scholarly journals Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice

2017 ◽  
Author(s):  
Paul L. Maurizio ◽  
Martin T. Ferris ◽  
Gregory R. Keele ◽  
Darla R. Miller ◽  
Ginger D. Shaw ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Post Infection ◽  
Influenza A ◽  
Diallel Analysis ◽  
Respiratory Pathogen ◽  
Phenotypic Variance ◽  
Additive Effects ◽  
Statistical Framework ◽  
Independent Effects ◽  
Heritable Effects

1.ABSTRACTInfluenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8×8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

scholarly journals Bayesian Diallel Analysis RevealsMx1-Dependent andMx1-Independent Effects on Response to Influenza A Virus in Mice

2017 ◽  
Vol 8 (2) ◽  
pp. 427-445 ◽  
Author(s):  
Paul L. Maurizio ◽  
Martin T. Ferris ◽  
Gregory R. Keele ◽  
Darla R. Miller ◽  
Ginger D. Shaw ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Diallel Analysis ◽  
Independent Effects

Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus

2012 ◽  
Vol 90 (2) ◽  
pp. 123-130 ◽  
Author(s):  
Pu Xiuying ◽  
Liang Jianping ◽  
Shang Ruofeng ◽  
Zhou Liye ◽  
Wang Xuehong ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Lung Tissue ◽  
Post Infection ◽  
Therapeutic Efficacy ◽  
Influenza A ◽  
Hypericum Perforatum ◽  
Viral Titer ◽  
Tnf Α ◽  
Hypericum Perforatum L ◽  
Ifn Γ

Hypericum perforatum L., a plant used in Chinese herbal medicine, has been proven effective against many viral diseases. In the present study, the therapeutic efficacy of an extract of H. perforatum (HPE) against influenza A virus (IAV) was investigated in mice. Whether HPE would be a promising agent for influenza treatment was evaluated by measuring the protection rate, mean survival days, lung index, and viral titer, as well as the secretion of IL-6, interleukin-10 (IL-10), tumour necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ) in lung tissue and serum on days 3 and 5 post-infection. The results showed that HPE could reduce the lung index and viral titer of mice infected with IAV, decrease mortality, and prolong the mean survival time. HPE decreased the concentration of IL-6 and TNF-α in lung tissue and serum on day 5 post-infection. In contrast, HPE enhanced the lung and serum levels of IL-10 and IFN-γ on the days 3 and 5 post-infection. Our study indicates that HPE has significant therapeutic efficacy for mice infected with IAV. The possible reasons for these results were concluded to be pertaining to up-regulating the expression of IL-10 and IFN-γ, and down-regulating the secretion of IL-6 and TNF-α in lung and serum.

scholarly journals Understanding the within-host dynamics of influenza A virus: from theory to clinical implications

2016 ◽  
Vol 13 (119) ◽  
pp. 20160289 ◽  
Author(s):  
Christoforos Hadjichrysanthou ◽  
Emilie Cauët ◽  
Emma Lawrence ◽  
Carolin Vegvari ◽  
Frank de Wolf ◽  
...  
Keyword(s):  
Viral Load ◽  
Influenza A Virus ◽  
Post Infection ◽  
Influenza A ◽  
Antiviral Drugs ◽  
Load Curve ◽  
Clinical Endpoints ◽  
Time To Peak ◽  
Infection Dynamics ◽  
Peak Viral Load

Mathematical models have provided important insights into acute viral dynamics within individual patients. In this paper, we study the simplest target cell-limited models to investigate the within-host dynamics of influenza A virus infection in humans. Despite the biological simplicity of the models, we show how these can be used to understand the severity of the infection and the key attributes of possible immunotherapy and antiviral drugs for the treatment of infection at different times post infection. Through an analytic approach, we derive and estimate simple summary biological quantities that can provide novel insights into the infection dynamics and the definition of clinical endpoints. We focus on nine quantities, including the area under the viral load curve, peak viral load, the time to peak viral load and the level of cell death due to infection. Using Markov chain Monte Carlo methods, we fitted the models to data collected from 12 untreated volunteers who participated in two clinical studies that tested the antiviral drugs oseltamivir and zanamivir. Based on the results, we also discuss various difficulties in deriving precise estimates of the parameters, even in the very simple models considered, when experimental data are limited to viral load measures and/or there is a limited number of viral load measurements post infection.

scholarly journals FKBP5 Regulates RIG-I-Mediated NF-κB Activation and Influenza A Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 672
Author(s):  
Wenzhuo Hao ◽  
Lingyan Wang ◽  
Shitao Li
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Social Impact ◽  
Respiratory Pathogen ◽  
Innate Immune Responses ◽  
Interferon Stimulated Genes ◽  
Fk506 Binding Protein ◽  
Ikk Complex ◽  
Inducible Gene

Influenza A virus (IAV) is a highly transmissible respiratory pathogen and is a constant threat to global health with considerable economic and social impact. Influenza viral RNA is sensed by host pattern recognition receptors (PRRs), such as the Toll-like receptor 7 (TLR7) and retinoic acid-inducible gene I (RIG-I). The activation of these PRRs instigates the interferon regulatory factor (IRF) and nuclear factor kappa B (NF-κB) signaling pathways that induce the expression of interferon-stimulated genes (ISGs) and inflammatory genes. FK506-binding protein 5 (FKBP5) has been implied in the IκBα kinase (IKK) complex. However, the role of FKBP5 in the RIG-I signaling and IAV infection is not well elucidated. Here, we demonstrate that the knockout of FKBP5 increases IAV infection. Furthermore, FKBP5 binds IKKα, which is critical for RIG-I-induced innate immune responses and ISG expression. Taken together, FKBP5 is a novel anti-influenza host factor that restricts IAV infection by the activation of RIG-I-mediated NF-κB signaling.

scholarly journals Acute Influenza A Virus Infection Affects Cell Cycle and Lineage Output of Hematopoietic Stem Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2467-2467
Author(s):  
Marcel E G Rommel ◽  
Lisa Walz ◽  
Saskia Kohlscheen ◽  
Franziska Schenk ◽  
Yvonne Krebs ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Influenza A Virus ◽  
Inflammatory Cytokines ◽  
Acute Phase ◽  
Post Infection ◽  
Influenza A ◽  
Hematopoietic Stem ◽  
The Impact

Long-term hematopoietic stem cells (LT-HSC) persist in quiescence to maintain their hematopoietic potential throughout life. In the case of need LT-HSC can be activated to replenish the pool of blood cells. We investigated the impact of acute influenza A virus (IAV) infection on hematopoiesis in C57Bl/6N mice, focusing on the most immature HSC and progenitors. Mice were infected with a lethal dose of IAV PR/8/1934 H1N1 (humane endpoints reached within 6 days post infection (dpi)). In two further groups, mice were treated daily with oseltamivir (antiviral neuraminidase inhibitor, dpi 0-4) or were vaccinated with single-cycle vesicular stomatitis virus replicon particles expressing a miss-matched neuraminidase from influenza A virus Yamaguchi/7/2004 H5N1 four weeks prior to infection. Both treatments rescued mice from infection-induced mortality. Every day 6-9 mice were analyzed for differences in the bone marrow (BM) and blood by flow cytometry and multiplex cytokine assays as well as in the lung to determine viral tissue titers and histopathology. HSC functionality was analyzed in a competitive BM transplantation of infected and non-infected mice. Irrespective of the treatment, high IAV lung tissue titers (≥5x106 tissue culture infectious dose 50) in the first days post infection (dpi 1-5) were associated with activation of HSC into the cell cycle. LT-HSCs (LSK, CD150+, CD34- and CD48-) were 50% less quiescent and shifted into the G1/S-G2-M phase (dpi 2-6) and returned to quiescence state after virus clearance (dpi 10). Furthermore, we detected 1.5-fold increase in proliferation of phenotypic LT-HSC. Differentiation was increased towards lymphoid progenitors (≥3-fold more compared to non-infected mice) during the acute phase of infection in untreated and oseltamivir treated mice and myeloid progenitors were reduced ~50% in all groups (dpi 4-8). We found the inflammatory cytokines IFNγ, IL-1α, IL-6, and TNFα to be significantly upregulated in the BM of untreated and oseltamivir treated mice but less in vaccinated animals (dpi 2-4). IL-1α or IL-6 stimulation of LT-HSCs was sufficient to initiate proliferation in cell culture. In all groups the initial drop of the peripheral platelet count (~30% lower compared to non-infected mice, dpi 2) was replenished with an excessive production of platelets (~45% increased, dpi 8-15). Histopathology and electron microscopy revealed the sequestration and accumulation of platelets in pulmonary capillaries and vessels. Subsequently, we detected twice as many mature megakaryocytes in the BM (dpi 2-4) and elevated CD41 expression on HSCs (LSK, CD150+ and CD34-; 3-fold more compared to non-infected mice dpi 2-6) indicating a myeloid/platelet-biased HSC compartment in response to infection. Competitive whole BM transplantation with activated LT-HSCs from the acute phase of infection vs non-infected mice showed delayed reconstitution of T-cells but a preferential differentiation towards platelets in recipient mice. Taken together, local IAV infection in the lung substantially affected LT-HSC quiescence and differentiation by inflammatory cytokines with systemic consequences and a myeloid/platelet-biased lineage output. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Evaluation of the New High-Throughput Luminex NxTAG Respiratory Pathogen Panel Assay for Multiplex Respiratory Pathogen Detection

2016 ◽  
Vol 54 (7) ◽  
pp. 1820-1825 ◽  
Author(s):  
Jonathan H. K. Chen ◽  
Ho-Yin Lam ◽  
Cyril C. Y. Yip ◽  
Sally C. Y. Wong ◽  
Jasper F. W. Chan ◽  
...  
Keyword(s):  
Real Time ◽  
Influenza A Virus ◽  
Real Time Pcr ◽  
Influenza A ◽  
Respiratory Pathogen ◽  
Gene Target ◽  
Viral Culture ◽  
Matrix Gene ◽  
Sample Throughput ◽  
Respiratory Specimens

A broad range of viral and bacterial pathogens can cause acute respiratory tract infection. For rapid detection of a broad respiratory pathogen spectrum, multiplex real-time PCR is ideal. This study evaluated the performance of the new Luminex NxTAG Respiratory Pathogen Panel (NxTAG-RPP) in comparison with the BioFire FilmArray Respiratory Panel (FA-RP) or singleplex real-time PCR as reference. A total of 284 clinical respiratory specimens and 3 influenza A/H7N9 viral culture samples were tested. All clinical specimens were processed and analyzed in parallel using NxTAG-RPP and the reference standard method. The H7N9 viral culture samples were tested using NxTAG-RPP only. Overall, the NxTAG-RPP demonstrated ≥93% sensitivity and specificity for all respiratory targets except human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1. The H7N9 virus was detected by the influenza A virus matrix gene target, while other influenza A virus subtyping gene targets in the panel remained negative. Complete concordance between NxTAG-RPP and FA-RP was observed in 98.8% (318/322) of positive results (kappa = 0.92). Substantial agreement was found for most respiratory targets, but significant differences were observed in human metapneumovirus (P= 0.001) and parainfluenza virus type 3 (P= 0.031). NxTAG-RPP has a higher sample throughput than FA-RP (96 samples versus 1 sample per run) while the turnaround times for NxTAG-RPP and FA-RP were 5 h (up to 96 samples) and 1 h (for one sample), respectively. Overall, NxTAG-RPP demonstrated good diagnostic performance for most respiratory pathogens. The high sample throughput with reasonable turnaround time of this new assay makes it a suitable multiplex platform for routine screening of respiratory specimens in hospital-based laboratories.

scholarly journals TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Girish Patil ◽  
Mengmeng Zhao ◽  
Kun Song ◽  
Wenzhuo Hao ◽  
Daniel Bouchereau ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Influenza A Virus ◽  
Influenza A ◽  
E3 Ligase ◽  
Lung Epithelial Cells ◽  
Host Susceptibility ◽  
Respiratory Pathogen ◽  
Restriction Factor ◽  
Viral Inhibition ◽  
Ubiquitin E3 Ligase

ABSTRACTInfluenza A virus (IAV) is a highly transmissible respiratory pathogen and a major cause of morbidity and mortality around the world. Nucleoprotein (NP) is an abundant IAV protein essential for multiple steps of the viral life cycle. Our recent proteomic study of the IAV-host interaction network found that TRIM41 (tripartite motif-containing 41), a ubiquitin E3 ligase, interacted with NP. However, the role of TRIM41 in IAV infection is unknown. Here, we report that TRIM41 interacts with NP through its SPRY domain. Furthermore, TRIM41 is constitutively expressed in lung epithelial cells, and overexpression of TRIM41 inhibits IAV infection. Conversely, RNA interference (RNAi) and knockout of TRIM41 increase host susceptibility to IAV infection. As a ubiquitin E3 ligase, TRIM41 ubiquitinates NPin vitroand in cells. The TRIM41 mutant lacking E3 ligase activity fails to inhibit IAV infection, suggesting that the E3 ligase activity is indispensable for TRIM41 antiviral function. Mechanistic analysis further revealed that the polyubiquitination leads to NP protein degradation and viral inhibition. Taking these observations together, TRIM41 is a constitutively expressed intrinsic IAV restriction factor that targets NP for ubiquitination and protein degradation.IMPORTANCEInfluenza control strategies rely on annual immunization and require frequent updates of the vaccine, which is not always a foolproof process. Furthermore, the current antivirals are also losing effectiveness as new viral strains are often refractory to conventional treatments. Thus, there is an urgent need to find new antiviral mechanisms and develop therapeutic drugs based on these mechanisms. Targeting the virus-host interface is an emerging new strategy because host factors controlling viral replication activity will be ideal candidates, and cellular proteins are less likely to mutate under drug-mediated selective pressure. Here, we show that the ubiquitin E3 ligase TRIM41 is an intrinsic host restriction factor to IAV. TRIM41 directly binds the viral nucleoprotein and targets it for ubiquitination and proteasomal degradation, thereby limiting viral infection. Exploitation of this natural defense pathway may open new avenues to develop antiviral drugs targeting the influenza virus.

scholarly journals Segment-Specific Kinetics of mRNA, cRNA, and vRNA Accumulation during Influenza Virus Infection

2021 ◽  
Vol 95 (10) ◽  
Author(s):  
Thu Phan ◽  
Elizabeth J. Fay ◽  
Zion Lee ◽  
Stephanie Aron ◽  
Wei-Shou Hu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Rna Virus ◽  
Gene Segment ◽  
Influenza Virus Infection ◽  
Respiratory Pathogen ◽  
Future Research ◽  
Global Threat ◽  
Kinetics Of ◽  
Segmented Genome

ABSTRACT Influenza A virus (IAV) is a segmented negative-sense RNA virus and is the cause of major epidemics and pandemics. The replication of IAV is complex, involving the production of three distinct RNA species, namely mRNA, cRNA, and viral RNA (vRNA), for all eight genome segments. While understanding IAV replication kinetics is important for drug development and improving vaccine production, current methods for studying IAV kinetics have been limited by the ability to detect all three different RNA species in a scalable manner. Here, we report the development of a novel pipeline using total stranded RNA sequencing (RNA-Seq), which we named influenza virus enumerator of RNA transcripts (InVERT), that allows for the simultaneous quantification of all three RNA species produced by IAV. Using InVERT, we provide a full landscape of the IAV replication kinetics and found that different groups of viral genes follow different kinetics. The segments coding for RNA-dependent RNA polymerase (RdRP) produced more vRNA than mRNA, while some other segments (NP, NS, and hemagglutinin [HA]) consistently made more mRNA than vRNA. vRNA expression levels did not correlate with cRNA expression, suggesting complex regulation of vRNA synthesis. Furthermore, by studying the kinetics of a virus lacking the capacity to generate new polymerase complexes, we found evidence that further supports a model in which cRNA synthesis requires newly synthesized RdRP and that incoming RdRP can only generate mRNA. Overall, InVERT is a powerful tool for quantifying IAV RNA species to elucidate key features of IAV replication. IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen that has caused significant mortality throughout history and remains a global threat to human health. Although much is known about IAV replication, the regulation of IAV replication dynamics is not completely understood. This is due in part to both technical limitations and the complicated replication of the virus, which has a segmented genome and produces three distinct RNA species for each gene segment. We developed a new approach that allows the methodical study of IAV replication kinetics, shedding light on many interesting features of IAV replication biology. This study advances our understanding of the kinetics of IAV replication and will help to facilitate future research in the field.

scholarly journals Interleukin 16 Enhances the Host Susceptibility to Influenza A Virus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Ran Jia ◽  
Congwei Jiang ◽  
Long Li ◽  
Chenxu Huang ◽  
Lijuan Lu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Body Weight Loss ◽  
Lavage Fluid ◽  
Host Susceptibility ◽  
Respiratory Pathogen ◽  
Serum Samples ◽  
Pandemic Flu

Influenza A virus (IAV) is a major respiratory pathogen that causes seasonal and pandemic flu, being a threat to global health. Various viral and cellular factors have been characterized to support or limit IAV infection. Interleukin 16 (IL16) has been known as one of the blood signature biomarkers discriminating systemic inflammation due to viral infection vs. other etiologies. Here, we report that the level of IL16 was elevated in the serum samples, lung homogenates, and bronchoalveolar lavage fluid of IAV-infected mice. IL16 overexpression facilitated IAV replication. Conversely, loss of IL16 reduced the host susceptibility to IAV infection in vitro and in vivo. Furthermore, IL16 deficiency blocked IAV-induced body weight loss and attenuated lung injury in the infected mice. Molecular mechanism analyses further revealed that IL16 could directly inhibit IFN-β transcription and suppress the expression of IFN-β and IFN-stimulated gene. In conclusion, these findings demonstrate that IL16 is a supporting factor for IAV infection.

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