Materiały źródłowe

• #1 Pathogenicity and virulence of influenza

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10283447/

  Influenza viruses, including four major types (A, B, C, and D), can cause mild-to-severe and lethal diseases in humans and animals. […] Severe influenza viral disease is caused by both direct viral cytopathic effects and exacerbated host immune response against high viral loads. […] Significant progress has also been made in identifying and characterizing the host components that mediate antiviral responses, pro-viral functions, or immunopathogenesis following influenza viral infections. […] Understanding the molecular mechanisms of viral virulence factors and virus-host interactions is critical for the development of preventive and therapeutic measures against influenza diseases. […] Influenza virus causes the death of epithelial cells through various mechanisms. In addition, infected epithelial cells release cytokines and chemokines to attract infiltrating inflammatory cells such as neutrophils and macrophages and activate adjacent endothelial cells.

• #1 Pathogenesis of influenza in humans | Virology Blog

  https://virology.ws/2009/06/02/pathogenesis-of-influenza-in-humans/

  When influenza virus is introduced into the respiratory tract, by aerosol or by contact with saliva or other respiratory secretions from an infected individual, it attaches to and replicates in epithelial cells. The virus replicates in cells of both the upper and lower respiratory tract. Viral replication combined with the immune response to infection lead to destruction and loss of cells lining the respiratory tract. […] In primary viral pneumonia, the virus replicates in alveolar epithelial cells, leading to rupture of walls of alveoli and bronchioles. Influenza H5N1 viruses frequently cause primary viral pneumonia characterized by diffuse alveolar damage and interstitial fibrosis. […] The reasons why influenza virus infections may lead to pneumonia are not understood. Several hypotheses have been proposed and disproved over the years, including one in which reduced numbers of lymphocytes allow increased susceptibility to superinfection.

• #1 Influenza – Wikipedia

  https://en.wikipedia.org/wiki/Influenza

  The viral life cycle begins by binding to a target cell. Binding is mediated by the viral HA proteins on the surface of the envelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane. […] Antigenic drift is when an influenza virus’ antigens change due to the gradual accumulation of mutations in the antigen’s (HA or NA) gene. […] Antigenic shift is a sudden, drastic change in an influenza virus’ antigen, usually HA. During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.

• #1 Influenza – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459363/

  Influenza is an acute disease that targets the upper respiratory tract and causes inflammation of the upper respiratory tree and trachea. […] The immune reaction to the viral infection and the interferon response are responsible for the viral syndrome which includes high fever, coryza, and body aches. […] High-risk groups who have chronic lung diseases, cardiac disease, and pregnancy are more prone to severe complications such as primary viral pneumonia, secondary bacterial pneumonia, hemorrhagic bronchitis, and death. […] The virus replicates in the upper and lower respiratory passages starting from the time of inoculation and peaking after 48 hours, on average. […] For virulence, both neuraminidase and hemagglutinin are vital as they are the key targets of the neutralizing antibodies.

• #1 Influenza virus infection mechanism and symptoms, labelled animation – Stock Video Clip – K011/2282 – Science Photo Library

  https://www.sciencephoto.com/media/1382237/view/influenza-virus-infection-mechanism-and-symptoms-labelled-animation

  Labelled animation showing the mechanism by which influenza (flu) viruses infect humans and a summary of the typical symptoms of flu. Virus particles enter the host’s cells by being engulfed by the cell membrane (endocytosis). […] Viral RNA is then released within the host cell, where it can enter the nucleus. Here the host cell machinery is used to produce more viral proteins, allowing replication of the virus. The host cell will eventually die, releasing many viruses which can go on to infect other cells.

• #1 Influenza – Wikipedia

  https://en.wikipedia.org/wiki/Influenza

  Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. […] In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract. Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system’s response to infection. […] Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm. […] The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells. Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an -2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.

• #1 Influenza virus-related critical illness: pathophysiology and epidemiology | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2539-x

  Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individuals contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix. […] The primary mechanism of influenza pathophysiology is a result of lung inflammation and compromise caused by direct viral infection of the respiratory epithelium, combined with the effects of lung inflammation caused by immune responses recruited to handle the spreading virus. This inflammation can spread systemically and manifest as a multiorgan failure, but these consequences are generally downstream of lung compromise and severe respiratory distress.

• #1 The Mechanism behind Influenza Virus Cytokine Storm

  https://www.mdpi.com/1999-4915/13/7/1362

  A severe cytokine storm can cause acute respiratory distress syndrome (ARDS). Clinically, the characteristic alveolar changes of influenza-virus pneumonia caused by cytokine storms include capillary thrombosis, focal necrosis and congestion of the alveolar wall, inflammatory infiltration, hyaline membrane formation, and pulmonary edema. […] The aggressive immune response of patients with a cytokine storm is enhanced by coagulation dysfunction, which is manifested by the activation of pulmonary endothelial cells, vascular leakage, diffuse intravascular coagulation, and pulmonary microembolisms. Severe cytokine storms also lead to multiple organ dysfunction syndromes, systemic inflammation, and even death. […] The cytokine storm and clinical manifestations caused by the influenza B virus in children are similar to those caused by the influenza A virus. However, due to the insufficient sample size, it is not enough to rule out important differences. […] In this review, we mainly focus on the mechanism behind the dysregulation of the cytokine storm in the influenza virus.

• #1

  https://www.jci.org/articles/view/44947

  Influenza A viruses cause recurrent, seasonal epidemics and occasional global pandemics with devastating levels of morbidity and mortality. The ability of influenza A viruses to adapt to various hosts and undergo reassortment events ensures constant generation of new strains with unpredictable degrees of pathogenicity, transmissibility, and pandemic potential. […] Identification and characterization of influenza A virus virulence determinants may provide insight into genotypic signatures of pathogenicity as well as a more thorough understanding of the factors that give rise to pandemics. […] The pathogenicity of influenza virus is considered multigenic; it is determined by the constellation of genes within a particular influenza virus strain within a specific host. There are, however, particular genetic mutations that can enhance various aspects of the viral life cycle, including virus binding and entry, genome transcription and translation, virion assembly and release, and evasion of innate immune responses. These so-called virulence determinants can contribute to a highly pathogenic phenotype in infected animals.

• #1 Pathogenicity and virulence of influenza

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10283447/

  Thus, the pathogenesis of severe influenza disease is caused not only by direct viral cytopathic effects but also by exacerbated host inflammatory responses. […] Therefore, effective therapeutics should aim to reduce both viral replication and pathogenic airway inflammation. […] Extensive studies have been conducted to identify and characterize viral determinants associated with increased pathogenicity, virulence, and transmission. […] The major virulence determinants include changes that affect viral entry, increase viral polymerase activity, and modulation of host responses. […] Identifying viral outbreaks of pandemic potential through active surveillance of the prevalence and evolution of influenza A viruses in avian, swine, and human hosts to identify molecular markers of virulence is an important component of the pandemic preparedness plan.

• #1 Pathogenesis and Pathogenicity of Influenza Viruses | Veterian Key

  https://veteriankey.com/pathogenesis-and-pathogenicity-of-influenza-viruses/

  The constellation of genes coding for viral RNA polymerase complex (PB1, PB2, PA and NP) appears to have an important role in virulence. […] The host range restriction and virulence of influenza viruses is significantly affected, even in H5 and H7 viruses, by the type of amino acid present at 627 position of PB2 protein. […] The efficiency of growth influenza viruses in mammalian cells is enhanced by the presence of lysine at 627 position of PB2 protein. […] The PB2 protein of an HPAI virus strain A/chicken/Yamaguchi/7/2004 (H5N1) has been found to determine its replication capability in pigs. […] The PB1-F2 protein of influenza A virus plays a role in viral pathogenesis in mice. […] The pathophysiology and severity of influenza virus disease was found to be contributed by PB1-F2 protein induced activation of the NLRP3 inflammasome.

• #1 Pathogenesis and Pathogenicity of Influenza Viruses | Veterian Key

  https://veteriankey.com/pathogenesis-and-pathogenicity-of-influenza-viruses/

  The interaction of C-terminal region of PB2 with importin is involved in host adaptation of influenza viruses. […] The viral polymerase helps in the adaptation of an avian influenza virus to mammalian host. […] It has been observed that adaptive mutations that result in enhanced polymerase activity can increase the virulence of influenza A virus in mice. […] The NA protein has also been reported to have a role in host range restriction and pathogenicity. […] The NS1 protein may affect the pathogenicity of influenza viruses due to the differences in their abilities to counteract the effects of cellular interferon or induction of high levels of proinflammatory cytokines. […] The pathogenicity of a HPAI virus A/whooper swan/Mongolia/3/2005 (H5N1) in ducks was shown to correlate with the PB2, PA, HA, NP and NS genes.

• #1 Influenza: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/219557-overview

  Major typing of influenza A occurs through identification of both H and N proteins. Seventeen H and nine N types have been identified. All hemagglutinins and neuraminidases infect wild waterfowl, and the various combinations of H and N yield 144 potential subtypes of influenza. […] Because the viral RNA polymerase lacks error-checking mechanisms, the year-to-year antigenic drift is sufficient to ensure that there is a significant susceptible host population each year. However, the segmented genome also has the potential to allow reassortment of genome segments from different strains of influenza in a coinfected host. […] Influenza A is a genetically labile virus, with mutation rates as high as 300 times that of other microbes. Changes in its major functional and antigenic proteins occur by means of two well-described mechanisms: antigenic drift and antigenic shift.

• #1 Influenza: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/219557-overview

  Antigenic drift is the process by which inaccurate viral RNA polymerase frequently produces point mutations in certain error-prone regions in the genes. These mutations are ongoing, and they are responsible for the ability of the virus to evade annually acquired immunity in humans. Drift can also alter the virulence of the strain. […] Antigenic shift is less frequent than antigenic drift. In a shift event, influenza genes between two strains are reassorted, presumably during coinfection of a single host. Segmentation of the viral genome, which consists of 10 genes on eight RNA molecules, facilitates genetic reassortment. […] The reassortment of an avian strain with a mammalian strain may produce a chimeric virus that is transmissible between mammals; such mutation products may contain H or N proteins that are unrecognizable to the immune systems of mammals. This antigenic shift results in a much greater population of susceptible individuals in whom more severe disease is possible. […] Such an antigenic shift can result in a virulent strain of influenza that possesses the triad of infectivity, lethality, and transmissibility and can cause a pandemic.

• #1 Influenza Virus (Flu) | BCM

  https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/specific-agents/influenza-virus-flu

  Flu, or influenza, is a contagious respiratory illness that spreads from person to person through the air via coughs or sneezes or through contact with infected surfaces. It is caused by a group of continuously changing viruses called influenza viruses. […] Influenza viruses change easily and often, they are unpredictable, and they can be deadly. It is always a great concern when a new flu virus emerges, because the general population does not have immunity and almost everyone is susceptible to infection and disease. […] Influenza virus is one of the most changeable viruses known. There are two ways that influenza virus changes these are called drift and shift. […] Drifting, or antigenic drift, is a gradual, continuous change that occurs when the virus makes small mistakes when copying its genetic information. This can result in a slight difference in the HA or NA proteins.

• #1 Flu (Influenza) Vaccine, Causes, Symptoms, Treatment

  https://www.medicinenet.com/influenza/article.htm

  The 2009 pandemic-causing H1N1 virus was a classic example of antigenic shift. Research showed that novel H1N1 swine flu has an RNA genome that contains five RNA strands derived from various swine flu strains, two RNA strands from bird flu (also termed avian flu) strains, and only one RNA strand from human flu strains. […] The flu is typically contagious about 24-48 hours before symptoms appear (from about the last day of the incubation period) and in normal healthy adults is contagious for another 5-7 days. […] Most individuals who contract influenza recover in a week or two, however, others develop potentially life-threatening complications like pneumonia. […] The flu can lead to serious complications, especially in certain groups of people. […] The flu or influenza is usually a mild illness that goes away on its own. However, the flu can lead to serious complications, especially in certain groups of people.

• #1 Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-021-00542-7

  In contrast to viral load, specific cytokines and inflammatory profiles in both serum or plasma and respiratory samples are consistently associated with the severity of infection, including in SARS-CoV-2 infection. […] High systemic levels of multiple cytokines, and their association with severity, have frequently been referred to as a cytokine storm. […] The initial signalling cascades necessary for a coordinated host response to influenza virus entry culminate in the production of hundreds of interferon-stimulated genes (ISGs) and pro-inflammatory cytokines via activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor B (NF-B). […] The type I interferon response to SARS-CoV-2 may be crucial. […] The presence of neutralizing autoantibodies targeting type I interferons was associated with onset of severe disease.

• #1 Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-021-00542-7

  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. […] The effectiveness of the host strategy in response to influenza virus or SARS-CoV-2 infection may depend on the compartment in the respiratory tract. […] Type I and type III interferons have a crucial role in initially controlling viral replication in the URT and limiting spread to the lower airways. […] When this resistance is broken, and the virus spreads, the LRT may require a tolerant defence that favours preservation of the crucial alveolar structures that perform gas exchange. […] In human disease, viral load in respiratory samples is neither a consistent correlate of disease severity nor a reliable predictor of infection outcome.

• #1 Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs

  https://www.mdpi.com/2076-0817/13/2/127

  Influenza virus has been one of the most prevalent and researched viruses globally. Consequently, there is ample information available about influenza virus lifecycle and pathogenesis. However, there is plenty yet to be known about the determinants of influenza virus pathogenesis and disease severity. Influenza virus exploits host factors to promote each step of its lifecycle. In turn, the host deploys antiviral or restriction factors that inhibit or restrict the influenza virus lifecycle at each of those steps. Two broad categories of host restriction factors can exist in virus-infected cells: (1) encoded by the interferon-stimulated genes (ISGs) and (2) encoded by the constitutively expressed genes that are not stimulated by interferons (non-ISGs). There are hundreds of ISGs known, and many, e.g., Mx, IFITMs, and TRIMs, have been characterized to restrict influenza virus infection at different stages of its lifecycle by (1) blocking viral entry or progeny release, (2) sequestering or degrading viral components and interfering with viral synthesis and assembly, or (3) bolstering host innate defenses. Also, many non-ISGs, e.g., cyclophilins, ncRNAs, and HDACs, have been identified and characterized to restrict influenza virus infection at different lifecycle stages by similar mechanisms. This review provides an overview of those ISGs and non-ISGs and how the influenza virus escapes the restriction imposed by them and aims to improve our understanding of the host restriction mechanisms of the influenza virus.

• #1 The Mechanism behind Influenza Virus Cytokine Storm

  https://www.mdpi.com/1999-4915/13/7/1362

  Influenza viruses are still a serious threat to human health. Cytokines are essential for cell-to-cell communication and viral clearance in the immune system, but excessive cytokines can cause serious immune pathology. Deaths caused by severe influenza are usually related to cytokine storms. […] The influenza virus first infects the upper respiratory tract, enters epithelial cells through endocytosis, and infects the lower respiratory tract as the disease worsens. The influenza virus infects epithelial cells, endothelial cells, and alveolar macrophages to produce the first wave of cytokines; then, adaptive immune cells are activated and regulated to secrete the second wave of cytokines that promote viral clearance. If excessive production of proinflammatory cytokines leads to aggressive proinflammatory responses and the insufficient control of anti-inflammatory responses, this series of events is called a cytokine storm, which is one of the reasons for the increased mortality during influenza-virus infection. The cytokine storm induced by the influenza virus can lead to major immunopathology and serious disease consequences.

• #1 Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-021-00542-7

  In addition to an interferon and pro-inflammatory response to infection, altruistic programmed cell death (PCD) is an essential component of the initial cellular response to IAV infection. […] Epithelial cells help to define the tissue microenvironment. […] Epithelial cells produce molecules that promote tissue repair and tolerance by interacting with diverse cell types in the LRT. […] During IAV-induced lung injury, alveolar type II epithelial cells are primary producers of GM-CSF in the distal lung. […] Epithelial cells can also alter the tissue microenvironment through regulation of surface molecules and communication with nearby cells. […] The regeneration of alveolar tissue and restoration of function is essential for survival following a severe respiratory infection. […] Recent studies have demonstrated that the extent and severity of influenza virus infection determines the quality of alveolar epithelial repair.

• #1 Pathogenesis of Influenza | SpringerLink

  https://link.springer.com/chapter/10.1007/978-94-024-0908-6_4

  The pathological changes of simplex influenza include impaired upper and middle respiratory tract, obviously involved trachea, degenerated ciliated epithelial cells with apoptosis and shedding, detectable inclusion bodies in the cytoplasm, mucosal congestion and edema as well as infiltrated mononuclear cells. However, the layer of basal cells remains intact. About 45 days after onset, the basal cells begin to proliferate to form undifferentiated epithelial cells. Two weeks later, ciliated epithelial cells are formed for recovery. Pneumonia induced by influenza virus is pathologically characterized by intrapulmonary extensive hemorrhage in a color of dark red with accompanying edema, bloody secretions in the trachea and bronchi, mucosal congestion, necrosis and shedding of tracheal and bronchial ciliated epithelial cells, submucosal focal hemorrhage, edema and slight inflammatory cells infiltration as well as alveolar fibrin exudates containing neutrophils and mononuclear cells.

• #1 Influenza virus type A: Infectious substances pathogen safety data sheet – Canada.ca

  https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/influenza-virus-type-a.html

  The high frequency of antigenic drifts or shifts in the influenza virus genome leads to epidemics by introducing virulence factors the population does not yet have immunity to. […] The cross-species transmission of avian influenza viruses could result in a reassortment which may be infectious to humans with antigenic characteristics for which the current population is immunologically nave.

• #1 Pathogenicity and transmissibility of bovine H5N1 influenza virus | Nature

  https://www.nature.com/articles/s41586-024-07766-6

  Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. […] Bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals. […] HPAI H5N1 viruses rarely infect mammals and typically do not transmit among them. […] The basic characteristics of the bovine H5N1 viruses are unknown. […] To evaluate the public health risk of H5N1 virus-containing milk, we previously demonstrated that oral consumption of milk from an HPAI H5N1-infected cow led to rapid induction of disease symptoms (by day 1 postinfection) and virus dissemination to respiratory and non-respiratory organs (by day 4 postinfection) in BALB/cJ mice.

• #1

  https://www.who.int/initiatives/pandemic-influenza-preparedness-framework/virus-sharing

  Influenza virus sharing is vital to global pandemic preparedness. The sharing of viruses facilitates pandemic risk assessment, the development of candidate vaccine viruses, updating of diagnostic reagents and test kits, and surveillance for resistance to antiviral medicines. […] Influenza virus sharing is coordinated by the WHO Global Influenza Surveillance and Response System (GISRS), an international network of influenza laboratories that conduct year-round surveillance of influenza, assessing the risk of pandemic influenza and assisting in preparedness measures. GISRS serves as a global alert mechanism for the emergence of influenza viruses with pandemic potential. […] The Influenza Virus Traceability Mechanism (IVTM) is a publicly accessible, electronic, internet-based system that records the transfer and movement of PIP biological materials into, within and to parties outside the WHO GISRS. The purpose of the system is to allow users to see where PIP biological materials have been sent.

• #1 RFK, Jr., Funds Universal Vaccines for Flu and COVID—Here’s What That Means | Scientific American

  https://www.scientificamerican.com/article/rfk-jr-funds-universal-vaccines-for-flu-and-covid-heres-what-that-means/

  Scientists have spent decades in hot pursuit of a universal influenza vaccinea single shot to protect people from past and possible future strains of a frequently mutating virus. […] Scientists have been trying to develop such universal influenza and COVID vaccines, looking to get parts of the virus that are the same from strain to strain. There are external parts of the virus that mutate and change, and we make our current vaccines to adapt to those external changes. But there are more internal structures that are, as we say, conserved. That is, theyre the same no matter what the strain is. If we could get the immune system to respond to those stable parts of the virus, we would have a universal vaccine so that no matter how much the virus had changed, we would still be protected. […] The NIH and HHSs new initiative is focusing on a whole-virus platform for universal vaccines. How would this work? There are different ways to try to create a vaccine, and one of the oldest ways is to do it very simply: you get the whole virus, and you just kill it, and then you use itor all of its broken-up parts, depending on how you kill itas the vaccine. Often when you kill the virus, you bang it and break it up. So you hope that the immune system not only will respond to those external pieces but will get greater access to those internal structures that are more stable and constant from mutation to mutation.

• #1 Influenza – Infectious Diseases – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/infectious-diseases/respiratory-viruses/influenza

  Neuraminidase inhibitors interfere with release of influenza virus from infected cells and thus halt spread of infection. […] The endonuclease inhibitor baloxavir marboxil interferes with viral replication by blocking viral RNA transcription. It is active against influenza A and B and may be an important new treatment option should resistance to neuraminidase inhibitors develop. […] Adamantanes block the M2 ion channel and thus interfere with viral uncoating inside the cell. They were effective only against influenza A viruses (influenza B viruses lack the M2 protein). […] Minor antigenic drift in H and/or NA antigens produces strains that cause seasonal epidemics; rare antigenic shifts resulting in new combinations of H and NA antigens can cause a pandemic with significant mortality.

• #1 Plasminogen Controls Inflammation and Pathogenesis of Influenza Virus Infections via Fibrinolysis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003229

  Detrimental inflammation of the lungs is a hallmark of severe influenza virus infections. […] Here, using combined pharmacological and gene-deletion approaches, we show that plasminogen controls lung inflammation and pathogenesis of infections with influenza A/PR/8/34, highly pathogenic H5N1 and 2009 pandemic H1N1 viruses. […] Our findings show that plasminogen plays an important role in lung inflammation upon IAV infections, mainly through fibrinolysis. Therefore, targeting host factors, such as the fibrinolytic molecule plasminogen may be of interest for the development of new therapeutics against IAV infections. […] Plasminogen promotes IAV pathogenesis. […] Thus, we concluded that without plasminogen, pathogenesis of IAV infections was dampened and mortality reduced in a subtype-independent manner.

• #1 Effect of Prior Influenza A(H1N1)pdm09 Virus Infection on Pathogenesis and Transmission of Human Influenza A(H5N1) Clade 2.3.4.4b Virus in Ferret Model – Volume 31, Number 3—March 2025 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/31/3/24-1489_article

  Reports of human infections with influenza A(H5N1) clade 2.3.4.4b viruses associated with outbreaks in dairy cows in the United States underscore the need to assess the potential cross-protection conferred by existing influenza immunity. […] Our results showed that prior influenza A(H1N1)pdm09 virus infection more effectively reduced the replication and transmission of the H5N1 virus than did the H7N9 virus, a finding supported by the presence of group 1 hemagglutinin stalk and N1 neuraminidase antibodies in preimmune ferrets. […] Our findings suggest that prior influenza A(H1N1)pdm09 virus infection may confer some level of protection against influenza A(H5N1) clade 2.3.4.4.b virus. […] We showed that ferrets with existing pH1N1 virus immunity had reduced disease severity and limited viral systemic spread after aerosol inhalation exposure to Texas/37 virus.

• #1 Dr. Roach: Series of infections follows after an intense bout of influenza A

  https://www.detroitnews.com/story/life/advice/2025/05/06/dr-roach-series-of-infections-follows-after-an-intense-bout-of-influenza-a/83365578007/

  It seems to me that we humans have a protective mechanism that lets us forget just how sick we were when we had the flu. […] Like with COVID, after getting the flu, people can have long-lasting symptoms of the lungs (cough and shortness of breath), heart, and central nervous system (brain fog). But the effect it undoubtedly has on depressing our immune and inflammatory systems are part of why people can get other viruses and bacterial infections after a bad case of influenza. […] To be clear, I don’t think you still have the flu; I think your system was sufficiently weakened by the initial infection that you’ve had a series of other infections afterward. For example, when your nasal passages are congested, the sinuses cannot drain properly, which makes a bacterial infection more likely.

• #1 Influenza (flu) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/flu/symptoms-causes/syc-20351719

  Influenza is caused by viruses. These viruses travel through the air in droplets when someone with the infection coughs, sneezes or talks. You can inhale the droplets directly. Or you can pick up the virus from touching an object, such as a computer keyboard, and then touching your eyes, nose or mouth. […] Influenza viruses are constantly changing, with new strains appearing often. […] A person’s first flu infection gives some long-term protection against similar strains of flu. But the vaccines offered each year are made to match the flu virus strains that are most likely to spread that season. The protection these vaccines offer lasts for months in most people. […] If you’re young and healthy, the flu usually isn’t serious. Although you may feel awful while you have it, the flu usually goes away in a week or two with no lasting effects.

• #2 Influenza – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459363/

  Influenza is an acute disease that targets the upper respiratory tract and causes inflammation of the upper respiratory tree and trachea. […] The immune reaction to the viral infection and the interferon response are responsible for the viral syndrome which includes high fever, coryza, and body aches. […] High-risk groups who have chronic lung diseases, cardiac disease, and pregnancy are more prone to severe complications such as primary viral pneumonia, secondary bacterial pneumonia, hemorrhagic bronchitis, and death. […] The virus replicates in the upper and lower respiratory passages starting from the time of inoculation and peaking after 48 hours, on average. […] For virulence, both neuraminidase and hemagglutinin are vital as they are the key targets of the neutralizing antibodies.

• #2 Pathogenicity and virulence of influenza

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10283447/

  Thus, the pathogenesis of severe influenza disease is caused not only by direct viral cytopathic effects but also by exacerbated host inflammatory responses. […] Therefore, effective therapeutics should aim to reduce both viral replication and pathogenic airway inflammation. […] Extensive studies have been conducted to identify and characterize viral determinants associated with increased pathogenicity, virulence, and transmission. […] The major virulence determinants include changes that affect viral entry, increase viral polymerase activity, and modulation of host responses. […] Identifying viral outbreaks of pandemic potential through active surveillance of the prevalence and evolution of influenza A viruses in avian, swine, and human hosts to identify molecular markers of virulence is an important component of the pandemic preparedness plan.

• #2 Influenza virus-related critical illness: pathophysiology and epidemiology | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2539-x

  Influenza virus infects respiratory epithelial cells that line the upper (including nasal) through lower (to the alveoli) respiratory tract. A key parameter in determining the extent of associated disease is the degree to which the lower respiratory tract becomes invaded by the virus. The infection of alveolar epithelial cells in particular appears to drive the development of severe disease, destroying the key mediators of gas exchange and allowing viral exposure to endothelial cells. […] Ultimately, the involvement of significant portions of the airways in an infectious response, either by direct viral infection or by damage from the responding immune system, represents a physiological failure. The inability of the lung to perform its primary function of gas exchange can result from multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix that maintains the structure of the lung.

• #2 Influenza – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459363/

  Hemagglutinin adheres to the epithelial cells in the respiratory tract allowing for the progression of the infection. […] Neuraminidase cleaves the bond that holds the virus together and helps to spread the virions. […] An important aspect of the influenza A virus is that it is a genetically labile virus with a high rate of mutations. This results in major changes in antigenic and functional proteins.

• #2 Pathogenesis and Pathogenicity of Influenza Viruses | Veterian Key

  https://veteriankey.com/pathogenesis-and-pathogenicity-of-influenza-viruses/

  The constellation of genes coding for viral RNA polymerase complex (PB1, PB2, PA and NP) appears to have an important role in virulence. […] The host range restriction and virulence of influenza viruses is significantly affected, even in H5 and H7 viruses, by the type of amino acid present at 627 position of PB2 protein. […] The efficiency of growth influenza viruses in mammalian cells is enhanced by the presence of lysine at 627 position of PB2 protein. […] The PB2 protein of an HPAI virus strain A/chicken/Yamaguchi/7/2004 (H5N1) has been found to determine its replication capability in pigs. […] The PB1-F2 protein of influenza A virus plays a role in viral pathogenesis in mice. […] The pathophysiology and severity of influenza virus disease was found to be contributed by PB1-F2 protein induced activation of the NLRP3 inflammasome.

• #2

  https://www.jci.org/articles/view/44947

  The adaptation of an avian influenza A virus to recognize human-type receptors is considered a requirement for efficient human-to-human transmission and thus for the development of a pandemic virus. The pandemic viruses of 1918, 1957, and 1968 had HAs of avian origin, but acquired the ability to bind human-like receptors. […] A major virulence determinant in influenza virus is a multi-basic cleavage site within HA. Cleavage of the HA precursor, HA0, into HA1 and HA2 exposes the amino terminus of HA2 containing the fusion peptide, allowing for virus envelope fusion with a host endosomal membrane. […] The viral polymerase complex has been recognized as an important contributor to viral pathogenicity, most likely by directly controlling levels of vRNA replication. Numerous substitutions within the PB2 subunit have been shown to alter host range and virulence. […] As an IFN antagonist, NS1 forges a multipronged attack against the innate immune response triggered by influenza virus infection. NS1 prevents activation of transcription factors that induce IFN- by blocking recognition of influenza pathogen-associated molecular patterns through retinoid-inducible gene1. […] Optimal influenza virus replication requires a functional balance between HA sialic acid binding affinity and receptor-destroying, enzymatic activity of NA. This balance can be perturbed by a number of events, such as reassortment, introduction into a novel host, and antiviral therapy.

• #2 Influenza Virus (Flu) | BCM

  https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/specific-agents/influenza-virus-flu

  Flu, or influenza, is a contagious respiratory illness that spreads from person to person through the air via coughs or sneezes or through contact with infected surfaces. It is caused by a group of continuously changing viruses called influenza viruses. […] Influenza viruses change easily and often, they are unpredictable, and they can be deadly. It is always a great concern when a new flu virus emerges, because the general population does not have immunity and almost everyone is susceptible to infection and disease. […] Influenza virus is one of the most changeable viruses known. There are two ways that influenza virus changes these are called drift and shift. […] Drifting, or antigenic drift, is a gradual, continuous change that occurs when the virus makes small mistakes when copying its genetic information. This can result in a slight difference in the HA or NA proteins.

• #2 Flu (Influenza) Vaccine, Causes, Symptoms, Treatment

  https://www.medicinenet.com/influenza/article.htm

  When spread by droplets or direct contact, the virus, if not killed by the host’s immune system, replicates in the respiratory tract and damages host cells. In people who are immune compromised (for example, pregnant women, infants, cancer patients, asthma patients, people with pulmonary disease, and many others), the virus can cause viral pneumonia or stress the individual’s system to make them more susceptible to bacterial infections, especially bacterial pneumonia. Both pneumonia types, viral and bacterial, can cause severe disease and sometimes death. […] Influenza type A viruses undergo two major kinds of changes. One is a series of mutations that occurs over time and causes a gradual evolution of the virus. This is called antigenic „drift.” The other kind of change is an abrupt change in the hemagglutinin and/or the neuraminidase proteins. This is called antigenic „shift.” In this case, a new subtype of the virus suddenly emerges.

• #2 Influenza: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/219557-overview

  Major typing of influenza A occurs through identification of both H and N proteins. Seventeen H and nine N types have been identified. All hemagglutinins and neuraminidases infect wild waterfowl, and the various combinations of H and N yield 144 potential subtypes of influenza. […] Because the viral RNA polymerase lacks error-checking mechanisms, the year-to-year antigenic drift is sufficient to ensure that there is a significant susceptible host population each year. However, the segmented genome also has the potential to allow reassortment of genome segments from different strains of influenza in a coinfected host. […] Influenza A is a genetically labile virus, with mutation rates as high as 300 times that of other microbes. Changes in its major functional and antigenic proteins occur by means of two well-described mechanisms: antigenic drift and antigenic shift.

• #2 Influenza Virus (Flu) | BCM

  https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/specific-agents/influenza-virus-flu

  Shifting, or antigenic shift, is an abrupt, major change in the virus, which produces a new combination of the HA and NA proteins. […] The danger occurs when there are two different subtypes of influenza A inside the same cell, and the segments become mixed to create a new virus. […] The most effective way to prevent the widespread infection and high mortality rate that a new influenza virus could inflict upon the human population would be to vaccinate people, so that the human immune system would be prepared to fight off an infection. […] Proteins like NS1 that are involved in pathogenesis are important targets for novel antiviral therapeutics. The goal of this project is to identify cellular proteins that interact with NS1 and play a role in the pathogenesis of avian influenza virus infection.

• #2 Novel Influenza (Flu) A Viruses – Epidemiology

  https://www.vdh.virginia.gov/epidemiology/influenza-flu-in-virginia/novel-variant-and-pandemic-influenza/

  Influenza (flu) viruses constantly change. The changes can happen slowly over time or suddenly. […] Slow changes are called antigenic drift. […] Sudden changes to flu viruses are called antigenic shift. Shift is an abrupt, major change in a flu A virus, resulting in new (or novel) flu viruses that infect humans. […] Novel influenza viruses can originate in animals where they gain the ability to infect and spread to or among humans. […] Human infections with other kinds of influenza A viruses are uncommon. However, human infections and outbreaks have occurred. These have usually occurred after unprotected exposure to sick or dead infected poultry, cattle, swine, or virus-contaminated environments.

• #2 Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-021-00542-7

  Influenza viruses cause annual epidemics and occasional pandemics of respiratory tract infections that produce a wide spectrum of clinical disease severity in humans. […] Both viral and host factors determine the extent and severity of virus-induced lung damage. […] The hosts response to viral infection is necessary for viral clearance but may be deleterious and contribute to severe disease phenotypes. […] 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.

• #2 Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs

  https://www.mdpi.com/2076-0817/13/2/127

  A variety of host factors facilitate and restrict the influenza virus lifecycle at each stage. The host factors that restrict the infection are called host restriction factors or antiviral factors and, broadly, can be of two types: (1) encoded by the interferon-stimulated genes (ISGs) and (2) encoded by the genes that are constitutively expressed or are not stimulated by interferons (non-ISGs). Many host restriction factors in both categories have been identified, some through the latest genetic techniques, such as RNA interference and CRISPR-Cas9, and characterized to restrict influenza virus infection. This review compiles those host restriction factors and summarizes their infection restriction mechanisms. Also, this review identifies any strategies the influenza virus employs to escape the restriction imposed by host restriction factors.

• #2

  https://www.jci.org/articles/view/44947

  Influenza A viruses cause recurrent, seasonal epidemics and occasional global pandemics with devastating levels of morbidity and mortality. The ability of influenza A viruses to adapt to various hosts and undergo reassortment events ensures constant generation of new strains with unpredictable degrees of pathogenicity, transmissibility, and pandemic potential. […] Identification and characterization of influenza A virus virulence determinants may provide insight into genotypic signatures of pathogenicity as well as a more thorough understanding of the factors that give rise to pandemics. […] The pathogenicity of influenza virus is considered multigenic; it is determined by the constellation of genes within a particular influenza virus strain within a specific host. There are, however, particular genetic mutations that can enhance various aspects of the viral life cycle, including virus binding and entry, genome transcription and translation, virion assembly and release, and evasion of innate immune responses. These so-called virulence determinants can contribute to a highly pathogenic phenotype in infected animals.

• #2 Pathogenicity and transmissibility of bovine H5N1 influenza virus | Nature

  https://www.nature.com/articles/s41586-024-07766-6

  Together, our pathogenicity studies in mice and ferrets revealed that (1) HPAI H5N1 derived from lactating dairy cattle may induce severe disease after oral ingestion or respiratory infection; and (2) infection by either the oral or respiratory route can lead to systemic spread of virus to non-respiratory tissues including the eye, mammary gland, teat and/or muscle. […] HPAI H5N1 influenza viruses do not transmit efficiently among mammals. […] The discovery that HPAI H5N1 viruses may acquire the ability to transmit among mammals is a paradigm shift and increases the pandemic potential of these viruses. […] Collectively, our study demonstrates that bovine H5N1 viruses may differ from previously circulating HPAI H5N1 viruses by possessing dual human/avian-type receptor-binding specificity with limited respiratory droplet transmission in ferrets.

• #2 Plasminogen Controls Inflammation and Pathogenesis of Influenza Virus Infections via Fibrinolysis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003229

  Plasminogen plays a deleterious role in lung inflammation, independent of virus replication in the lungs. […] Plasminogen-deficiency protected mice against inflammation induced by A/PR/8/34 and A/Netherlands/602/09 viruses, showing that plasminogen plays a deleterious role in lung inflammation, independent of virus replication in the lungs. […] Fibrinolysis plays a central role in the inflammatory response and the pathogenesis of IAV infections. […] Our findings reveal a previously unrecognized role for fibrinolysis and plasminogen in the pathogenesis of IAV infections. Thus, targeting plasminogen, its conversion into plasmin or regulating fibrinolysis may be a venue for the development of novel intervention strategies for the treatment of severe IAV infections.

• #2 Effect of Prior Influenza A(H1N1)pdm09 Virus Infection on Pathogenesis and Transmission of Human Influenza A(H5N1) Clade 2.3.4.4b Virus in Ferret Model – Volume 31, Number 3—March 2025 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/31/3/24-1489_article

  Moreover, direct-contact transmission was abolished when either the donor or recipient animals had prior H1N1 immunity. […] However, the protective effect of pH1N1 immunity did not extend to the virus with an HA from different phylogenetic group and NA from a distinct subtype, as evidenced by the minimal effect that pH1N1 immunity had on infection and transmission after challenge with a group 2 H7N9 virus. […] Our results showed that prior pH1N1 virus infection more effectively reduced the replication and transmission of H5N1 virus than it did H7N9 virus in a ferret model. […] Those results suggest that pH1N1 virus immunity may confer some level of protection against H5N1 clade 2.3.4.4.b virus in humans.

• #3 Influenza virus-related critical illness: pathophysiology and epidemiology | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2539-x

  Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individuals contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix. […] The primary mechanism of influenza pathophysiology is a result of lung inflammation and compromise caused by direct viral infection of the respiratory epithelium, combined with the effects of lung inflammation caused by immune responses recruited to handle the spreading virus. This inflammation can spread systemically and manifest as a multiorgan failure, but these consequences are generally downstream of lung compromise and severe respiratory distress.

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