Glycomic analysis of host response reveals high mannose as a key mediator of influenza severity

Influenza virus infections cause a wide variety of outcomes, from mild disease to 3 to 5 million cases of severe illness and ∼290,000 to 645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose-dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity.

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Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity

10.1101/2020.04.21.054098 ◽

2020 ◽

Author(s):

Daniel W. Heindel ◽

Sujeethraj Koppolu ◽

Yue Zhang ◽

Brian Kasper ◽

Lawrence Meche ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Molecular Mechanisms ◽

Influenza Virus Infection ◽

Host Responses ◽

Differential Host ◽

Unfolded Protein ◽

High Mannose ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACTInfluenza virus infections cause a wide variety of outcomes, from mild disease to 3-5 million cases of severe illness and ~290,000-645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity.SIGNIFICANCEInfluenza virus infection causes a range of outcomes from mild illness to death. The molecular mechanisms leading to these differential host responses are currently unknown. Herein, we identify the induction of high mannose, a glycan epitope, as a key mediator of severe disease outcome. We propose a mechanism in which activation of the unfolded protein response (UPR) upon influenza virus infection turns on expression of high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and leading to subsequent inflammation. This work is the first to systematically study host glycomic changes in response to influenza virus infection, identifying high mannose as a key feature of differential host response.

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Impact of influenza virus during pregnancy: from disease severity to vaccine efficacy

Future Virology ◽

10.2217/fvl-2020-0024 ◽

2020 ◽

Vol 15 (7) ◽

pp. 441-453

Author(s):

Ana Vazquez-Pagan ◽

Rebekah Honce ◽

Stacey Schultz-Cherry

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

Pregnant Women ◽

Disease Severity ◽

Influenza A ◽

Antiviral Treatment ◽

Influenza Virus Infection ◽

Severe Influenza ◽

The Impact

Pregnant women are among the individuals at the highest risk for severe influenza virus infection. Infection of the mother during pregnancy increases the probability of adverse fetal outcomes such as small for gestational age, preterm birth and fetal death. Animal models of syngeneic and allogeneic mating can recapitulate the increased disease severity observed in pregnant women and are used to define the mechanism(s) of that increased severity. This review focuses on influenza A virus pathogenesis, the unique immunological landscape during pregnancy, the impact of maternal influenza virus infection on the fetus and the immune responses at the maternal–fetal interface. Finally, we summarize the importance of immunization and antiviral treatment in this population and highlight issues that warrant further investigation.

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Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans

Science Translational Medicine ◽

10.1126/scitranslmed.abd3601 ◽

2020 ◽

Vol 12 (573) ◽

pp. eabd3601

Author(s):

Haley L. Dugan ◽

Jenna J. Guthmiller ◽

Philip Arevalo ◽

Min Huang ◽

Yao-Qing Chen ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

Virus Infection ◽

Natural Infection ◽

Influenza Virus Infection ◽

Memory B Cells ◽

Antibody Responses ◽

Protective Antibody ◽

The Impact ◽

Neutralizing Epitopes

Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.

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IFN-γ Treatment at Early Stages of Influenza Virus Infection Protects Mice from Death in a NK Cell-Dependent Manner

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2009.0084 ◽

2010 ◽

Vol 30 (6) ◽

pp. 439-449 ◽

Cited By ~ 57

Author(s):

Ido D. Weiss ◽

Ori Wald ◽

Hanna Wald ◽

Katia Beider ◽

Michal Abraham ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Nk Cell ◽

Influenza Virus Infection ◽

Dependent Manner ◽

Early Stages ◽

Ifn Γ

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Review on the impact of pregnancy and obesity on influenza virus infection

Influenza and Other Respiratory Viruses ◽

10.1111/j.1750-2659.2012.00342.x ◽

2012 ◽

Vol 6 (6) ◽

pp. 449-460 ◽

Cited By ~ 32

Author(s):

Erik A. Karlsson ◽

Glendie Marcelin ◽

Richard J. Webby ◽

Stacey Schultz-Cherry

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

The Impact

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A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0812689106 ◽

2009 ◽

Vol 106 (5) ◽

pp. 1560-1565 ◽

Cited By ~ 90

Author(s):

D. Marsolais ◽

B. Hahm ◽

K. B. Walsh ◽

K. H. Edelmann ◽

D. McGavern ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Critical Role ◽

Influenza Virus Infection ◽

Cytokine Response

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Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms

Molecular and Cellular Biology ◽

10.1128/mcb.21.24.8301-8317.2001 ◽

2001 ◽

Vol 21 (24) ◽

pp. 8301-8317 ◽

Cited By ~ 38

Author(s):

Kalpana Ghoshal ◽

Sarmila Majumder ◽

Qin Zhu ◽

John Hunzeker ◽

Jharna Datta ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Glucocorticoid Receptor ◽

Influenza A ◽

Molecular Mechanisms ◽

Influenza Virus Infection ◽

Upper Respiratory Tract ◽

Response Element ◽

Induction Process ◽

Ifn Γ

ABSTRACT Metallothionein I (MT-I) and MT-II have been implicated in the protection of cells against reactive oxygen species (ROS), heavy metals, and a variety of pathological and environmental stressors. Here, we show a robust increase in MT-I/MT-II mRNA level and MT proteins in the livers and lungs of C57BL/6 mice exposed to the influenza A/PR8 virus that infects the upper respiratory tract and lungs. Interleukin-6 (IL-6) had a pronounced effect on the induction of these genes in the liver but not the lung. Treatment of the animals with RU-486, a glucocorticoid receptor antagonist, inhibited induction of MT-I/MT-II in both liver and lung, revealing a direct role of glucocorticoid that is increased upon infection in this induction process. In vivo genomic footprinting (IVGF) analysis demonstrated involvement of almost all metal response elements, major late transcription factor/antioxidant response element (MLTF/ARE), the STAT3 binding site on the MT-I upstream promoter, and the glucocorticoid responsive element (GRE1), located upstream of the MT-II gene, in the induction process in the liver and lung. In the lung, inducible footprinting was also identified at a unique gamma interferon (IFN-γ) response element (γ-IRE) and at Sp1 sites. The mobility shift analysis showed activation of STAT3 and the glucocorticoid receptor in the liver and lung nuclear extracts, which was consistent with the IVGF data. Analysis of the newly synthesized mRNA for cytokines in the infected lung by real-time PCR showed a robust increase in the levels of IL-10 and IFN-γ mRNA that can activate STAT3 and STAT1, respectively. A STAT1-containing complex that binds to the γ-IRE in vitro was activated in the infected lung. No major change in MLTF/ARE DNA binding activity in the liver and lung occurred after infection. These results have demonstrated that MT-I and MT-II can be induced robustly in the liver and lung following experimental influenza virus infection by overlapping but distinct molecular mechanisms.

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Low pathogenic avian influenza virus infection retards colon microbiome diversification in two different chicken lines

10.1101/2021.03.15.435422 ◽

2021 ◽

Author(s):

Klaudia Chrzastek ◽

Joy Leng ◽

Mohammad Khalid Zakaria ◽

Dagmara Bialy ◽

Roberto LaRagione ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Rhode Island ◽

Post Infection ◽

Influenza Infection ◽

Influenza Virus Infection ◽

Virus Infectivity ◽

The Impact

A commensal microbiome regulates and is in turn regulated by viruses during host infection which can influence virus infectivity. In this study, analysis of colon microbiome population changes following a low pathogenicity avian influenza virus (AIV) of the H9N2 subtype infection of two different chicken breeds was conducted. Using 16S rRNA sequencing and subsequent data analysis we found reduced microbiome alpha diversity in the acute period of AIV infection (day 2-3) in both Rhode Island Red and VALO chicken lines. From day 4 post infection a gradual increase in diversity of the colon microbiome was observed, but the diversity did not reach the same level as in uninfected chickens by day 10 post infection, suggesting that AIV infection retards the natural accumulation of colon microbiome diversity, which may further influence chicken health following recovery from infection. Beta diversity analysis indicated differences in diversity between the chicken lines during and following acute influenza infection suggesting the impact of host gut microflora dysbiosis following H9N2 influenza virus infection could differ for different breeds.

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Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans

mBio ◽

10.1128/mbio.01996-15 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 72

Author(s):

Raffael Nachbagauer ◽

Angela Choi ◽

Ruvim Izikson ◽

Manon M. Cox ◽

Peter Palese ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

The Elderly ◽

Influenza Viruses ◽

Influenza B Virus ◽

Enzyme Linked Immunosorbent Assay ◽

Influenza B ◽

Dependent Manner ◽

Specific Antibodies

ABSTRACT Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the virus undergoes extensive antigenic drift. Antibodies that target the highly conserved hemagglutinin stalk can protect against drifted viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal influenza virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and influenza B virus hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low influenza virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.) IMPORTANCE The present study provides evidence that titers of broadly neutralizing hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent influenza viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of influenza viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against influenza virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.

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