Fighting Flu—Recent Advances in Influenza Research

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 12662

Special Issue Editors

School of Molecular Sciences/LIMS, La Trobe University, Melbourne, VIC 3086, Australia
Interests: anti-viral immunity; specifically T cell responses towards viral infections; CD8+ T cells towards influenza and SARS-CoV-2
School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK
Interests: virus; cancer; infection; molecular; immunity
School of Molecular Sciences/LIMS, La Trobe University, Melbourne, VIC 3086, Australia
Interests: anti-viral immunity; specifically T cell responses towards viral infections; CD8+ T cells towards influenza and SARS-CoV-2

Special Issue Information

Dear Colleagues,

Influenza viruses are a significant health burden to both human and animal populations worldwide. In humans, influenza viruses continue to cause significant morbidity and mortality annually. Influenza viruses are categorized into four subtypes (influenza A–D) and are able to infect a wide host range from aquatic animals, to poultry, horses, swine, and humans, among other species. In humans, influenza viruses cause seasonal epidemics, which cause up to 650,000 deaths annually, and pandemics, of which there have been four in the last century, which have resulted in tens of millions of deaths in the past. There is a continual threat of future influenza pandemics, most likely from influenza viruses crossing the species barrier, leading to novel, antigenically distinct strains.

Anti-viral drugs, such as oseltamivir, are effective at preventing virus budding, thereby reducing viral load and disease severity. However, there is a short window in which such drugs are effective, and viral mutations resulting from selective immune pressure can also render them ineffective. Additionally, there are vaccines available; however, the majority focus on establishing humoral immunity towards the highly variable surface glycoprotein, haemagglutinin, mandating that they be updated and administered annually. As such, there is an urgent need to further understand the influenza virus, its interactions within its host, the host’s immune response (or lack thereof), and how influenza viruses adapt to this immune pressure, to help inform the rational design of future therapeutics and vaccines.

Researchers in our field are doing an amazing job at understanding the virology of different influenza virus strains, and dissecting the resulting host innate and adaptive immune responses following influenza virus infection. This Special Issue will focus on advances in influenza virus research, collating multi-disciplinary studies to give a global overview on the current state of influenza virus research and highlighting, going forward, key areas that require additional research.

Dr. Emma Grant
Dr. Sarah Hulin-Curtis
Guest Editors
Ms. Andrea Nguyen
Assistant Guest Editor

Manuscript Submission Information

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Keywords

  • Influenza
  • Vaccine
  • Virology
  • Viral load
  • Viral mutations
  • Immunity
  • Innate immunity
  • Adaptive immunity
  • T cell
  • Drug discovery
  • Antivirals

Published Papers (5 papers)

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Research

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10 pages, 604 KiB  
Article
Markers of Infection-Mediated Cardiac Damage in Influenza and COVID-19
by Francesco Robert Burkert, Lukas Lanser, Alex Pizzini, Rosa Bellmann-Weiler and Günter Weiss
Pathogens 2022, 11(10), 1191; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11101191 - 16 Oct 2022
Cited by 1 | Viewed by 1177
Abstract
Introduction: Influenza and the coronavirus disease 2019 (COVID-19) are two potentially severe viral infections causing significant morbidity and mortality. The causative viruses, influenza A/B and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) can cause both pulmonary and extra-pulmonary disease, including cardiovascular involvement. [...] Read more.
Introduction: Influenza and the coronavirus disease 2019 (COVID-19) are two potentially severe viral infections causing significant morbidity and mortality. The causative viruses, influenza A/B and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) can cause both pulmonary and extra-pulmonary disease, including cardiovascular involvement. The objective of this study was to determine the levels of cardiac biomarkers in hospitalized patients infected with influenza or COVID-19 and their correlation with secondary outcomes. Methods: We performed a retrospective comparative analysis of cardiac biomarkers in patients hospitalized at our department with influenza or COVID-19 by measuring high-sensitivity troponin-T (hs-TnT) and creatinine kinase (CK) in plasma. Secondary outcomes were intensive care unit (ICU) admission and all-cause in-hospital mortality. Results: We analyzed the data of 250 influenza patients and 366 COVID-19 patients. 58.6% of patients with influenza and 46.2% of patients with COVID-19 presented with increased hs-TnT levels. Patients of both groups with increased hs-TnT levels were significantly more likely to require ICU treatment or to die during their hospital stay. Compared with COVID-19, cardiac biomarkers were significantly higher in patients affected by influenza of all age groups, regardless of pre-existing cardiovascular disease. In patients aged under 65 years, no significant difference in ICU admission and mortality was detected between influenza and COVID-19, whereas significantly more COVID-19 patients 65 years or older died or required intensive care treatment. Conclusions: Our study shows that increased cardiac biomarkers are associated with higher mortality and ICU admission in both, influenza and SARS-CoV-2-infected patients. Cardiac biomarkers are higher in the influenza cohort; however, this does not translate into worse outcomes when compared with the COVID-19 cohort. Full article
(This article belongs to the Special Issue Fighting Flu—Recent Advances in Influenza Research)
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10 pages, 5277 KiB  
Article
Generation and Characterization of Drug-Resistant Influenza B Viruses Selected In Vitro with Baloxavir Acid
by Amel Saim-Mamoun, Yacine Abed, Julie Carbonneau and Guy Boivin
Pathogens 2022, 11(9), 1048; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11091048 - 15 Sep 2022
Cited by 3 | Viewed by 1726
Abstract
Baloxavir marboxil (BXM) is an antiviral drug that targets the endonuclease of the influenza polymerase acidic (PA) protein. Antiviral resistance, mainly mediated by the I38T PA substitution, readily occurs in both A(H1N1) and A(H3N2) viruses following a single dose of BXM. Influenza B [...] Read more.
Baloxavir marboxil (BXM) is an antiviral drug that targets the endonuclease of the influenza polymerase acidic (PA) protein. Antiviral resistance, mainly mediated by the I38T PA substitution, readily occurs in both A(H1N1) and A(H3N2) viruses following a single dose of BXM. Influenza B resistance to BXM remains poorly documented. We aimed to generate baloxavir-resistant contemporary influenza B/Yamagata/16/1988- and B/Victoria/2/1987-like viruses by in vitro passages under baloxavir acid (BXA) pressure to identify resistance mutations and to characterize the fitness of drug-resistant variants. Influenza B/Phuket/3073/2013 recombinant virus (rg-PKT13, a B/Yamagata/16/1988-like virus) and B/Quebec/MCV-11/2019 (MCV19, a B/Victoria/2/1987-like isolate) were passaged in ST6GalI-MDCK cells in the presence of increasing concentrations of BXA. At defined passages, viral RNA was extracted for sequencing the PA gene. The I38T PA substitution was selected in MCV19 after six passages in presence of BXA whereas no PA change was detected in rg-PKT13. The I38T substitution increased the BXA IC50 value by 13.7-fold in the MCV19 background and resulted in reduced viral titers compared to the wild type (WT) at early time points in ST6GalI-MDCK and at all time-points in human epithelial cells. By contrast, the I38T substitution had no impact on MCV19 polymerase activity, and this mutation was genetically stable over four passages. In conclusion, our results show a similar pathway of resistance to BXA in influenza B viruses highlighting the major role of the I38T PA substitution and suggest that I38T may differently impact the fitness of influenza variants depending on the viral type, subtype, or lineage. Full article
(This article belongs to the Special Issue Fighting Flu—Recent Advances in Influenza Research)
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10 pages, 906 KiB  
Article
Inhibition of Influenza Virus Replication by Oseltamivir Derivatives
by Renee W. Y. Chan, Kin P. Tao, Jiqing Ye, Kevin K. Y. Lui, Xiao Yang, Cong Ma and Paul K. S. Chan
Pathogens 2022, 11(2), 237; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11020237 - 11 Feb 2022
Cited by 5 | Viewed by 2218
Abstract
Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the [...] Read more.
Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concentration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200. Full article
(This article belongs to the Special Issue Fighting Flu—Recent Advances in Influenza Research)
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Review

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25 pages, 2825 KiB  
Review
Immune Responses to IAV Infection and the Roles of L-Selectin and ADAM17 in Lymphocyte Homing
by Sophie G. Reed and Ann Ager
Pathogens 2022, 11(2), 150; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11020150 - 25 Jan 2022
Cited by 4 | Viewed by 4723
Abstract
Influenza A virus (IAV) infection is a global public health burden causing up to 650,000 deaths per year. Yearly vaccination programmes and anti-viral drugs currently have limited benefits; therefore, research into IAV is fundamental. Leukocyte trafficking is a crucial process which orchestrates the [...] Read more.
Influenza A virus (IAV) infection is a global public health burden causing up to 650,000 deaths per year. Yearly vaccination programmes and anti-viral drugs currently have limited benefits; therefore, research into IAV is fundamental. Leukocyte trafficking is a crucial process which orchestrates the immune response to infection to protect the host. It involves several homing molecules and receptors on both blood vessels and leukocytes. A key mediator of this process is the transmembrane glycoprotein L-selectin, which binds to vascular addressins on blood vessel endothelial cells. L-selectin classically mediates homing of naïve and central memory lymphocytes to lymph nodes via high endothelial venules (HEVs). Recent studies have found that L-selectin is essential for homing of activated CD8+ T cells to influenza-infected lungs and reduction in virus load. A disintegrin and metalloproteinase 17 (ADAM17) is the primary regulator of cell surface levels of L-selectin. Understanding the mechanisms that regulate these two proteins are central to comprehending recruitment of T cells to sites of IAV infection. This review summarises the immune response to IAV infection in humans and mice and discusses the roles of L-selectin and ADAM17 in T lymphocyte homing during IAV infection. Full article
(This article belongs to the Special Issue Fighting Flu—Recent Advances in Influenza Research)
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Other

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9 pages, 235 KiB  
Hypothesis
Patients with Obesity and a History of Metformin Treatment Have Lower Influenza Mortality: A Retrospective Cohort Study
by Tammy H. Cummings, Joseph Magagnoli, James W. Hardin and S. Scott Sutton
Pathogens 2022, 11(2), 270; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11020270 - 19 Feb 2022
Cited by 5 | Viewed by 1883
Abstract
Background: Obesity is a risk factor for the development of influenza by leading to a chronic inflammatory state and T-cell dysfunction. Based upon preclinical research, metformin has influenza activity by restoring T-cell function and improving the immune response. Objective: We aimed to evaluate [...] Read more.
Background: Obesity is a risk factor for the development of influenza by leading to a chronic inflammatory state and T-cell dysfunction. Based upon preclinical research, metformin has influenza activity by restoring T-cell function and improving the immune response. Objective: We aimed to evaluate the potential drug repurposing of metformin for the management of influenza among patients with obesity utilizing national claims data in an electronic health record database. Methods: The VA Informatics and Computing Infrastructure (VINCI) was utilized to obtain individual-level information on demographics, administrative claims, and pharmacy dispensation. A cohort was created among individuals with laboratory confirmed diagnosis of influenza with a diagnosis of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome was death after diagnosis of influenza. Cohorts were formed using diabetes status and metformin exposure prior to a positive influenza diagnosis. Hazard ratios for mortality were estimated using a cox proportional hazards model adjusting for baseline covariates and a sub-analysis was conducted utilizing propensity score matching. A greedy nearest neighbor algorithm was utilized to match 1 to 1 non-metformin diabetic controls and non-diabetic controls to diabetic patients receiving metformin. Results: A total of 3551 patients met the inclusion criteria and were evaluated in our study. The cohorts consisted of 1461 patients in the non-diabetic cohort, 1597 patients in the diabetic / metformin cohort, and 493 patients in the diabetic no metformin cohort. Compared to non-diabetic patients, diabetic patients with metformin had a lower rate of death (aHR 0.78, 95% CI 0.609–0.999). There was not a statistical difference between the non-diabetic patients and the diabetic patients without metformin (aHR 1.046, 95% CI 0.781–1.400). The propensity score matched cohorts revealed consistent results with the primary analysis. Conclusion: Our results demonstrated patients with obesity and a history of metformin treatment have lower influenza mortality. Full article
(This article belongs to the Special Issue Fighting Flu—Recent Advances in Influenza Research)
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