Type I IFN Receptor Signals Directly Stimulate Local B Cells Early following Influenza Virus Infection

ABSTRACT Obese individuals are considered a high-risk group for developing severe influenza virus infection. While the exact mechanisms for increased disease severity remain under investigation, obese-mouse models suggest that increased acute lung injury (ALI), potentially due to enhanced viral spread and decreased wound repair, is likely involved. We previously demonstrated that upregulation of the lung epithelial cell β6 integrin during influenza virus infection was involved in disease severity. Knocking out β6 (β6 KO) resulted in improved survival. Of interest, obese mice have increased lung β6 integrin levels at homeostasis. Thus, we hypothesized that the protective effect seen in β6 KO mice would extend to the highly susceptible obese-mouse model. In the current study, we show that crossing β6 KO mice with genetically obese (ob/ob) mice (OBKO) resulted in reduced ALI and impaired viral spread, like their lean counterparts. Mechanistically, OBKO alveolar macrophages and epithelial cells had increased type I interferon (IFN) signaling, potentially through upregulated type I IFN receptor expression, which was important for the enhanced protection during infection. Taken together, our results indicate that the absence of an epithelial integrin can beneficially alter the pulmonary microenvironment by increasing protective type I IFN responses even in a highly susceptible obese-mouse model. These studies increase our understanding of influenza virus pathogenesis in high-risk populations and may lead to the development of novel therapies. IMPORTANCE Obesity is a risk factor for developing severe influenza virus infection. However, the reasons for this are unknown. We found that the lungs of obese mice have increased expression of the epithelial integrin β6, a host factor associated with increased disease severity. Knocking out integrin β6 in obese mice favorably altered the pulmonary environment by increasing type I IFN signaling, resulting in decreased viral spread, reduced lung injury, and increased survival. This study furthers our understanding of influenza virus pathogenesis in the high-risk obese population and may potentially lead to the development of novel therapies for influenza virus infection.

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Rapid Differentiation of Monocytes into Type I IFN-Producing Myeloid Dendritic Cells as an Antiviral Strategy against Influenza Virus Infection

The Journal of Immunology ◽

10.4049/jimmunol.1200168 ◽

2012 ◽

Vol 189 (5) ◽

pp. 2257-2265 ◽

Cited By ~ 33

Author(s):

Weiping Cao ◽

Andrew K. Taylor ◽

Renata E. Biber ◽

William G. Davis ◽

Jin Hyang Kim ◽

...

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

Type I ◽

Type I Ifn ◽

Myeloid Dendritic Cells

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Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus

Journal of Virology ◽

10.1128/jvi.00169-19 ◽

2019 ◽

Vol 93 (8) ◽

Cited By ~ 21

Author(s):

Brenda L. Tesini ◽

Preshetha Kanagaiah ◽

Jiong Wang ◽

Megan Hahn ◽

Jessica L. Halliley ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

Virus Infection ◽

B Cell ◽

Specific Antibody ◽

Early Life ◽

Influenza Virus Infection ◽

Memory B Cells ◽

Specific Memory ◽

Original Antigenic Sin

ABSTRACTMemory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection “imprints” for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.IMPORTANCERapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

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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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Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.03.211 ◽

2019 ◽

Vol 513 (2) ◽

pp. 405-411 ◽

Cited By ~ 4

Author(s):

Ho Namkoong ◽

Makoto Ishii ◽

Hideki Fujii ◽

Takahiro Asami ◽

Kazuma Yagi ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Type I Interferon ◽

Influenza Virus Infection ◽

Type I ◽

Interferon Induction

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Influenza virus infection exacerbates experimental autoimmune encephalomyelitis disease by promoting type I T cells infiltration into central nervous system

Journal of Autoimmunity ◽

10.1016/j.jaut.2016.10.006 ◽

2017 ◽

Vol 77 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Qingyun Chen ◽

Yinping Liu ◽

Aizhen Lu ◽

Ke Ni ◽

Zheng Xiang ◽

...

Keyword(s):

Central Nervous System ◽

T Cells ◽

Nervous System ◽

Influenza Virus ◽

Virus Infection ◽

Experimental Autoimmune Encephalomyelitis ◽

Influenza Virus Infection ◽

Type I ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

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Immunopathogenesis of SARS-CoV-2-induced pneumonia: lessons from influenza virus infection

Inflammation and Regeneration ◽

10.1186/s41232-020-00148-1 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 3

Author(s):

Masaaki Miyazawa

Keyword(s):

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Tissue Injury ◽

Influenza Virus Infection ◽

T Cell Responses ◽

Type I ◽

Upper Respiratory Tract ◽

Viral Spread ◽

Cell Responses

Abstract Factors determining the progression of frequently mild or asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection into life-threatening pneumonia remain poorly understood. Viral and host factors involved in the development of diffuse alveolar damage have been extensively studied in influenza virus infection. Influenza is a self-limited upper respiratory tract infection that causes acute and severe systemic symptoms and its spread to the lungs is limited by CD4+ T-cell responses. A vicious cycle of CCL2- and CXCL2-mediated inflammatory monocyte and neutrophil infiltration and activation and resultant massive production of effector molecules including tumor necrosis factor (TNF)-α, nitric oxide, and TNF-related apoptosis-inducing ligand are involved in the pathogenesis of progressive tissue injury. SARS-CoV-2 directly infects alveolar epithelial cells and macrophages and induces foci of pulmonary lesions even in asymptomatic individuals. Mechanisms of tissue injury in SARS-CoV-2-induced pneumonia share some aspects with influenza virus infection, but IL-1β seems to play more important roles along with CCL2 and impaired type I interferon signaling might be associated with delayed virus clearance and disease severity. Further, data indicate that preexisting memory CD8+ T cells may play important roles in limiting viral spread in the lungs and prevent progression from mild to severe or critical pneumonia. However, it is also possible that T-cell responses are involved in alveolar interstitial inflammation and perhaps endothelial cell injury, the latter of which is characteristic of SARS-CoV-2-induced pathology.

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Bacterial Outer Membrane Vesicles Provide Broad-Spectrum Protection against Influenza Virus Infection via Recruitment and Activation of Macrophages

Journal of Innate Immunity ◽

10.1159/000494098 ◽

2019 ◽

Vol 11 (4) ◽

pp. 316-329 ◽

Cited By ~ 5

Author(s):

Eun-Hye Bae ◽

Sang Hwan Seo ◽

Chang-Ung Kim ◽

Min Seong Jang ◽

Min-Suk Song ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Protective Effect ◽

Outer Membrane ◽

Lethal Dose ◽

Influenza Virus Infection ◽

Outer Membrane Vesicles ◽

Type I ◽

Wide Range ◽

Bacterial Outer Membrane

Influenza A virus (IAV) poses a constant worldwide threat to human health. Although conventional vaccines are available, their protective efficacy is type or strain specific, and their production is time-consuming. For the control of an influenza pandemic in particular, agents that are immediately effective against a wide range of virus variants should be developed. Although pretreatment of various Toll-like receptor (TLR) ligands have already been reported to be effective in the defense against subsequent IAV infection, the efficacy was limited to specific subtypes, and safety concerns were also raised. In this study, we investigated the protective effect of an attenuated bacterial outer membrane vesicle harboring modified lipid A moiety of lipopolysaccharide (fmOMV) against IAV infection and the underlying mechanisms. Administration of fmOMV conferred significant protection against a lethal dose of pandemic H1N1, PR8, H5N2, and highly pathogenic H5N1 viruses; this broad antiviral activity was dependent on macrophages but independent of neutrophils. fmOMV induced recruitment and activation of macrophages and elicited type I IFNs. Intriguingly, fmOMV showed a more significant protective effect than other TLR ligands tested in previous reports, without exhibiting any adverse effect. These results show the potential of fmOMV as a prophylactic agent for the defense against influenza virus infection.

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Roles of CD4+ T and B cells in influenza virus infection

International Congress Series ◽

10.1016/s0531-5131(01)00644-6 ◽

2001 ◽

Vol 1219 ◽

pp. 311-318 ◽

Cited By ~ 1

Author(s):

Walter Gerhard ◽

Krystyna Mozdzanowska

Keyword(s):

Influenza Virus ◽

B Cells ◽

Virus Infection ◽

Influenza Virus Infection ◽

T And B Cells

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