Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria

Abstract Neutrophils are recruited into the airway in the early phase of uncomplicated influenza A virus (IAV) infection and during the bacterial superinfections that are a significant cause of morbidity and mortality in IAV-infected subjects. In this report, we show that IAV accelerates neutrophil apoptosis. Unopsonized Escherichia colihad similar effects, although apoptotic effects of opsonized E coli were greater. When neutrophils were treated with both IAV and unopsonized E coli, a marked enhancement of the rate and extent of neutrophil apoptosis occured as compared with that caused by either pathogen alone. Treatment of neutrophils with IAV markedly increased phagocytosis of E coli. Simultaneous treatment of neutrophils with IAV and E coli also elicited greater hydrogen peroxide production than did either pathogen alone. IAV increased neutrophil expression of Fas antigen and Fas ligand, and it also increased release of Fas ligand into the cell supernatant. These findings may have relevance to the understanding of inflammatory responses to IAV in vivo and of bacterial superinfection of IAV-infected subjects.

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Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria

Blood ◽

10.1182/blood.v93.7.2395.407a22_2395_2403 ◽

1999 ◽

Vol 93 (7) ◽

pp. 2395-2403 ◽

Cited By ~ 1

Author(s):

Maria Luisa Colamussi ◽

Mitchell R. White ◽

Erika Crouch ◽

Kevan L. Hartshorn

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Fas Ligand ◽

Inflammatory Responses ◽

Neutrophil Apoptosis ◽

Simultaneous Treatment ◽

E Coli ◽

Apoptotic Effects ◽

Bacterial Superinfection

Neutrophils are recruited into the airway in the early phase of uncomplicated influenza A virus (IAV) infection and during the bacterial superinfections that are a significant cause of morbidity and mortality in IAV-infected subjects. In this report, we show that IAV accelerates neutrophil apoptosis. Unopsonized Escherichia colihad similar effects, although apoptotic effects of opsonized E coli were greater. When neutrophils were treated with both IAV and unopsonized E coli, a marked enhancement of the rate and extent of neutrophil apoptosis occured as compared with that caused by either pathogen alone. Treatment of neutrophils with IAV markedly increased phagocytosis of E coli. Simultaneous treatment of neutrophils with IAV and E coli also elicited greater hydrogen peroxide production than did either pathogen alone. IAV increased neutrophil expression of Fas antigen and Fas ligand, and it also increased release of Fas ligand into the cell supernatant. These findings may have relevance to the understanding of inflammatory responses to IAV in vivo and of bacterial superinfection of IAV-infected subjects.

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Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00318.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. L111-L124 ◽

Cited By ~ 58

Author(s):

Sabine Teske ◽

Andrea A. Bohn ◽

Jean F. Regal ◽

Joshua J. Neumiller ◽

B. Paige Lawrence

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Influenza A Virus ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Neutrophil Function ◽

Aryl Hydrocarbon ◽

Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

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Histone H4 potentiates neutrophil inflammatory responses to influenza A virus: Down-modulation by H4 binding to C-reactive protein and Surfactant protein D

PLoS ONE ◽

10.1371/journal.pone.0247605 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247605

Author(s):

I-Ni Hsieh ◽

Mitchell White ◽

Marloes Hoeksema ◽

Xavier Deluna ◽

Kevan Hartshorn

Keyword(s):

Influenza A Virus ◽

Respiratory Burst ◽

Influenza A ◽

Inflammatory Responses ◽

Surfactant Protein ◽

Surfactant Protein D ◽

Histone H4 ◽

C Reactive Protein ◽

Reactive Protein

Neutrophils participate in the early phase of the innate response to uncomplicated influenza A virus (IAV) infection but also are a major component in later stages of severe IAV or COVID 19 infection where neutrophil extracellular traps (NETs) and associated cell free histones are highly pro-inflammatory. It is likely that IAV interacts with histones during infection. We show that histone H4 binds to IAV and aggregates viral particles. In addition, histone H4 markedly potentiates IAV induced neutrophil respiratory burst responses. Prior studies have shown reactive oxidants to be detrimental during severe IAV infection. C reactive protein (CRP) and surfactant protein D (SP-D) rise during IAV infection. We now show that both of these innate immune proteins bind to histone H4 and significantly down regulate respiratory burst and other responses to histone H4. Isolated constructs composed only of the neck and carbohydrate recognition domain of SP-D also bind to histone H4 and partially limit neutrophil responses to it. These studies indicate that complexes formed of histones and IAV are a potent neutrophil activating stimulus. This finding could account for excess inflammation during IAV or other severe viral infections. The ability of CRP and SP-D to bind to histone H4 may be part of a protective response against excessive inflammation in vivo.

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Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽

10.3390/vaccines9060629 ◽

2021 ◽

Vol 9 (6) ◽

pp. 629

Author(s):

Megan M. Dunagan ◽

Kala Hardy ◽

Toru Takimoto

Keyword(s):

Immune Response ◽

Immune Responses ◽

Influenza A Virus ◽

Influenza A ◽

Human Populations ◽

Lymphocyte Migration ◽

Host Immune Responses ◽

Mhc Molecules ◽

The Impact

Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.

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Viral dosing of influenza A infection reveals involvement of RIPK3 and FADD, but not MLKL

Cell Death and Disease ◽

10.1038/s41419-021-03746-0 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Teodora Oltean ◽

Emily Van San ◽

Tatyana Divert ◽

Tom Vanden Berghe ◽

Xavier Saelens ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Kinase Activity ◽

Dose Range ◽

Challenge Dose

AbstractRIPK3 was reported to play an important role in the protection against influenza A virus (IAV) in vivo. Here we show that the requirement of RIPK3 for protection against IAV infection in vivo is only apparent within a limited dose range of IAV challenge. We found that this protective outcome is independent from RIPK3 kinase activity and from MLKL. This shows that platform function of RIPK3 rather than its kinase activity is required for protection, suggesting that a RIPK3 function independent of necroptosis is implicated. In line with this finding, we show that FADD-dependent apoptosis has a crucial additional effect in protection against IAV infection. Altogether, we show that RIPK3 contributes to protection against IAV in a narrow challenge dose range by a mechanism that is independent of its kinase activity and its capacity to induce necroptosis.

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Antiviral activity of Ladania067, an extract from wild black currant leaves against influenza A virus in vitro and in vivo

Frontiers in Microbiology ◽

10.3389/fmicb.2014.00171 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Emanuel Haasbach ◽

Carmen Hartmayer ◽

Alice Hettler ◽

Alicja Sarnecka ◽

Ulrich Wulle ◽

...

Keyword(s):

Antiviral Activity ◽

Influenza A Virus ◽

Influenza A ◽

Black Currant

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Exacerbation of Influenza A Virus Disease Severity by Respiratory Syncytial Virus Co-Infection in a Mouse Model

Viruses ◽

10.3390/v13081630 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1630 ◽

Cited By ~ 1

Author(s):

Junu A. George ◽

Shaikha H. AlShamsi ◽

Maryam H. Alhammadi ◽

Ahmed R. Alsuwaidi

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Influenza A ◽

Immune Cell ◽

Virus Disease ◽

Viral Loads ◽

Syncytial Virus

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are leading causes of childhood infections. RSV and influenza are competitive in vitro. In this study, the in vivo effects of RSV and IAV co-infection were investigated. Mice were intranasally inoculated with RSV, with IAV, or with both viruses (RSV+IAV and IAV+RSV) administered sequentially, 24 h apart. On days 3 and 7 post-infection, lung tissues were processed for viral loads and immune cell populations. Lung functions were also evaluated. Mortality was observed only in the IAV+RSV group (50% of mice did not survive beyond 7 days). On day 3, the viral loads in single-infected and co-infected mice were not significantly different. However, on day 7, the IAV titer was much higher in the IAV+RSV group, and the RSV viral load was reduced. CD4 T cells were reduced in all groups on day 7 except in single-infected mice. CD8 T cells were higher in all experimental groups except the RSV-alone group. Increased airway resistance and reduced thoracic compliance were demonstrated in both co-infected groups. This model indicates that, among all the infection types we studied, infection with IAV followed by RSV is associated with the highest IAV viral loads and the most morbidity and mortality.

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The combination of ribavirin and ozeltamivir effectively inhibits reproduction of influenza a virus resistant to rimantadine (Amantadine) in vitro and in vivo

Doklady Biochemistry and Biophysics ◽

10.1134/s1607672914020100 ◽

2014 ◽

Vol 455 (1) ◽

pp. 80-83 ◽

Cited By ~ 3

Author(s):

P. G. Deryabin ◽

G. A. Galegov ◽

I. D. Konstantinova ◽

I. S. Muzyka ◽

A. I. Miroshnikov ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A

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Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609316113 ◽

2016 ◽

Vol 113 (42) ◽

pp. 11931-11936 ◽

Cited By ~ 88

Author(s):

Wenqian He ◽

Gene S. Tan ◽

Caitlin E. Mullarkey ◽

Amanda J. Lee ◽

Mannie Man Wai Lam ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Neutralizing Antibodies ◽

Influenza A ◽

Critical Role ◽

Host Cells ◽

Viral Glycoprotein ◽

Effector Functions ◽

Dependent Cell

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising “universal” influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.

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