key: cord-0897876-138qtoy8
authors: Makarov, Vadim; Riabova, Olga; Ekins, Sean; Pluzhnikov, Nikolay; Chepur, Sergei
title: The past, present and future of RNA respiratory viruses: Influenza and coronaviruses
date: 2020-08-29
journal: Pathog Dis
DOI: 10.1093/femspd/ftaa046
sha: 03c5a4e6ab1d946874c747f5885475d6e45ced5c
doc_id: 897876
cord_uid: 138qtoy8

Influenza virus and coronaviruses continue to cause pandemics across the globe. We know have a greater understanding of their function. Unfortunately the number of drugs in our armory to defend us against them are inadequate. This may require us to think about what mechanisms to address. We now review the biological properties of these viruses, their genetic evolution and antiviral therapies that can be used or have been attempted. We will describe several classes of drugs such as serine protease inhibitors, heparin, and heparan sulphate receptor inhibitors, chelating agents, immunomodulators and many others. We also briefly describe some of the drug repurposing efforts which have taken place in an effort to rapidly identify molecules to treat patients with COVID-19. While we have a heavy emphasis on the past and present efforts, we also provide some thoughts about what we need to do to prepare for respiratory viral threats in the future.

It is generally thought that the first large outbreak of a respiratory infection with clinical symptoms similar to those of influenza was described in detail by Hippocrates in the year 412 BC as contagious cough of Perinthus (Kuszewski and Brydak 2000; Pappas 2008 ). Next a detailed written report of an epidemic respiratory disease similar to influenza was noted in England and named peasant fever and lasted from 1173-1174 (Potter 2001 ). The first pandemic of influenza was clearly documented in 1580 (Potter 2001; Daly et al. 2007 ). In the 16th century this infection was named influenza (from the Latin influentia, influence), as this disease was considered a bad influence from the heavens (Broxmeyer 2006) . Since this time no less than 31 pandemics of influenza have been documented, including 3 in the 20th century and one in the 21st century (Al-Muharrmi 2010; Daly et al. 2007; Kilbourne 2006) (Table 1) .

Although a targeted search for pathogens able to produce an epidemic/pandemic of Human coronaviruses were for the first time isolated from a patient with acute respiratory diseases in 1965 (Tyrrell and Bynoe 1966; Hamre and Procknow 1966) .

Their characteristic corona seen under the electronic microscope was reflected in the name coronaviruses (Tyrrell et al. 1975) . During the next three decades (until the pandemic strains appeared), the coronaviruses were not of any special interest for most scientists.

It is apparent that pandemic outbreaks of respiratory viral infections represented a danger for humanity in the past, and there are no reasons to believe that they would not repeat in the future. It is as yet impossible to predict the time and place of the start of a new pandemic as well as the virulence of pandemic viral strains. However, there are certain factors that increase the potential for these viruses to spillover from other species (Johnson et al. 2020; Bobrowski et al. 2020; Gomes and Ruiz 2020) .

Influenza viruses belong to the orthomyxoviruses family (Orhtomyxoviridae, RNA viruses with segmented genome) and are represented by four monotypic genera: There are 18 known types of hemagglutinin (H1 to H18) and 11 identified serotypes of neuraminidase (N1 to N11), so in theory, 198 diverse combinations of these proteins (and thus subtypes of the influenza A virus) are possible (Skehel 2009; Tong et al. 2013; Quan et al. 2016; Zhao et al. 2019; Kosik and Yewdell 2019) ; of them, more than 120 combinations have been identified in nature (Tsai and Chen, 2011; Rejmanek et al. 2015 ).

There are 8 negative polar segments of RNA genome of the influenza virus which code at least 10 structural and 9 regulatory proteins (Varga et al. 2011; Muramoto et al. 2013; Hutchinson et al. 2014; Vasin et al. 2014) . Some uncertainty regarding the proteome of the influenza A viruses is related to the fact that, unlike most RNA viruses, the transcription and translation of the genome of these viruses take place in the nucleus and not in the cytoplasm of infected cells. This permits influenza A viruses ( highly glycosylated proteins which give them functional activity and provides for immune evasion by shielding antigenic determinants (Kim et al. 2018; York et al. 2019) .

Unlike influenza viruses, coronaviruses are enveloped RNA viruses (with nonsegmented positive polar RNA) of the Nidovirales order, Coronaviridae family, Orthocoronavirinae subfamily (Fehr and Perlman 2015) . Coronaviral virions have a spherical shape with the typical bulbous projections (Bárcena et al. 2009; Neuman et al. 2006) . The viral envelope is made of a bilipid layer where S-, M-and E-proteins are fixed (Lai and Cavanagh 1997; de Haan and Rottier 2005) (Figure 1, B) .

The S-protein functions in the form of highly glycosylated three-dimensional complexes (Zheng et al. 2017; Parsons et al. 2019) , providing the interaction of the virion with the receptors of epithelial cells followed by the internalization of the viral genome (Li 2016).

Also known as the spike protein -for SARS-CoV-2 there are crystal structures described (Wang Q et al. 2020 ).

The M-protein functions in the form of a dimer with a glycolyzed N-terminal ectodomain (Nal et al. 2005 ) and can be present in two different conformations. The conformers of this glycoprotein ensure the correct assembly and formation of a viral particle (Neuman et al. 2011) .

The E-protein is a transmembrane protein which is present in low quantities and has several functions namely in virion assembly, envelope forming and release of a viral particle from the cell. There is indirect evidence that it has the structure of a glycoprotein (Schoeman and Fielding 2019) .

The N-protein is the only protein present inside the virion; it is responsible for the viral genome packaging (McBride et al. 2014 ).

The fact that deserves particular attention is that the proteins of both the envelopes of both influenza A viruses and coronaviruses are made up of glycoproteins. An influenza virus enters a cell during a process that involves several steps. A critically important moment in the lifecycle of an influenza virus is the recognition of the specific cellular receptors which are glycoproteins or glycolipids containing a terminal α2,6-or α2,3-sialic acid in the glycan (Leung et al. 2012; Byrd-Leotis et al. 2017) . When viral HA binds sialic glycoproteins or glycolipids on the plasma membrane of an epithelial cell,

this results in the initiation of several mechanisms of endocytosis which quickly lead to the formation of endosomes, each of which contains a viral particle (Chardonnet and Dales 1970; Matlin et al. 1981; Kartenbeck et al. 1989; Rojek et al. 2008; Nanbo et al. 2010; Watanabe et al. 2010; Boulant et al. 2015) .

The next step of the internalization is the release of the viral genome (RNA segments) into the cellular cytoplasm; this phase depends on the activity of Na + /K + -ATPase located in the endosomal membrane and which functions as a proton pump. Na + /K + -ATPase is responsible for the acidification of the internal environment of endosomes/lysosomes (to pH 5.0) (Cain et al. 1989) . The acidification of the internal endosomal medium, i.e. the accumulation of protons (Н + ) inside the endosomes, helps the tetramers of the M2protein of the viral envelop to realize its potential as a protonophore (Pinto et al. 1992; Sugrue and Hay 1991; Manzoor et al. 2017) . When hydrogen ions enter a viral particle, it mediates conformational changes and decomposition of the structural components of the viral envelope, which finally leads to an increase in the lability of its genome (Yoshimura and Ohnishi 1984; Shibata et al. 1983) . But the fusion of the viral envelope membrane and the endosomal membrane, which releases the RNA genome of the virus into the cellular cytoplasm, is possible only with the participation of the viral HA after the previous proteolytic processing with serine (secretory trypsin-like) proteases (Klink 1975; Lazarowitz and Choppin 1975; Tashiro et al. 1987; Steinhauer 1999; Kido et al. 2009 ).

The translocation of RNA segments of the influenza viral genome from the cytoplasm to the nucleus is necessary for their replication, during which viral mRNA exits the nucleus to synthetize viral proteins in the cytoplasm. The viral self-assembly takes place at the

apical surface of the plasma membrane of epithelial cells, where HA and NA molecules are concentrated (Samji 2009; Dou et al. 2018 ).

The process of internalization of coronaviruses is determined by the functional activity of the S-protein (widely known as the spike protein) of the viral envelope. The S-protein of a coronavirus is a highly glycosylated supramolecular structure which enables the fixation of viral particles on the plasma membrane of epithelial cells, followed by the release of their RNA into the cellular cytoplasm (Li 2016; Watanabe et al. 2020) . Each S-protein has two receptor-binding domains located on its S 1 -subunit; these domains interact either with specific proteins or with sialoglycans of the epithelial cells (Li 2012; Shahwan et al. 2013; Hulswit et al. 2019) . For example, MERS-CoV preferentially binds the α 2,3 -bonded sialic acid (and to a lesser degree the α 2,6 -bonded sialic acid) (Li et al. 2017) . It seems that SARS-CoV-2 has the same affinity for the α 2,3 -sialic acid conjugates (Ou et al. 2020) .

After that, the internalization of the viral genome may proceed by endocytosis of the virion (which is in many respects a similar process to the internalization of the influenza viruses) or by the fusion of the membrane of a coronaviral envelope with the plasma membrane of an epithelial cell, without the formation of endosomes (directly on the plasma membrane). In any case, the release of the viral RNA into the cellular cytoplasm is preceded by the proteolytic (provided by serine proteases) cleavage of S 1 -subunit and modulation of the S 2 -subunit of the S-protein (Bosch et al. 2003; Belouzard et al. 2009; Simmons et al. 2013; Heurich et al. 2014; Zumla et al. 2016 ).

In the cytoplasm of an epithelial cell, the viral RNA genome functions as mRNA, where the complex of replication and transcription is responsible for both RNA genome

replication and synthesis of mRNA of structural viral proteins (Sola et al. 2015; Nakagawa et al. 2016) . After the posttranslational glycosylation in the Golgi apparatus cisternae (Nal et al. 2005; Tseng et al. 2010) , newly synthesized coronaviral proteins enter the cytoplasm and ensure the self-assembly of viral particles. The latter particles migrate to the cellular membrane inside the cisternae and are released from the cell by exocytosis (Fehr and Perlman 2015; Lim et al. 2016) .

Taking into account the importance of serine proteases, glycoproteins and glycolipids in the lifecycle of influenza viruses and coronaviruses, it seems logical to suggest that the factors which modulate the profile of glycosylation of proteins and lipids of epithelial cells and viruses, as well as control the activity of serine proteases on the epithelial lining of respiratory ways, may significantly limit the virulence of influenza viruses and coronaviruses and represent therapeutic drug targets.

When influenza viruses circulate in their natural reservoirs, they are characterized by high genetic variability which is reflected in the formation of quasi-subtypes activity in case of significant changes in the primary structure of the polypeptide chain (Thyagarajan and Bloom 2014; Visher et al. 2016 ).

An important and prevalent phenomenon in the evolution of influenza A viruses is socalled antigenic shift (Holmes et al. 2005 , Dugan et al. 2008 . The antigenic shift is the interchange of RNA segments of viral genome which code the HA and/or NA structure, in case of simultaneous infection of a cell by several strains of the influenza A virus (Taubenberger and Kash, 2010) . It is the antigenic shift that permits new subtypes of influenza A virus to overcome cross-species barriers (Scholtissek et al. 1978; Garten et al. 2009 ).

Unlike other RNA-viruses, the coronavirus genome replication involves RNA-dependent RNA-polymerase which has 3`-exonuclease corrective activity (Smith et al. 2014) . With the objective of immune evasion in humans and maintenance of the genotype in the Homosapiens population, as has been demonstrated for the coronaviral strain HCoV-OC43, coronaviruses also maintain the antigenic drift (Ren et al. 2015) . In addition, the genome of coronaviruses uses RNA-RNA recombination for its evolution (Keck et al. 1988; Huang et al. 2016; Forni et al. 2017) . Homologous RNA recombination represents a redistribution of the genetic material by interchange of RNA segments in the conditions of co-infection (Makino et al. 1986; Lai 1990; Lai and Cavanagh 1997) . In Pneumonias associated with respiratory viral infections are an independent factor in disease severity and mortality (Maruyama et al. 2016; Ishiguro et al. 2017) . This means that the main problem of severe viral infections, in the past as well as in the present, has been the problem of viral, viral-bacterial, and secondary bacterial pneumonias.

The biology of influenza viruses and coronaviruses inevitably leads to the appearance of new pandemic strains; it is impossible to predict the moment of their development, genomic variability, and antigenic properties. This means that pandemics of new respiratory infections will always start in the absence of immune prophylactics and treatments. This underlines the necessity of prior research and development of treatments for the prevention and treatment of respiratory viral infections and in

particular for coronaviruses and influenza A viruses. Several antiviral drugs that will be described herein are presented in Table 3 .

The nature of RNA viruses suggests that systemic interferon alfa-2b might be effective as non-specific background therapy, taking into account the weakened state of patients.

The efficacy of topical interferon solutions is doubtful, but they may be considered in and its activity strongly increases in hypoxic conditions (Poss et al. 1996; Terada et al. 1997; Linder et al. 2003) as well as under the influence of proinflammatory mediators and cytokines (Page et al. 1998; Brandes et al. 1999) . Melatonin is also widely used to promote sleep, so this may be undesirable in an antiviral during the daytime.

The superoxide anion-radical may act on organic and inorganic compounds, depending on their chemical properties, as an oxidant (E 0 (Wood 1987; Wood 1988 

system is extremely dangerous because in the presence of free ferric ions biological fluids lose their antibacterial properties (Bullen et al. 1991; Griffiths 1991; Sritharan 2006 ). The elimination of free ferric ions from the biological media of a body is a life/death issue in case of viral pneumonias. There were earlier attempts to use available complexones (for example, deferoxamine) to bind ferric ions during viral pneumonia; contrary to the expected, not only did they show no positive effects on the pathological process, but they also led to increased mortality (Dolganova and Sharanov 1997). The explanation of this paradox is that deferoxamine (desferal) has approximately the same affinity constant for ferric ions as siderophores of microorganisms (Hallaway et al. 1989; Askwith et al. 1996) ; for this reason it is unable to limit the availability of Fe 3+ for pathogenic organisms (Kim et al. 2007; Cassat and Skaar 2013) . At the same time, it seems that ferric ions chelated by deferoxamine do not completely lose their ability to redox-transformation and thus support the reactions of Fenton and Osipov (Borg and Schaich 1986; Klebanoff et al. 1989; Dulchavsky et al. 1996; Niihara et al. 2002; Francisco et al. 2010 ).

In contrast, 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol, emoxipine) has noticeable iron-chelating activity (Andrusishina et al. 2015) , antioxidative activity (Voronina 2001) and the ability to inhibit serine proteases and matrix metalloproteases (Akhmedov et al. 2010 ). Mexidol has many such biological effects and has been proposed for the effective use as a supportive agent in the treatment of pneumonia (Ilyashenko et al. 2001; Luzhnikov et al. 2006 ) and viral infections (Pavelkina 2010).

In clinical practice, chloroquine has been widely used as a safe, effective, and affordable medication for more than seven decades ( Chloroquine and the many analogs of it (such as hydroxychloroquine etc.) have properties of weakly acidic amines in unprotonated form as they easily permeate cellular membranes (Chinappi et al. 2010 ) and after the protonation accumulate in closed cellular compartments with acidic pH (i.e. endosomes or lysosomes) (Vincent et al. 2005) . The level of chloroquine in such compartments may be more than 100 times higher than its concentration in the cell (de Duve et al. 1974) . Chloroquine may stay in the isolated intracellular compartments for hundreds of hours (Schrezenmeier and Dorner 2020) . Accumulating in endosomes/lysosomes, chloroquine shifts the pH to alkali (Homewood et al. 1972 ; focused on the past and present efforts at addressing these viruses. Clearly our future will be very much defined by such viral outbreaks if we are not able to identify broad spectrum antivirals or vaccines. Looking at the past research may provide some important clues as to how we can identify such therapeutics. The reliance on a single magic bullet for every disease may be unrealistic and we therefore need to consider the combination of diverse antiviral treatments as we currently do for HIV and HBV.

Considering molecules that are traditionally not considered 'antivirals' may also be critical to open our eyes to accessing additional targets and mechanisms. Host targeted mechanisms may also be of interest such as those that stimulate the immune system.

Clearly, we are seeing many drugs that are lysosomotropic, while long term use of such molecules may be detrimental, short term use may prevent viral entry and protect the individual. There is certainly much more research that can be performed to understand how combinations of drugs for these respiratory viruses may work together. While interest in antiviral research and development has apparently languished for decades, the COVID-19 may permanently change that. If we continue to ignore such viruses the cost will be unimaginable and continue to hold back human progress. 

Caly, 2020

Binding of human xanthine oxidase to sulphated glycosaminoglycans on the endothelial-cell surface

Xanthine oxidoreductase: a journey from purine metabolism to cardiovascular excitation-contraction coupling

Dimethyl sulfoxide inhibits NLRP3 activation

Dependence on O 2 -generation by xanthine oxidase of pathogenesis of influenza virus infection in mice

The matrix metalloproteinase

TIMP-1 activities in patients with chronic and recurrent pancreatitis

Mechanisms of implementation of alpha-tocopherol antioxidant effects

The hypothesis of the aperiodic polysaccharides matrix synthesis. Advances in current biology

The chronology of the 2002-2003 SARS mini pandemic

Generation and characterization of influenza A viruses with altered polymerase fidelity

On the mechanism of chloroquine resistance in Plasmodium falciparum

CoV-2 replication in vitro

Effects of primaquine and chloroquine on oxidative stress parameters in rats

Research inequities: avoiding the next pandemic. Pathogens and global health, 2020; 1-2. Advance online publication

The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults

Iron and bacterial virulence -a brief overview

Ambroxol -resurgence of an old molecule as an anti-inflammatory agent in chronic obstructive airway diseases

Modulating the structure and properties of cell membranes: the molecular mechanism of action of dimethyl sulfoxide

Wholegenome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses

Fields Virology: 4th Edition. Philadelphia: Lippincott Williams and Wilkins

Lysosomes, pH and the anti-malarial action of chloroquine

A bat-derived putative cross-family recombinant coronavirus with a reovirus gene

Melatonin possesses an anti-influenza potential through its immune modulatory effect

The continuing 2019-nCoV epidemic threat of a novel coronaviruses to global health -the latest

Conserved and host-specific features of influenza virion architecture

Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells

Research Institute for Emergency Medicine, assignees. Russian Federation patent RU 2205641C2

Clinical characteristics of influenza-associated pneumonia of adults: clinical features and factors contributing to severity and mortality

Efficacy of Chloroquine against

Proteus vulgaris: An in vitro study

A mammalian functional reductase that regulates nitrite and nitric oxide homeostasis

Influenza pandemics of the 20 th century

A widespread deferoxamine-mediated iron-uptake system in Vibrio vulnificus

Glycosylation of hemagglutinin and neuraminidase of influenza A virus as signature for ecological spillover and adaptation among influenza reservoirs

Chloroquine in cancer therapy: a double-edged sword of autophagy

Changes to taxonomy and the international code of virus classification and nomenclature ratified by the International Committee on Taxonomy of Viruses

Oxygen-based free radicals generation by ferrous ions and deferoxamine

Activation of influenza A viruses by trypsin treatment

Influenza hemagglutinin and neuraminidase: Yin-Yang proteins coevolving to thwart immunity

Sialic acid tissue distribution and influenza virus tropism. Influenza Other Respir Viruses

The epidemiology and history of influenza

Coronavirus: organization, replication and expression of genome

The molecular biology of coronaviruses

Enhancement of the infectivity of influenza A and B viruses by proteolytic cleavage of the hemagglutinin polypeptide

The effect of chloroquine on the development of dry eye in Sjogren syndrome animal model

Entry of influenza A virus with a α2,6-linked sialic acid binding preference requires host fibronectin

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

Ambroxol interferes with Pseudomonas aeruginosa quorum sensing

The use of "Mexidol" in comprehensive treating patients with acute exogenous poisoning

High-frequency RNA recombination of murine coronaviruses

Influenza A virus M2 protein: roles from ingress to egress

Community-acquired respiratory coinfection in critically ill patients with pandemic 2009 influenza A(H1N1) virus

Outcomes and prognostic features of patients with influenza requiring hospitalization and receiving early antiviral therapy: a prospective multicenter cohort study

Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy

Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia

The coronavirus nucleocapsid is a multifunctional protein

Low carotid intima-media thickness

Seroepidemiological studies of coronavirus infection in adults and children

Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection

Identification of novel influenza A virus proteins translated from PA mRNA

Viral and cellular mRNA translation in coronavirus-infected cells

Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins

Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoproteindependent manner

Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy

A structural analysis of M protein in coronavirus assembly and morphology

Desferrioxamine decreases NAD redox potential of intact red blood cells: evidence for desferrioxamine as an inducer of oxidant stress in red blood cells

replication by chloroquine

Pneumonia complicating Asian influenza

Antioxidant activity of quercetin: a mechanistic review

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol

Xanthine oxidoreductase in human mammary epithelial cells: activation in response to inflammatory cytokines

Streptococcus pneumoniae coinfection is correlated with the severity of HINI pandemic influenza

Insights into infectious disease in the era of

Glycosylation of the viral attachment protein of avian coronavirus is essential for host cell and receptor binding

Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection

Influenza virus M2 protein has ion channel activity

Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumonia

Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia

A history of influenza

The efficacy of adjuvant use low molecular weight heparins in patients with community-acquired pneumonia

Progress in developing virus-like particle influenza vaccines

Middle East respiratory syndrome coronavirus (MERS-CoV): a review

Vacuolar ATPase inactivation blocks recycling to the trans-Golgi network from the plasma membrane

Melatonin as a mitochondria-targeted antioxidant: one of evolution`s best ideas

Evolutionary dynamics and global diversity of influenza A virus

Genetic drift of human coronavirus OC43 spike gene during adaptive evolution

Elevated Golgi pH in breast and colorectal cancer cells correlates with the expression of oncofetal carbohydrate T-antigen

Cellular entry of lymphocytic choriomeningitis virus

Xanthine oxidoreductase is asymmetrically localized on the outer surface of human endothelial and epithelial cells in culture

Influenza A: understanding the viral life cycle

disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models

Antioxidant properties of dimethyl sulfoxide and its viability as a solvent in the evaluation of neuroprotective antioxidants

Coronavirus envelope protein: current knowledge

On the origin of the human influenza virus subtypes H2N2 and H3N2

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Oxidative stress during viral infection: a review

Cell-specific modulation of surfactant proteins by ambroxol treatment

Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production

Sialic acid binding properties of soluble coronavirus spike (S1) proteins: differences between infectious bronchitis virus and transmissible gastroenteritis virus

A novel role for PDZ-binding motif of influenza A virus nonstructural protein 1 in regulation of host susceptibility to postinfluenza bacterial superinfections

Mechanisms of uncoating of influenza B virus in MDCK cells: action of chloroquine

Avian flu: influenza virus receptors in the human airway

Chloroquine protects human corneal epithelial cells from desiccation stress induced inflammation without altering the autophagy flux

Novel opportunities to study and block interactions between viruses and cell surface heparan sulfates

Influenza virus damages the alveolar barrier by disrupting epithelial tight junctions

An overview of influenza haemagglutinin and neuraminidase

Inosine Pranobex: A Key Player in the Game Against a Wide Range of Viral Infections and Non-Infectious Diseases

Evidence of human coronavirus HKU1 and human bocavirus in Australian children

Influenza infection leads to increased susceptibility to subsequent bacterial superinfection by impairing NK cell responses in the lung

Thinking outside the triangle: replication fidelity of the largest RNA viruses

A virus obtained from influenza patients

Chloroquine in hepatic amebiasis

In vitro synergism between chloroquine and antibiotics against Orientia tsutsugamushi

Flu, grippe, avian influenza, grippe aviaire, fowl plaque, swine influenza, hog flu, pig flu, equine influenza, canine influenza

Available from: cfsph.iastate.edu/Factsheets/pdfs/influenza

Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease

Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat Endocr Metab Immune Drug Discov

Iron and bacterial virulence

Mosaic evolution of the severe acute respiratory syndrome coronavirus

High nucleotide substitution error frequencies in clonal pools of vesicular stomatitis virus

Influenza infection suppresses NADPH oxidase-dependent phagocytic bacterial clearance and enhances susceptibility to secondary methicillinresistant Staphylococcus aureus infection

Detection of human coronavirus-NL63 in children in Japan

Canine Respiratory Coronavirus, Bovine Coronavirus, and Human Coronavirus OC43: Receptors and Attachment Factors

Ebola virus disease: potential use of melatonin as a treatment

Synergistic role of staphylococcal proteases in the induction of influenza virus pathogenicity

Influenza virus evolution, host adaptation and pandemic formation

Hypoxia regulates xanthine dehydrogenase activity at pre-and posttranslational levels

Mitochondrial reactive oxygen species contribute to pathological inflammation during influenza A virus infection in mice

New world bats harbor diverse influenza A viruses

Structural basis for human coronavirus attachment to sialic acid receptors

Influenza genome diversity and evolution

Self-assembly of severe acute respiratory syndrome coronavirus membrane protein

The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein

Molecular mechanisms enhancing the proteome of influenza A viruses: an overview of recently discovered proteins

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

The mutational robustness of influenza A virus

New treatment guidelines for Sjogren`s disease

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Structural and functional basis of SARS-CoV-2 entry by using human ACE2

Cellular networks involved in the influenza virus life cycle

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

A case for the ancient origin of coronaviruses

FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro

GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

The two redox potentials for oxygen reduction to superoxide

The potential diagram for oxygen at pH 7

Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry

A structural mechanism of flavonoids in inhibiting serine proteases

Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro

Ambroxol inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells

Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model

Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia

Influenza virus N-linked glycosylation and innate immunity

Flavonoids: promising natural compounds against viral infection

COVID-19: melatonin as potential adjuvant treatment

Potential Interventions for Novel Coronavirus in China: A Systemic Review

Semiaquatic mammals might be intermediate hosts to spread avian influenza virus from avian to human

Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1

Identification of Nlinked glycosylation sites in the spike protein and their functional impact on the