Pathogenesis Of Influenza Research Articles

The Role of EGFR in Influenza Pathogenicity: Multiple Network-Based Approaches to Identify a Key Regulator of Non-lethal Infections.

Despite high sequence similarity between pandemic and seasonal influenza viruses, there is extreme variation in host pathogenicity from one viral strain to the next. Identifying the underlying mechanisms of variability in pathogenicity is a critical task for understanding influenza virus infection and effective management of highly pathogenic influenza virus disease. We applied a network-based modeling approach to identify critical functions related to influenza virus pathogenicity using large transcriptomic and proteomic datasets from mice infected with six influenza virus strains or mutants. Our analysis revealed two pathogenicity-related gene expression clusters; these results were corroborated by matching proteomics data. We also identified parallel downstream processes that were altered during influenza pathogenesis. We found that network bottlenecks (nodes that bridge different network regions) were highly enriched in pathogenicity-related genes, while network hubs (highly connected network nodes) were significantly depleted in these genes. We confirmed that this trend persisted in a distinct virus: Severe Acute Respiratory Syndrome Coronavirus (SARS). The role of epidermal growth factor receptor (EGFR) in influenza pathogenesis, one of the bottleneck regulators with corroborating signals across transcript and protein expression data, was tested and validated in additional mouse infection experiments. We demonstrate that EGFR is important during influenza infection, but the role it plays changes for lethal versus non-lethal infections. Our results show that by using association networks, bottleneck genes that lack hub characteristics can be used to predict a gene’s involvement in influenza virus pathogenicity. We also demonstrate the utility of employing multiple network approaches for analyzing host response data from viral infections.

Testosterone treatment of aged male mice improves some but not all aspects of age-associated increases in influenza severity

The severity of influenza increases with age, with worse disease in aged males than females. Testosterone concentrations decline with age in males, which may impact influenza pathogenesis. Aged male mice were treated with testosterone or placebo and outcomes during influenza A virus (IAV) infection were compared with adult male mice. Aged males experienced greater morbidity and mortality than adult males, which was partially improved by testosterone treatment of aged males. Aged males cleared IAV from lungs slower than adult males, regardless of testosterone treatment. As compared with adult males, aged males experienced pulmonary, but not systemic, cytokine dysregulation, and delayed influx and contraction of IAV-specific CD8+ T cells in the lungs. Testosterone treatment in aged males partially restored pulmonary cytokine responses to levels consistent with adult males but did not alter the age-associated changes in IAV-specific CD8+ T cells. Testosterone only modestly improves outcomes of influenza in aged males.

Exosome-delivered and Y RNA-derived small RNA suppresses influenza virus replication

BackgroundMultiple interplays between viral and host factors are involved in influenza virus replication and pathogenesis. Several small RNAs have recently emerged as important regulators of host response to viral infections. The aim of this study was to characterize the functional role of hsa-miR-1975, a Y5 RNA-derived small RNA, in defending influenza virus and delineate the mechanisms.MethodsWe performed high throughput sequencing of small RNAs in influenza virus-infected cells to identify up- or down- regulated small RNA species. The expression of the most abundant RNA species (hsa-miR-1975) was validated by stem-loop reverse transcription-polymerase chain reaction (RT-PCR). Antiviral effects of hsa-miR-1975 were confirmed by Western Blot, RT-PCR and plaque assay. In vitro perturbation of hsa-miR-1975 combined with exosomes isolation was used to elucidate the role and mechanism of hsa-miR-1975 in the context of antiviral immunity.ResultsSmall RNA sequencing revealed that hsa-miR-1975 was the most up-regulated small RNA in influenza virus-infected cells. The amount of intracellular hsa-miR-1975 increased in the late stage of the influenza virus replication cycle. The increased hsa-miR-1975 was at least partially derived from degradation of Y5RNA as a result of cellular apoptosis. Unexpectedly, hsa-miR-1975 mimics inhibited influenza virus replication while hsa-miR-1975 sponges enhanced the virus replication. Moreover, hsa-miR-1975 was secreted in exosomes and taken up by the neighboring cells to induce interferon expression.ConclusionsOur findings unravel a critical role of Y-class small RNA in host’s defense against influenza virus infection and reveal its antiviral mechanism through exosome delivery. This may provide a new candidate for targeting influenza virus.

Progress and Current Status of Influenza Researches in China.

Influenza pandemics with different extent occur every year in the world. It can cause high morbidity and mortality, arouse fear panic in public, and attract extensive attention worldwide. This paper reviews the research progress in epidemiological characteristics, detection methods, pathogenesis, treatment and prophylactic measures of influenza in China. It will be helpful for us to understand the current situation of influenza.

Virus-induced pathogenesis, vaccine development, and diagnosis of novel H7N9 avian influenza A virus in humans: a systemic literature review.

H7N9 avian influenza virus (AIV) caused human infections in 2013 in China. Phylogenetic analyses indicate that H7N9 AIV is a novel reassortant strain with pandemic potential. We conducted a systemic review regarding virus-induced pathogenesis, vaccine development, and diagnosis of H7N9 AIV infection in humans. We followed PRISMA guidelines and searched PubMed, Web of Science, and Google Scholar to identify relevant articles published between January 2013 and December 2018. Pathogenesis data indicated that H7N9 AIV belongs to low pathogenic avian influenza, which is mostly asymptomatic in avian species; however, H7N9 induces high mortality in humans. Sporadic human infections have recently been reported, caused by highly pathogenic avian influenza viruses detected in poultry. H7N9 AIVs resistant to adamantine and oseltamivir cause severe human infection by rapidly inducing progressive acute community-acquired pneumonia, multiorgan dysfunction, and cytokine dysregulation; however, mechanisms via which the virus induces severe syndromes remain unclear. An H7N9 AIV vaccine is lacking; designs under evaluation include synthesized peptide, baculovirus-insect system, and virus-like particle vaccines. Molecular diagnosis of H7N9 AIVs is suggested over conventional assays, for biosafety reasons. Several advanced or modified diagnostic assays are under investigation and development. We summarized virus-induced pathogenesis, vaccine development, and current diagnostic assays in H7N9 AIVs.

To hit or not to hit: Large-scale sequence analysis and structure characterization of influenza A NS1 unlocks new antiviral target potential

Influenza NS1 protein is among the most promising novel druggable anti-influenza target, based on its structure; multiple interactions; and global function in influenza replication and pathogenesis. Notwithstanding, drug development guidance based on NS1 structural biology is lacking. Here, we design a promising strategy directed to highly conserved druggable regions as a result of an exhaustive large-scale sequence analysis and structure characterization of NS1 protein across human-infecting influenza A subtypes, over the past 100 years. We have identified 3 druggable pockets and 8 new potential hot spot residues in the NS1 protein, not described before, additionally to other 16 sites previously identified, which represent attractive targets for pharmacological modulation. This study provides a rationale towards structure-function studies of NS1 druggable sites, which have the potential to accelerate the NS1 target validation. This research also contributes to a deeper comprehension and insight into the evolutionary dynamics of influenza A NS1 protein.

Neutrophils Induce a Novel Chemokine Receptors Repertoire During Influenza Pneumonia.

Exaggerated host innate immune responses have been implicated in severe influenza pneumonia. We have previously demonstrated that excessive neutrophils recruited during influenza infection drive pulmonary pathology through induction of neutrophil extracellular traps (NETs) and release of extracellular histones. Chemokine receptors (CRs) are essential in the recruitment and activation of leukocytes. Although neutrophils have been implicated in influenza pathogenesis, little is known about their phenotypic changes, including expression of CRs occurring in the infected -lung microenvironment. Here, we examined CC and CXC CRs detection in circulating as well as lung-recruited neutrophils during influenza infection in mice using flow cytometry analyses. Our studies revealed that lung-recruited neutrophils displayed induction of CRs, including CCR1, CCR2, CCR3, CCR5, CXCR1, CXCR3, and CXCR4, all of which were marginally induced in circulating neutrophils. CXCR2 was the most predominant CR observed in both circulating and lung-infiltrated neutrophils after infection. The stimulation of these induced CRs modulated neutrophil phagocytic activity, ligand-specific neutrophil migration, bacterial killing, and NETs induction ex vivo. These findings indicate that neutrophils induce a novel CR repertoire in the infectious lung microenvironment, which alters their functionality during influenza pneumonia.

Influenza in obese travellers: increased risk and complications, decreased vaccine effectiveness.

Obesity is a worldwide epidemic and was empirically shown to increase the risk of developing severe influenza virus infection. As international travel becomes more common and obesity is now prevalent even in low- and middle-income countries, travellers may have an increased risk of contracting influenza virus especially during peak influenza season. An analysis of the literature, centred on publications from 2014-19, was performed, with an emphasis on human epidemiological data, human studies ex vivo and studies in mouse models of obesity. Our search efforts focused on influenza disease severity, pathogenesis, evolutionary dynamics and measures of infection control in the obese and overweight host. Obesity is associated with an increased risk of infection, as well as a greater chance for hospitalization and severe complications. Studies in mouse models of obesity have uncovered that obese hosts suffer increased viral spread, delayed viral clearance and heightened damage to the respiratory epithelium. Innate and adaptive immune responses are delayed, thus increasing morbidity and mortality. Further, infection control measures, including vaccination and antivirals, prove less effective in obese hosts. Finally, the obese microenvironment allows for increased duration and amount of viral shedding and potentially increases the chance for emergence of virulent minor variants in the viral population. Together, obese hosts are at high risk of influenza infection, as well as severe sequelae following infection. Obese travellers should be aware of influenza activity in the regions visited, as well as take protective measures prior to travel. Vaccination is highly recommended for all travellers, but especially highly susceptible obese travellers.

Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection.

Host cell proteases are involved in influenza pathogenesis. We examined the role of tissue kallikrein 1 (KLK1) by comparing wild-type (WT) and KLK1-deficient mice infected with influenza H3N2 virus. The levels of KLK1 in lung tissue and in bronchoalveolar lavage (BAL) fluid increased substantially during infection. KLK1 did not promote virus infectivity despite its trypsin-like activity, but it did decrease the initial virus load. We examined two cell types involved in the early control of pathogen infections, alveolar macrophages (AMs) and natural killer (NK) cells to learn more about the antiviral action of KLK1. Inactivating the Klk1 gene or treating WT mice with an anti-KLK1 monoclonal antibody to remove KLK1 activity accelerated the initial virus-induced apoptotic depletion of AMs. Intranasal instillation of deficient mice with recombinant KLK1 (rKLK1) reversed the phenotype. The levels of granulocyte-macrophage colony-stimulating factor in infected BAL fluid were significantly lower in KLK1-deficient mice than in WT mice. Treating lung epithelial cells with rKLK1 increased secretion of this factor known to enhance AM resistance to pathogen-induced apoptosis. The recruitment of NK cells to the air spaces peaked 3 days after infection in WT mice but not in KLK1-deficient mice, as did increases in several NK-attracting chemokines (CCL2, CCL3, CCL5, and CXCL10) in BAL. Chronic obstructive pulmonary disease (COPD) patients are highly susceptible to viral infection, and we observed that the KLK1 mRNA levels decreased with increasing COPD severity. Our findings indicate that KLK1 intervenes early in the antiviral defense modulating the severity of influenza infection. Decreased KLK1 expression in COPD patients could contribute to the worsening of influenza.

House dust mite exposure attenuates influenza A infection in a mouse model of pulmonary allergic inflammation

Environmental allergens elicit complex immune responses in the lungs that can promote the development of asthma or exacerbate preexisting asthma in susceptible individuals. House dust mites are one of the most common indoor allergens and are a significant driver of allergic disease. Respiratory infections are known factors in acute exacerbations of asthma but the impact of allergen on the pathogen is not well understood. We investigated the pathogenesis of influenza A infection following exposure to house dust mites. Mice exposed to house dust mites lose less weight following infection and had more transcription of interferon-lambda than controls. These data correlated with less transcription of the influenza polymerase acidic gene suggesting diminished viral replication in house dust mite exposed mice. Altogether, these data suggest that exposure to environmental allergens can influence the pathogenesis of influenza infection.

Revealing hub pathway cross-talk for premature newborns with bronchopulmonary dysplasia by the integration of pathway analysis and Monte Carlo Cross-Validation.

The objective of this study was to reveal hub pathway cross-talk for premature newborns with bronchopulmonary dysplasia (BPD) based on the pathway enrichment analysis and Monte Carlo Cross-Validation (MCCV) method. The inference of key pathway cross-talk consisted of four parts: i) Identifying differentially expressed genes (DEGs); ii) detecting differentially expressed pathways (DEPs); iii) computing discriminating score (DS) for each pair of DEPs or cross-talk and investigating seed cross-talk through the random forest (RF) algorithm and iv) extracting hub cross-talk dependent on the MCCV method. The results showed that a total of 132 DEGs and 137 DEPs were obtained across BPD patients and normal controls. Using the DS and RF algorithm, 10 seed DEP cross-talk were detected. By conducting the MCCV on seed cross-talk, 3 hub cross-talk for BPD were uncovered: i) The pair of pathways role of interleukin-17F (IL-17F) in allergic inflammatory airway diseases and role of IL-17A in psoriasis; ii) the pair of pathways role of IL random forest 17A in psoriasis and IL-17A signaling in fibroblasts and ii) the pair of pathways IL-17A signaling in airway cells and role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza. These 3 hub cross-talk among DEPs might give an insight to reveal the molecular mechanism underlying the premature newborns with BPD.

Th17 serum cytokines in relation to laboratory-confirmed respiratory viral infection: A pilot study.

BackgroundTh17 cytokines are associated with modulation of inflammation and may be beneficial in clearing influenza infection in experimental models. The Th17 cytokine profile was evaluated in a pilot study of respiratory virus infections.MethodsConsecutive patients with symptoms of respiratory tract infection visiting the emergency department of a tertiary care hospital during the winter influenza season of 2014 to 2015 were evaluated. CLART PneumoVir kit, (GENOMICA, Madrid, Spain) was used for viral detection of all known respiratory viruses. Th17 cytokine profile was evaluated with the MILLIPLEX MAP Human TH17 Magnetic Bead Panel (Millipore Corp., Billerica, MA). Correlation of the TH17 profile with viral detection was performed with univariate and multivariate analysis.ResultsSeventy‐six patients were evaluated (median age 56 years, 51.3% female); a respiratory virus was identified in 60 (78.9%) patients; 45% had confirmed influenza. Influenza A (H3N2) correlated with higher levels of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), interleukin 1β (IL‐1β), IL‐17A, IL‐17E, IL‐17F, IL‐21, IL‐22, and IL‐23 (P < 0.05 by analysis of variance [ANOVA]) compared with respiratory syncytial virus (RSV). Parainfluenza virus (PIV) similarly had higher levels of GM‐CSF, IL‐1b, IL‐17A, IL‐22 compared with those detected in RSV, influenza B and any other virus infection ( P < 0.05; ANOVA). Increasing age (β‐coefficient = 1.11, 95% CI, 1.04‐1.2, P < 0.01) as well as IL‐17A levels (β‐coefficient = 1.03, 95% CI, 1.001‐1.05, P = 0.04) predicted hospital admission.ConclusionMain Th17 cell effector cytokines were upregulated in laboratory‐confirmed A(H3N2) influenza and PIV. Excessive amounts of Th17 cytokines may be implicated in the pathogenesis and immune control of acute influenza and PIV infection in humans and may predict the severity of disease.

Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics

Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons.

Pathogenesis of severe influenza in children

Children are at high risk for influenza and for severe cases.This article discussed the pathogenesis of severe influenza in children, including evaluation methods, immune system development, energy metabolism, genetic background and influenza virus strains.Try to provide some ideas for early identification, diagnosis and treatment of severe influenza in children. Key words: Influenza; Pathogenesis; Child

C57BL/6J and C57BL/6NJ Mice Are Differentially Susceptible to Inflammation-Associated Disease Caused by Influenza A Virus

Influenza viruses cause seasonal epidemics and sporadic pandemics, and are a major burden on human health. To develop better countermeasures and improve influenza disease outcomes, a clearer understanding of influenza pathogenesis is necessary. Host genetic factors have emerged as potential regulators of human influenza disease susceptibility, and in the mouse model, genetic background has been clearly linked to influenza pathogenicity. Here, we show that C57BL/6J mice are significantly more susceptible to disease caused by a 2009 pandemic H1N1 virus, an H7N9 virus, and a highly pathogenic H5N1 influenza virus compared to the closely related substrain, C57BL/6NJ. Mechanistically, influenza virus infection in C57BL/6J mice results in earlier presentation of edema, increased immune cell infiltration, higher levels of inflammatory cytokines, greater tissue damage, and delayed activation of regenerative processes in infected lung tissues compared to C57BL/6NJ mice. These differences are not dependent on virus replication levels. Six genes with known coding region differences between C57BL/6J and C57BL/6NJ strains exhibit increased transcript levels in influenza virus-infected mouse lungs, suggesting potential contributions to regulation of disease susceptibility. This work uncovers a previously unappreciated difference in disease susceptibility between the closely related C57BL/6J and C57BL/6NJ mice, which may be exploited in future studies to identify host factors and/or specific genetic elements that regulate host-dependent inflammatory mechanisms involved in influenza virus pathogenicity.

Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease.

Influenza viruses continue to be a major global health threat. Severity and clinical outcome of influenza disease is determined by both viral and host factors. Viral factors have long been the subject of intense research and many molecular determinants have been identified. However, research into the host factors that protect or predispose to severe and fatal influenza A virus infections is lagging. The goal of this review is to highlight the recent insights into host determinants of influenza pathogenesis.

\u201cWith fever it\u2019s the real flu I would say\u201d: laypersons\u2019 perception of common cold and influenza and their differences - a qualitative study in Austria, Belgium and Croatia

BackgroundThere is little research on laypersons’ perceptions regarding common cold and influenza, their symptomatic distinction and considerations of risk. This study investigates understanding of pathogenesis across three European countries and provides a knowledge base from which adequate prevention recommendations and treatment advice can be derived.MethodsThis is a qualitative research study. Semi-structured face-to-face interviews were conducted with 85 participants from three European countries (Austria n = 31, Belgium n = 30, Croatia n = 24) about their experiences, perceptions and risk considerations regarding the common cold and influenza. We performed a qualitative thematic content analysis.ResultsThree main themes were identified: common cold as harmless with individualistic symptoms; influenza as mainly distinguishable by fever, confinement to bed and severity of symptoms, but description about onset and duration are diverse; and views on pathogenesis contain references to disease causing agents and circumstances. Overall we found that risk perception is based largely on personal experience and risk is assumed moderate for both diseases.ConclusionsStudy participants possessed a fairly good understanding of symptoms, differences and pathogenesis of common cold and influenza; but explanations integrated misconceptions, such as misinterpretation of fever, disease continuums, diverse onset ideas etc. Perceptions were largely based on lived experiences and interventions for prevention and treatment should be led by health care workers and focus on these issues. Basic consultations, awareness raising activities and other knowledge disseminations strategies should include aspects of communicableness and the self-limiting nature of both diseases. An informed understanding of both infectious diseases is crucial and may also increase influenza vaccination coverage in the three respective countries effectively.

Comprehensive analysis of N-glycans in IgG purified from ferrets with or without influenza A virus infection

Influenza viruses cause contagious respiratory infections, resulting in significant economic burdens to communities. Production of influenza-specific Igs, specifically IgGs, is one of the major protective immune mechanisms against influenza viruses. In humans, N-glycosylation of IgGs plays a critical role in antigen binding and effector functions. The ferret is the most commonly used animal model for studying influenza pathogenesis, virus transmission, and vaccine development, but its IgG structure and functions remain largely undefined. Here we show that ferret IgGs are N-glycosylated and that their N-glycan structures are diverse. Using a comprehensive strategy based on MS and ultra-HPLC analyses in combination with exoglycosidase digestions, we assigned 42 N-glycan structures in ferret IgGs. We observed that N-glycans of ferret IgGs consist mainly of complex-type glycans, including some high-mannose and hybrid glycans, similar to those observed in human IgG. The complex-type glycans of ferret IgGs were primarily core-fucosylated. Furthermore, a fraction of N-glycans carried bisecting GlcNAc. Ferret IgGs also had a minor fraction of glycans carrying α2-6Neu5Ac(s). We noted that, unlike human IgG, ferret IgGs have αGal epitopes on some N-glycans. Interestingly, influenza A infection caused prominent changes in the N-glycans of ferret IgG, mainly because of an increase in bisecting GlcNAc and F1A2G0 and a corresponding decrease in F1A2G1. This suggests that the glycosylation of virus-specific IgG may play a role in its functionality. Our study highlights the need to further elucidate the structure-function relationships of IgGs in universal influenza vaccine development.

723. Validation of a Wild-Type Influenza A/Texas-Like H3N2 Human Challenge Model with Comparison to the Validated A(H1N1)pdm09 Model

BackgroundHealthy volunteer challenge studies provide an opportunity to better understand influenza pathogenesis and correlates of protection. The development of vaccines and therapeutics has relied on these studies as will future universal vaccine candidates. The first fully validated wild-type human infection model with A(H1N1)pdm09 was developed at the NIH Clinical Center (CC) in 2012 and this study represents the first validation of a wild-type seasonal H3N2 human infection model. The objective of this study was to characterize a wild-type Influenza A/Texas-like H3N2 challenge virus in healthy volunteers.MethodsHealthy volunteers were isolated at the NIH CC for a minimum of 9 days. Subjects received a single dose of a reverse genetics, cell-based, GMP, wild-type A H3N2 virus intranasally. Dose escalation was performed from 104 to 107 TCID50. Viral shedding and clinical disease were evaluated daily, including clinician assessments and a validated patient-reported outcome tool, FLU-PRO©.ResultsA total of 37 subjects were challenged. Sixteen (43%) subjects had viral shedding and 27 (73%) developed influenza symptoms, with 12 subjects (32%) experiencing mild-to-moderate influenza disease (MMID) defined as symptoms and shedding. Only subjects receiving the 106 and 107 TCID50 doses experienced MMID at 44% and 40%, respectively. Nose and throat symptoms were most common and peaked by Days 2–3 post-challenge. Although serum antibody responses were observed, many of these responses were limited in a significant number of subjects.ConclusionThe A/Texas-like H3N2 Influenza challenge virus safely induced MMID in healthy volunteers, but was less effective than the A(H1N1)pdm09 challenge virus. This lower MMID rate of 40% was observed at the 107 TCID50 dose and was driven by less detection of shedding as the incidence of symptoms was similar to A(H1N1)pdm09. The limited serum antibody responses observed demonstrate that preexisting immunity in healthy volunteers against the seasonal H3N2 lineage may limit shedding compared with the more recently emerged seasonal A(H1N1)pdm09 lineage. The successful characterization of this H3N2 model makes future studies using this model to explore viral pathogenesis or evaluate vaccines possible.This research was supported by the Intramural Research Program of the NIH, NIAID.Disclosures All authors: No reported disclosures.

234 - Lung epithelial PDIA3 plays a critical role in influenza infection

Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and that this interaction is required for efficient oxidative folding of HA in vitro. However it is unknown whether these host-viral protein interactions occur during active infection and whether this interaction represent a putative target for the treatment of influenza infection. Current therapies targeting viral proteins are often limited in their effectiveness due to rapid development of viral resistance; targeting host proteins may avoid these limitations. Here we show that PDIA3 is specifically upregulated in IAV infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Among PDI inhibitors tested, we found LOC14 inhibits PDIA3 at an IC50 of 5μM. Treatment with LOC14 inhibits PDIA3 activity in lung epithelial cells and subsequently decreases disulfide bonds, and oligomerization (maturation) of HA in both pandemic H1N1 and seasonal H3N2 infected lung epithelial cells. Disulfide labeling analysis indicated that inhibition of PDIA3 activity also decreased disulfide bonds in IAV-neuraminidase (NA) and these differences in oxidative folding correspond to a subsequent decrease in NA activity. Furthermore, these decreases in disulfide bonds significantly decrease viral load, and pro-inflammatory response from primary lung epithelial cells. Lung epithelial specific deletion of PDIA3 in mice results in a significant decreases in viral burden and levels of inflammatory-immune markers in mouse lung, as well as significantly improved airway mechanics (function). Taken together, these results suggest PDIA3 is required for effective influenza pathogenesis in vivo, and inhibition of PDIA3 may aid future development anti-influenza therapies based on inhibition of host PDIs to circumvent antigenic drifts and shifts of influenza and may lend critically needed help during pandemic and severe influenza seasons.