Special Issue-Immunity to Influenza Viruses.

Influenza viruses remain a constant global threat with significant health and socioeconomic impact every year and have the potential to cause devastating pandemics [...].

Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges.

The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.

Influenza and RSV incidence during COVID-19 pandemic-an observational study from in-hospital point-of-care testing.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has forced the implementation of unprecedented public health measures strategies which might also have a significant impact on the spreading of other viral pathogens such as influenza and Respiratory Syncytial Virus (RSV) . The present study compares the incidences of the most relevant respiratory viruses before and during the SARS-CoV-2 pandemic in emergency room patients. We analyzed the results of in total 14,946 polymerase chain reaction point-of-care tests (POCT-PCR) for Influenza A, Influenza B, RSV and SARS-CoV-2 in an adult and a pediatric emergency room between December 1, 2018 and March 31, 2021. Despite a fivefold increase in the number of tests performed, the positivity rate for Influenza A dropped from 19.32% (165 positives of 854 tests in 2018/19), 14.57% (149 positives of 1023 in 2019-20) to 0% (0 positives of 4915 tests) in 2020/21. In analogy, the positivity rate for Influenza B and RSV dropped from 0.35 to 1.47%, respectively, 10.65-21.08% to 0% for both in 2020/21. The positivity rate for SARS-CoV2 reached 9.74% (110 of 1129 tests performed) during the so-called second wave in December 2020. Compared to the two previous years, seasonal influenza and RSV incidence was eliminated during the COVID-19 pandemic. Corona-related measures and human behavior patterns could lead to a significant decline or even complete suppression of other respiratory viruses such as influenza and RSV.

Kallikreins emerge as new regulators of viral infections.

Kallikrein-related peptidases (KLKs) or kallikreins have been linked to diverse (patho) physiological processes, such as the epidermal desquamation and inflammation, seminal clot liquefaction, neurodegeneration, and cancer. Recent mounting evidence suggests that KLKs also represent important regulators of viral infections. It is well-established that certain enveloped viruses, including influenza and coronaviruses, require proteolytic processing of their hemagglutinin or spike proteins, respectively, to infect host cells. Similarly, the capsid protein of the non-enveloped papillomavirus L1 should be proteolytically cleaved for viral uncoating. Consequently, extracellular or membrane-bound proteases of the host cells are instrumental for viral infections and represent potential targets for drug development. Here, we summarize how extracellular proteolysis mediated by the kallikreins is implicated in the process of influenza (and potentially coronavirus and papillomavirus) entry into host cells. Besides direct proteolytic activation of viruses, KLK5 and 12 promote viral entry indirectly through proteolytic cascade events, like the activation of thrombolytic enzymes that also can process hemagglutinin, while additional functions of KLKs in infection cannot be excluded. In the light of recent evidence, KLKs represent potential host targets for the development of new antivirals. Humanized animal models to validate their key functions in viral infections will be valuable.

Surface Plasmon Resonance (SPR)- and Localized SPR (LSPR)-Based Virus Sensing Systems: Optical Vibration of Nano- and Micro-Metallic Materials for the Development of Next-Generation Virus Detection Technology.

The global damage that a widespread viral infection can cause is evident from the ongoing COVID-19 pandemic. The importance of virus detection to prevent the spread of viruses has been reaffirmed by the pandemic and the associated social and economic damage. Surface plasmon resonance (SPR) in microscale and localized SPR (LSPR) in nanoscale virus sensing systems are thought to be useful as next-generation detection methods. Many studies have been conducted on ultra-sensitive technologies, especially those based on signal amplification. In some cases, it has been reported that even a low viral load can be measured, indicating that the virus can be detected in patients even in the early stages of the viral infection. These findings corroborate that SPR and LSPR are effective in minimizing false-positives and false-negatives that are prevalent in the existing virus detection techniques. In this review, the methods and signal responses of SPR and LSPR-based virus detection technologies are summarized. Furthermore, this review surveys some of the recent developments reported and discusses the limitations of SPR and LSPR-based virus detection as the next-generation detection technologies.

How Influenza Virus Uses Host Cell Pathways during Uncoating.

Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recent findings of host cell pathways and cytosolic proteins that assist influenza uncoating during host cell entry.

Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome.

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.

Impact of COVID-19 outbreaks and interventions on influenza in China and the United States.

Coronavirus disease 2019 (COVID-19) was detected in China during the 2019-2020 seasonal influenza epidemic. Non-pharmaceutical interventions (NPIs) and behavioral changes to mitigate COVID-19 could have affected transmission dynamics of influenza and other respiratory diseases. By comparing 2019-2020 seasonal influenza activity through March 29, 2020 with the 2011-2019 seasons, we found that COVID-19 outbreaks and related NPIs may have reduced influenza in Southern and Northern China and the United States by 79.2% (lower and upper bounds: 48.8%-87.2%), 79.4% (44.9%-87.4%) and 67.2% (11.5%-80.5%). Decreases in influenza virus infection were also associated with the timing of NPIs. Without COVID-19 NPIs, influenza activity in China and the United States would likely have remained high during the 2019-2020 season. Our findings provide evidence that NPIs can partially mitigate seasonal and, potentially, pandemic influenza.

Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract.

Influenza viruses cause annual epidemics and occasional pandemics of respiratory tract infections that produce a wide spectrum of clinical disease severity in humans. The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and has since caused a pandemic. Both viral and host factors determine the extent and severity of virus-induced lung damage. The host's response to viral infection is necessary for viral clearance but may be deleterious and contribute to severe disease phenotypes. Similarly, tissue repair mechanisms are required for recovery from infection across the spectrum of disease severity; however, dysregulated repair responses may lead to chronic lung dysfunction. Understanding of the mechanisms of immunopathology and tissue repair following viral lower respiratory tract infection may broaden treatment options. In this Review, we discuss the pathogenesis, the contribution of the host response to severe clinical phenotypes and highlight early and late epithelial repair mechanisms following influenza virus infection, each of which has been well characterized. Although we are still learning about SARS-CoV-2 and its disease manifestations in humans, throughout the Review we discuss what is known about SARS-CoV-2 in the context of this broad knowledge of influenza virus, highlighting the similarities and differences between the respiratory viruses.

A Comparative Systematic Review of COVID-19 and Influenza.

BACKGROUND: Both SARS-CoV-2 and influenza virus share similarities such as clinical features and outcome, laboratory, and radiological findings. METHODS: Literature search was done using PubMed to find MEDLINE indexed articles relevant to this study. As of 25 November 2020, the search has been conducted by combining the MeSH words "COVID-19" and "Influenza". RESULTS: Eighteen articles were finally selected in adult patients. Comorbidities such as cardiovascular diseases, diabetes, and obesity were significantly higher in COVID-19 patients, while pulmonary diseases and immunocompromised conditions were significantly more common in influenza patients. The incidence rates of fever, vomiting, ocular and otorhinolaryngological symptoms were found to be significantly higher in influenza patients when compared with COVID-19 patients. However, neurologic symptoms and diarrhea were statistically more frequent in COVID-19 patients. The level of white cell count and procalcitonin was significantly higher in influenza patients, whereas thrombopenia and elevated transaminases were significantly more common in COVID-19 patients. Ground-grass opacities, interlobular septal thickening, and a peripheral distribution were more common in COVID-19 patients than in influenza patients where consolidations and linear opacities were described instead. COVID-19 patients were significantly more often transferred to intensive care unit with a higher rate of mortality. CONCLUSIONS: This study estimated differences of COVID-19 and influenza patients which can help clinicians during the co-circulation of the two viruses.

Influenza infection, SARS, MERS and COVID-19: Cytokine storm - The common denominator and the lessons to be learned.

The outbreak of COVID-19 reminds us that the emerging and reemerging respiratory virus infections pose a continuing threat to human life. Cytokine storm syndromes of viral origin seem to have a common pathogenesis of the imbalanced immune response with the exaggerated inflammatory reaction combined with the reduction and functional exhaustion of T cells. Immunomodulatory therapy is gaining interest in COVID-19, but this strategy has received less attention in other respiratory viral infections than it deserved. In this review we suggest that based on the similarities of the immune dysfunction in the severe cases of different respiratory viral infections, some lessons from the immunomodulatory therapy of COVID-19 (particularly regarding the choice of an immunomodulatory drug, the selection of patients and optimal time window for this kind of therapy) could be applied for some cases of severe influenza infection and probably for some future outbreaks of novel severe respiratory viral infections.

Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2.

Influenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses with EC50 values ranging from 0.3 to 1.4 µg/ml, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an EC50 value of 0.9 ± 1.1 µg/ml. No toxicity to the host cells was observed at concentrations up to 300 µg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing virus entry. Moreover, its intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection with several respiratory viruses.

Systematically comparing COVID-19 with the 2009 influenza pandemic for hospitalized patients.

OBJECTIVES: This study aimed to comprehensively compare the clinical features of hospitalized COVID-19 patients with hospitalized 2009 influenza pandemic patients. METHODS: Medline, Embase, Web of Science, Cochrane CENTRAL, and Google scholar were systematically searched to identify studies related to COVID-19 and the 2009 influenza pandemic. The pooled incidence rates of clinical features were estimated using the DerSimonian-Laird random-effects model with the Freeman-Tukey double arcsine transformation method. RESULTS: The incidence rates of fever, cough, shortness of breath, sore throat, rhinorrhea, myalgia/muscle pain, or vomiting were found to be significantly higher in influenza patients when compared with COVID-19 patients. The incidence rates of comorbidities, including cardiovascular disease/hypertension and diabetes, were significantly higher in COVID-19 compared with influenza patients. In contrast, comorbidities such as asthma, chronic obstructive pulmonary disease, and immunocompromised conditions were significantly more common in influenza compared with COVID-19 patients. Unexpectedly, the estimated rates of intensive care unit admission, treatment with extracorporeal membrane oxygenation, treatment with antibiotics, and fatality were comparable between hospitalized COVID-19 and 2009 influenza pandemic patients. CONCLUSIONS: This study comprehensively estimated the differences and similarities of the clinical features and burdens of hospitalized COVID-19 and 2009 influenza pandemic patients. This information will be important to better understand the current COVID-19 pandemic.

Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia.

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-ß present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.

Probiotics in Treatment of Viral Respiratory Infections and Neuroinflammatory Disorders.

Inflammation is a biological response to the activation of the immune system by various infectious or non-infectious agents, which may lead to tissue damage and various diseases. Gut commensal bacteria maintain a symbiotic relationship with the host and display a critical function in the homeostasis of the host immune system. Disturbance to the gut microbiota leads to immune dysfunction both locally and at distant sites, which causes inflammatory conditions not only in the intestine but also in the other organs such as lungs and brain, and may induce a disease state. Probiotics are well known to reinforce immunity and counteract inflammation by restoring symbiosis within the gut microbiota. As a result, probiotics protect against various diseases, including respiratory infections and neuroinflammatory disorders. A growing body of research supports the beneficial role of probiotics in lung and mental health through modulating the gut-lung and gut-brain axes. In the current paper, we discuss the potential role of probiotics in the treatment of viral respiratory infections, including the COVID-19 disease, as major public health crisis in 2020, and influenza virus infection, as well as treatment of neurological disorders like multiple sclerosis and other mental illnesses.

Bioactive Natural Antivirals: An Updated Review of the Available Plants and Isolated Molecules.

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.

Host factors involved in influenza virus infection.

Influenza virus causes an acute febrile respiratory disease in humans that is commonly known as 'flu'. Influenza virus has been around for centuries and is one of the most successful, and consequently most studied human viruses. This has generated tremendous amount of data and information, thus it is pertinent to summarise these for, particularly interdisciplinary readers. Viruses are acellular organisms and exist at the interface of living and non-living. Due to this unique characteristic, viruses require another organism, i.e. host to survive. Viruses multiply inside the host cell and are obligate intracellular pathogens, because their relationship with the host is almost always harmful to host. In mammalian cells, the life cycle of a virus, including influenza is divided into five main steps: attachment, entry, synthesis, assembly and release. To complete these steps, some viruses, e.g. influenza utilise all three parts - plasma membrane, cytoplasm and nucleus, of the cell; whereas others, e.g. SARS-CoV-2 utilise only plasma membrane and cytoplasm. Hence, viruses interact with numerous host factors to complete their life cycle, and these interactions are either exploitative or antagonistic in nature. The host factors involved in the life cycle of a virus could be divided in two broad categories - proviral and antiviral. This perspective has endeavoured to assimilate the information about the host factors which promote and suppress influenza virus infection. Furthermore, an insight into host factors that play a dual role during infection or contribute to influenza virus-host adaptation and disease severity has also been provided.

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection.

Influenza virus infection causes 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide annually. Although pneumonia is the most common complication associated with influenza, there are several reports demonstrating increased risk for cardiovascular diseases. Several clinical case reports, as well as both prospective and retrospective studies, have shown that influenza can trigger cardiovascular events including myocardial infarction (MI), myocarditis, ventricular arrhythmia, and heart failure. A recent study has demonstrated that influenza-infected patients are at highest risk of having MI during the first seven days of diagnosis. Influenza virus infection induces a variety of pro-inflammatory cytokines and chemokines and recruitment of immune cells as part of the host immune response. Understanding the cellular and molecular mechanisms involved in influenza-associated cardiovascular diseases will help to improve treatment plans. This review discusses the direct and indirect effects of influenza virus infection on triggering cardiovascular events. Further, we discussed the similarities and differences in epidemiological and pathogenic mechanisms involved in cardiovascular events associated with coronavirus disease 2019 (COVID-19) compared to influenza infection.

The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections.

Nonpharmaceutical interventions (NPIs) have been employed to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet these measures are already having similar effects on other directly transmitted, endemic diseases. Disruptions to the seasonal transmission patterns of these diseases may have consequences for the timing and severity of future outbreaks. Here we consider the implications of SARS-CoV-2 NPIs for two endemic infections circulating in the United States of America: respiratory syncytial virus (RSV) and seasonal influenza. Using laboratory surveillance data from 2020, we estimate that RSV transmission declined by at least 20% in the United States at the start of the NPI period. We simulate future trajectories of both RSV and influenza, using an epidemic model. As susceptibility increases over the NPI period, we find that substantial outbreaks of RSV may occur in future years, with peak outbreaks likely occurring in the winter of 2021-2022. Longer NPIs, in general, lead to larger future outbreaks although they may display complex interactions with baseline seasonality. Results for influenza broadly echo this picture, but are more uncertain; future outbreaks are likely dependent on the transmissibility and evolutionary dynamics of circulating strains.