A TLR5 mono-agonist restores inhibited immune responses to Streptococcus pneumoniae during influenza virus infection in human monocytes

Influenza A virus (IAV) predisposes individuals to often more severe secondary bacterial infections with Streptococcus pneumonia (S. pneumoniae). The outcomes of these infections may be made worse with the increase in antimicrobial resistance and a lack of new treatments to combat this. Th17 responses are crucial in clearing S. pneumoniae from the lung. We previously demonstrated that early IAV infection of human monocytes significantly reduced levels of S. pneumoniae-driven cytokines involved in the Th17 response. Here, we have further identified that IAV targets specific TLRs (TLR2, TLR4, TLR9) involved in sensing S. pneumoniae infection resulting, in a reduction in TLR agonist-induced IL-23 and TGF-β. The effect of IAV is more profound on the TLR2 and TLR9 pathways. We have established that IAV-mediated inhibition of TLR9-induction is related to a downregulation of RORC, a Th17 specific transcription factor. Other studies using mouse models demonstrated that TLR5 agonism improved the efficacy of antibiotics in the treatment of IAV/S. pneumoniae co-infections. Therefore, we investigated if TLR5 agonism could restore inhibited Th17 responses in human monocytes. Levels of pneumococcus-driven cytokines, which had previously been inhibited by IAV were not reduced in the presence of the TLR5 mono-agonist, suggesting that such treatment may overcome IAV inhibition of Th17 responses. The importance of our research is in demonstrating the IAV directly targets S. pneumoniae-associated TLR pathways. Additionally, the IAV-inhibition of Th17 responses can be restored by TLR5 agonism, which indicates that there may be a different Th17 signalling pathway which is not affected by IAV infection.

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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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Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses

Journal of Virology ◽

10.1128/jvi.00720-16 ◽

2016 ◽

Vol 91 (2) ◽

Cited By ~ 26

Author(s):

Catherine M. Crosby ◽

William E. Matchett ◽

Stephanie S. Anguiano-Zarate ◽

Christopher A. Parks ◽

Eric A. Weaver ◽

...

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Viral Vectors ◽

Rhesus Macaques ◽

Influenza Virus Infection ◽

Single Cycle ◽

Syrian Hamsters ◽

Hemagglutinin Protein

ABSTRACT Head-to-head comparisons of conventional influenza vaccines with adenovirus (Ad) gene-based vaccines demonstrated that these viral vectors can mediate more potent protection against influenza virus infection in animal models. In most cases, Ad vaccines are engineered to be replication-defective (RD-Ad) vectors. In contrast, replication-competent Ad (RC-Ad) vaccines are markedly more potent but risk causing adenovirus diseases in vaccine recipients and health care workers. To harness antigen gene replication but avoid production of infectious virions, we developed “single-cycle” adenovirus (SC-Ad) vectors. Previous work demonstrated that SC-Ads amplify transgene expression 100-fold and produce markedly stronger and more persistent immune responses than RD-Ad vectors in Syrian hamsters and rhesus macaques. To test them as potential vaccines, we engineered RD and SC versions of adenovirus serotype 6 (Ad6) to express the hemagglutinin (HA) gene from influenza A/PR/8/34 virus. We show here that it takes approximately 33 times less SC-Ad6 than RD-Ad6 to produce equal amounts of HA antigen in vitro. SC-Ad produced markedly higher HA binding and hemagglutination inhibition (HAI) titers than RD-Ad in Syrian hamsters. SC-Ad-vaccinated cotton rats had markedly lower influenza titers than RD-Ad-vaccinated animals after challenge with influenza A/PR/8/34 virus. These data suggest that SC-Ads may be more potent vaccine platforms than conventional RD-Ad vectors and may have utility as “needle-free” mucosal vaccines. IMPORTANCE Most adenovirus vaccines that are being tested are replication-defective adenoviruses (RD-Ads). This work describes testing newer single-cycle adenovirus (SC-Ad) vectors that replicate transgenes to amplify protein production and immune responses. We show that SC-Ads generate markedly more influenza virus hemagglutinin protein and require substantially less vector to generate the same immune responses as RD-Ad vectors. SC-Ads therefore hold promise to be more potent vectors and vaccines than current RD-Ad vectors.

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Effect of Vitamin A Deficiency in Dysregulating Immune Responses to Influenza Virus and Increasing Mortality Rates After Bacterial Coinfections

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa597 ◽

2020 ◽

Author(s):

Rhiannon R Penkert ◽

Amanda P Smith ◽

Eike R Hrincius ◽

Jonathan A McCullers ◽

Peter Vogel ◽

...

Keyword(s):

Influenza Virus ◽

T Cell ◽

Vitamin A ◽

Immune Responses ◽

Inflammatory Cytokines ◽

Bacterial Infections ◽

Vitamin A Deficiency ◽

Influenza Virus Infection ◽

Viral Clearance ◽

Lymphoid Structures

Abstract Background Secondary bacterial coinfections are ranked as a leading cause of hospitalization and morbid conditions associated with influenza. Because vitamin A deficiency (VAD) and insufficiency are frequent in both developed and developing countries, we asked how VAD influences coinfection severity. Methods VAD and control mice were infected with influenza virus for evaluation of inflammatory cytokines, cellular immune responses, and viral clearance. Influenza-infected mice were coinfected with Streptococcus pneumoniae to study weight loss and survival. Results Naive VAD mouse lungs exhibited dysregulated immune function. Neutrophils were enhanced in frequency and there was a significant reduction in RANTES (regulated on activation of normal T cells expressed and secreted), a chemokine instrumental in T-cell homing and recruitment. After influenza virus infection, VAD mice experienced failures in CD4+ T-cell recruitment and B-cell organization into lymphoid structures in the lung. VAD mice exhibited higher viral titers than controls and slow viral clearance. There were elevated levels of inflammatory cytokines and innate cell subsets in the lungs. However, arginase, a marker of alternatively activated M2 macrophages, was rare. When influenza-infected VAD animals were exposed to bacteria, they experienced a 100% mortality rate. Conclusion Data showed that VAD dysregulated the immune response. Consequently, secondary bacterial infections were 100% lethal in influenza-infected VAD mice.

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Disruption of nasal bacteria enhances protective immune responses to influenza A virus and SARS-CoV-2 infection in mice

10.1101/2020.12.25.424300 ◽

2020 ◽

Author(s):

Minami Nagai ◽

Miyu Moriyama ◽

Takeshi Ichinohe

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Critical Role ◽

Influenza Virus Infection ◽

Oral Bacteria ◽

Antibody Responses ◽

Adaptive Immune Responses ◽

Adjuvant Activity ◽

Adaptive Immune

AbstractGut microbiota plays a critical role in the induction of adaptive immune responses to influenza virus infection. However, the role of nasal bacteria in the induction of the virus-specific adaptive immunity is less clear. Here we demonstrate that while intranasal administration of influenza virus hemagglutinin vaccine alone was insufficient to induce the vaccine-specific antibody responses, disruption of nasal bacteria by lysozyme or addition of culturable oral bacteria from a healthy human volunteer rescued inability of the nasal bacteria to generate antibody responses to intranasally administered the split-virus vaccine. Myd88-depdnent signaling in the hematopoietic compartment was required for adjuvant activity of intranasally administered oral bacteria. In addition, we found that the oral bacteria-combined intranasal vaccine induced protective antibody response to influenza virus and SARS-CoV-2 infection. Our findings here have identified a previously unappreciated role for nasal bacteria in the induction of the virus-specific adaptive immune responses.

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Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00244.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. L845-L858 ◽

Cited By ~ 17

Author(s):

James David Londino ◽

Ahmed Lazrak ◽

James F. Collawn ◽

Zsuzsanna Bebok ◽

Kevin S. Harrod ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Bacterial Infections ◽

Alveolar Epithelial Cell ◽

Ionic Composition ◽

Influenza Virus Infection ◽

Alveolar Epithelial Cells ◽

Alveolar Cells ◽

Alveolar Epithelial

The cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial sodium channels (ENaC) are located in the apical membranes of airway and alveolar epithelial cells. These transporters play an important role in the regulation of lung fluid balance across airway and alveolar epithelia by being the conduits for chloride (Cl−) and bicarbonate ([Formula: see text]) secretion and sodium (Na+) ion absorption, respectively. The functional role of these channels in the respiratory tract is to maintain the optimum volume and ionic composition of the bronchial periciliary fluid (PCL) and alveolar lining fluid (ALF) layers. The PCL is required for proper mucociliary clearance of pathogens and debris, and the ALF is necessary for surfactant homeostasis and optimum gas exchange. Dysregulation of ion transport may lead to mucus accumulation, bacterial infections, inflammation, pulmonary edema, and compromised respiratory function. Influenza (or flu) in mammals is caused by influenza A and B viruses. Symptoms include dry cough, sore throat, and is often followed by secondary bacterial infections, accumulation of fluid in the alveolar spaces and acute lung injury. The underlying mechanisms of flu symptoms are not fully understood. This review summarizes our present knowledge of how influenza virus infections alter airway and alveolar epithelial cell CFTR and ENaC function in vivo and in vitro and the role of these changes in influenza pathogenesis.

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Innate Immune Sensing of Influenza A Virus

Viruses ◽

10.3390/v12070755 ◽

2020 ◽

Vol 12 (7) ◽

pp. 755

Author(s):

Gaurav Malik ◽

Yan Zhou

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Influenza Virus Infection ◽

Innate Immune ◽

Innate Immune Responses ◽

Pyrin Domain ◽

Immune Sensing ◽

Influenza Viral Infection

Influenza virus infection triggers host innate immune response by stimulating various pattern recognition receptors (PRRs). Activation of these PRRs leads to the activation of a plethora of signaling pathways, resulting in the production of interferon (IFN) and proinflammatory cytokines, followed by the expression of interferon-stimulated genes (ISGs), the recruitment of innate immune cells, or the activation of programmed cell death. All these antiviral approaches collectively restrict viral replication inside the host. However, influenza virus also engages in multiple mechanisms to subvert the innate immune responses. In this review, we discuss the role of PRRs such as Toll-like receptors (TLRs), Retinoic acid-inducible gene I (RIG-I), NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3), and Z-DNA binding protein 1 (ZBP1) in sensing and restricting influenza viral infection. Further, we also discuss the mechanisms influenza virus utilizes, especially the role of viral non-structure proteins NS1, PB1-F2, and PA-X, to evade the host innate immune responses.

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Benefits and Perils of Necroptosis in Influenza Virus Infection

Journal of Virology ◽

10.1128/jvi.01101-19 ◽

2020 ◽

Vol 94 (9) ◽

Cited By ~ 2

Author(s):

Siddharth Balachandran ◽

Glenn F. Rall

Keyword(s):

Cell Death ◽

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Influenza Virus Infection ◽

Cell Types ◽

Influenza A Viruses ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Infected Cells

ABSTRACT Influenza A viruses (IAV) are lytic viruses that have recently been found to activate necroptosis in many of the cell types they infect. Necroptotic cell death is potently immunogenic and limits IAV spread by directly eliminating infected cells and by mobilizing both innate and adaptive immune responses. The benefits of necroptosis to the host, however, may sometimes be outweighed by the potentially deleterious hyperinflammatory consequences of activating this death modality in pulmonary and other tissues.

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Could Interleukin-33 (IL-33) Govern the Outcome of an Equine Influenza Virus Infection? Learning from Other Species

Viruses ◽

10.3390/v13122519 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2519

Author(s):

Christoforos Rozario ◽

Luis Martínez-Sobrido ◽

Henry J. McSorley ◽

Caroline Chauché

Keyword(s):

Immune Responses ◽

Disease Severity ◽

Influenza A ◽

Bacterial Infections ◽

Influenza Virus Infection ◽

Airway Epithelial Cells ◽

Respiratory Pathogens ◽

Equine Influenza Virus ◽

Interleukin 33 ◽

Host Immune Responses

Influenza A viruses (IAVs) are important respiratory pathogens of horses and humans. Infected individuals develop typical respiratory disorders associated with the death of airway epithelial cells (AECs) in infected areas. Virulence and risk of secondary bacterial infections vary among IAV strains. The IAV non-structural proteins, NS1, PB1-F2, and PA-X are important virulence factors controlling AEC death and host immune responses to viral and bacterial infection. Polymorphism in these proteins impacts their function. Evidence from human and mouse studies indicates that upon IAV infection, the manner of AEC death impacts disease severity. Indeed, while apoptosis is considered anti-inflammatory, necrosis is thought to cause pulmonary damage with the release of damage-associated molecular patterns (DAMPs), such as interleukin-33 (IL-33). IL-33 is a potent inflammatory mediator released by necrotic cells, playing a crucial role in anti-viral and anti-bacterial immunity. Here, we discuss studies in human and murine models which investigate how viral determinants and host immune responses control AEC death and subsequent lung IL-33 release, impacting IAV disease severity. Confirming such data in horses and improving our understanding of early immunologic responses initiated by AEC death during IAV infection will better inform the development of novel therapeutic or vaccine strategies designed to protect life-long lung health in horses and humans, following a One Health approach.

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High ambient temperature dampens adaptive immune responses to influenza A virus infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815029116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 3118-3125 ◽

Cited By ~ 19

Author(s):

Miyu Moriyama ◽

Takeshi Ichinohe

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

Ambient Temperature ◽

Influenza A ◽

Influenza Virus Infection ◽

High Heat ◽

High Ambient Temperature ◽

Adaptive Immune Responses ◽

Adaptive Immune

Although climate change may expand the geographical distribution of several vector-borne diseases, the effects of environmental temperature in host defense to viral infection in vivo are unknown. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C impaired adaptive immune responses against infection with viral pathogens, influenza, Zika, and severe fever with thrombocytopenia syndrome phlebovirus. Following influenza virus infection, the high heat-exposed mice failed to stimulate inflammasome-dependent cytokine secretion and respiratory dendritic cell migration to lymph nodes. Although commensal microbiota composition remained intact, the high heat-exposed mice decreased their food intake and increased autophagy in lung tissue. Induction of autophagy in room temperature-exposed mice severely impaired virus-specific CD8 T cells and antibody responses following respiratory influenza virus infection. In addition, we found that administration of glucose or dietary short-chain fatty acids restored influenza virus-specific adaptive immune responses in high heat-exposed mice. These findings uncover an unexpected mechanism by which ambient temperature and nutritional status control virus-specific adaptive immune responses.

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A Fungal Cu/Zn-Containing Superoxide Dismutase Enhances the Therapeutic Efficacy of a Plant Polyphenol Extract in Experimental Influenza Virus Infection

Zeitschrift für Naturforschung C ◽

10.1515/znc-2010-5-616 ◽

2010 ◽

Vol 65 (5-6) ◽

pp. 419-428 ◽

Cited By ~ 1

Author(s):

Julia Serkedjieva ◽

Tsvetanka Stefanova ◽

Ekaterina Krumova

Keyword(s):

Superoxide Dismutase ◽

Influenza Virus ◽

Virus Infection ◽

Protective Effect ◽

Influenza A ◽

Influenza Virus Infection ◽

Protective Role ◽

Combined Application ◽

Combined Use ◽

Experimental Influenza

The combined protective effect of a polyphenol-rich extract, isolated from Geranium sanguineum L. (PC), and a novel naturally glycosylated Cu/Zn-containing superoxide dismutase, produced from the fungal strain Humicula lutea 103 (HL-SOD), in the experimental influenza A virus infection (EIVI) in mice, induced with the virus A/Aichi/2/68 (H3N2), was investigated. The combined application of HL-SOD and PC in doses, which by themselves do not defend significantly mice in EIVI, resulted in a synergistically increased protection, determined on the basis of protective indices and amelioration of lung injury. Lung weights and consolidation as well as infectious lung virus titers were all decreased significantly parallel to the reduction of the mortality rates; lung indices were raised. The excessive production of reactive oxygen species (ROS) by alveolar macrophages (aMØ) as well as the elevated levels of the lung antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), induced by EIVI, were brought to normal. For comparative reasons the combined protective effect of PC and vitamin C was investigated. The obtained results support the combined use of antioxidants for the treatment of influenza virus infection and in general indicate the beneficial protective role of combinations of viral inhibitors of natural origin with diverse modes of action.

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