negative males have an enhanced IFNγ-mediated immune response to influenza A virus

2021 ◽  
Author(s):  
Jamie A Sugrue ◽  
Megan Smith ◽  
Celine Posseme ◽  
Bruno Charbit ◽  
Nollaig M Bourke ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Human Immunology ◽  
Specific Effects ◽  
Specific Analysis ◽  
D Antigen

The Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and genomic data from the Milieu Interieur cohort of 1000 healthy individuals to explore the effect of RhD on immune responses. We used the rs590787 SNP in the RHD gene to classify the 1000 donors as either RhD-positive or -negative. Whole blood was stimulated with LPS, polyIC, and the live influenza A virus and the NanoString human immunology panel of 560 genes used to assess donor immune response and to investigate sex specific effects. Using regression analysis, we observed no significant differences in responses to polyIC or LPS between RhD-positive and -negative individuals. However, upon sex-specific analysis, we observed over 30 differentially expressed genes (DEGs) between RhD-positive (n=401) and RhD-negative males (n=78). Interestingly these Rhesus-associated differences were not seen in females. Further investigation, using gene set enrichment analysis, revealed enhanced IFNγ signalling in RhD-negative males. This amplified IFNγ signalling axis may explain the increased viral resistance previously described in RhD-negative individuals.

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