Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+-specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

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Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

Journal of Virology ◽

10.1128/jvi.02110-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 337-349 ◽

Cited By ~ 19

Author(s):

David J. Morales ◽

Kristen Monte ◽

Lulu Sun ◽

Jessica J. Struckhoff ◽

Eugene Agapov ◽

...

Keyword(s):

Tissue Culture ◽

Virus Infection ◽

Influenza A Virus ◽

Virus Replication ◽

Influenza A ◽

Type I Interferon ◽

Sendai Virus ◽

Type I ◽

Induced Genes

ABSTRACTISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15−/−mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replicationin vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15−/−mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15in vivo.IMPORTANCEIt has previously been demonstrated that ISG15−/−mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protectionin vivo. In these studies we have found that while ISG15−/−mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15in vivo.

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PA-X antagonises MAVS-dependent accumulation of early type I interferon messenger RNAs during influenza A virus infection

Scientific Reports ◽

10.1038/s41598-019-43632-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Rachel E. Rigby ◽

Helen M. Wise ◽

Nikki Smith ◽

Paul Digard ◽

Jan Rehwinkel

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Messenger Rnas ◽

Early Type ◽

Influenza A Virus Infection

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Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Journal of Virology ◽

10.1128/jvi.02749-15 ◽

2015 ◽

Vol 90 (5) ◽

pp. 2403-2417 ◽

Cited By ~ 41

Author(s):

Chuan Xia ◽

Madhuvanthi Vijayan ◽

Curtis J. Pritzl ◽

Serge Y. Fuchs ◽

Adrian B. McDermott ◽

...

Keyword(s):

Signaling Pathway ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Type I Ifn ◽

Type I Ifns ◽

Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

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Type I Interferon Plays Opposing Roles in Cytotoxicity and Interferon-γ Production by Natural Killer and CD8+ T Cells after Influenza A Virus Infection in Mice

Journal of Innate Immunity ◽

10.1159/000356824 ◽

2014 ◽

Vol 6 (4) ◽

pp. 456-466 ◽

Cited By ~ 7

Author(s):

Yojiro Arimori ◽

Risa Nakamura ◽

Hisakata Yamada ◽

Kensuke Shibata ◽

Naoyoshi Maeda ◽

...

Keyword(s):

T Cells ◽

Virus Infection ◽

Natural Killer ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Influenza A Virus Infection

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To Conquer the Host, Influenza Virus Is Packing It In: Interferon-Antagonistic Strategies beyond NS1

Journal of Virology ◽

10.1128/jvi.00041-16 ◽

2016 ◽

Vol 90 (19) ◽

pp. 8389-8394 ◽

Cited By ~ 10

Author(s):

Michaela Weber-Gerlach ◽

Friedemann Weber

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Host Defense ◽

Influenza A ◽

Type I Interferon ◽

Current Knowledge ◽

Nonstructural Protein ◽

Structural Proteins ◽

Type I ◽

Interferon System

The nonstructural protein NS1 is well established as a virulence factor of influenza A virus counteracting induction of the antiviral type I interferon system. Recent studies now show that viral structural proteins, their derivatives, and even the genome itself also contribute to keeping the host defense under control. Here, we summarize the current knowledge on these NS1-independent interferon escape strategies.

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Toll-like receptor 5 agonist flagellin reduces influenza A virus replication independently of type I interferon and interleukin 22 and improves antiviral efficacy of oseltamivir

Antiviral Research ◽

10.1016/j.antiviral.2019.05.002 ◽

2019 ◽

Vol 168 ◽

pp. 28-35 ◽

Cited By ~ 5

Author(s):

Anne-France Georgel ◽

Delphine Cayet ◽

Andrés Pizzorno ◽

Manuel Rosa-Calatrava ◽

Christophe Paget ◽

...

Keyword(s):

Influenza A Virus ◽

Virus Replication ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Toll Like Receptor ◽

Interleukin 22 ◽

Antiviral Efficacy ◽

Toll Like Receptor 5

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Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza and other community-acquired pneumonia.

10.21203/rs.3.rs-226162/v1 ◽

2021 ◽

Author(s):

Alex Schuurman ◽

Tom Reijnders ◽

Anno Saris ◽

Ivan Ramirez-Moral ◽

Michiel Schinkel ◽

...

Keyword(s):

Single Cell ◽

Host Response ◽

Influenza A ◽

Single Cell Analysis ◽

Type I Interferon ◽

Community Acquired Pneumonia ◽

Type I ◽

Cell Analysis ◽

The Common ◽

Peripheral Immune Response

Abstract The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by methodological heterogeneity and a lack of relevant disease controls. The absence of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in PBMCs from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach we describe shared and diverging transcriptional and phenotypic patterns – including increased levels of type I interferon stimulated NK cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups – and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.

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Faculty Opinions recommendation of Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor-dependent pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718071290.793504126 ◽

2015 ◽

Author(s):

Padmini Salgame ◽

Archana Gopalakrishnan

Keyword(s):

Mycobacterium Tuberculosis ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Interferon Receptor ◽

Dependent Pathway

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Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection

mBio ◽

10.1128/mbio.00506-16 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 22

Author(s):

Kelly M. Shepardson ◽

Kyle Larson ◽

Rachelle V. Morton ◽

Justin R. Prigge ◽

Edward E. Schmidt ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Influenza A Virus ◽

Virulence Factors ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Type I Ifn ◽

Mrsa Infection ◽

Bacterial Superinfection ◽

Increased Susceptibility

ABSTRACT Bacterial superinfections are a primary cause of death during influenza pandemics and epidemics. Type I interferon (IFN) signaling contributes to increased susceptibility of mice to bacterial superinfection around day 7 post-influenza A virus (IAV) infection. Here we demonstrate that the reduced susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) at day 3 post-IAV infection, which we previously reported was due to interleukin-13 (IL-13)/IFN-γ responses, is also dependent on type I IFN signaling and its subsequent requirement for protective IL-13 production. We found, through utilization of blocking antibodies, that reduced susceptibility to MRSA at day 3 post-IAV infection was IFN-β dependent, whereas the increased susceptibility at day 7 was IFN-α dependent. IFN-β signaling early in IAV infection was required for MRSA clearance, whereas IFN-α signaling late in infection was not, though it did mediate increased susceptibility to MRSA at that time. Type I IFN receptor (IFNAR) signaling in CD11c + and Ly6G + cells was required for the observed reduced susceptibility at day 3 post-IAV infection. Depletion of Ly6G + cells in mice in which IFNAR signaling was either blocked or deleted indicated that Ly6G + cells were responsible for the IFNAR signaling-dependent susceptibility to MRSA superinfection at day 7 post-IAV infection. Thus, during IAV infection, the temporal differences in type I IFN signaling increased bactericidal activity of both CD11c + and Ly6G + cells at day 3 and reduced effector function of Ly6G + cells at day 7. The temporal differential outcomes induced by IFN-β (day 3) and IFN-α (day 7) signaling through the same IFNAR resulted in differential susceptibility to MRSA at 3 and 7 days post-IAV infection. IMPORTANCE Approximately 114,000 hospitalizations and 40,000 annual deaths in the United States are associated with influenza A virus (IAV) infections. Frequently, these deaths are due to community-acquired Gram-positive bacterial species, many of which show increasing resistance to antibiotic therapy. Severe complications, including parapneumonic empyema and necrotizing pneumonia, can arise, depending on virulence factors expressed by either the virus or bacteria. Unfortunately, we are unable to control the expression of these virulence factors, making host responses a logical target for therapeutic interventions. Moreover, interactions between virus, host, and bacteria that exacerbate IAV-related morbidities and mortalities are largely unknown. Here, we show that type I interferon (IFN) expression can modulate susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) infection, with IFN-β reducing host susceptibility to MRSA infection while IFN-α increases susceptibility. Our data indicate that treatments designed to augment IFN-β and/or inhibit IFN-α production around day 7 post-IAV infection could reduce susceptibility to deadly superinfections.

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