Influenza A Virus (IAV)
Enveloped negative-sense segmented ssRNA virus with 8 genome segments encoding 10–14 proteins. Classified by two surface glycoproteins: haemagglutinin (HA; 18 subtypes) mediates receptor binding to sialic acid and endosomal membrane fusion; neuraminidase (NA; 11 subtypes) cleaves sialic acid to release progeny virions and is the target of oseltamivir and zanamivir. The segmented genome enables antigenic shift (segment reassortment between strains), generating novel HA/NA combinations against which the human population has no immunity — the basis of pandemic emergence. Antigenic drift (point mutations in HA/NA under immune selection) drives annual epidemic strain evolution, necessitating yearly vaccine reformulation. NS1 protein is the principal IFN antagonist, binding dsRNA to block RIG-I activation and inhibiting PKR. In severe avian influenza (H5N1) and pandemic strains, NS1-mediated IFN suppression is followed by exuberant cytokine storm driving alveolar damage and ARDS.
Classification & Structure
| Genome | 8 segments of negative-sense single-stranded RNA (~13.5 kb total); each segment encapsidated in ribonucleoprotein (RNP) complex with nucleoprotein (NP) and the RNA polymerase (PB1, PB2, PA); pleomorphic virion shape (spherical to filamentous) |
| Family / Classification | Orthomyxoviridae / Influenzavirus A; classified by HA (H1–H18) and NA (N1–N11) subtypes; current human seasonal strains: H1N1 (re-emerged 2009) and H3N2 (emerged 1968); zoonotic high-risk strains: H5N1, H7N9 |
| Envelope | Enveloped; lipid bilayer derived from host plasma membrane; ~500 HA homotrimers, ~100 NA homotetramers, and ~16–20 M2 ion channel tetramers per virion; M1 matrix protein lines inner envelope face |
| Size | ~80–120 nm diameter (spherical strains); filamentous forms up to several micrometres in fresh clinical isolates |
| Key proteins | HA (receptor binding; membrane fusion; antigenic target; haemagglutination inhibition (HAI) antibody target); NA (sialic acid cleavage; virion release; oseltamivir/zanamivir target); M2 (proton channel; uncoating; amantadine target — now resistance-limited); PB1/PB2/PA (RNA polymerase complex); NS1 (IFN antagonist); PA-X (host mRNA degradation / shutoff); NP (RNA encapsidation); M1 (matrix scaffold); NS2/NEP (nuclear export) |
Infection Mechanism
1 · Sialic acid receptor binding and cell tropism
Influenza A HA binds sialic acid (Sia) residues on host cell glycoproteins and glycolipids. The linkage of sialic acid to the penultimate galactose determines tropism: α-2,6 Sia (predominant in human upper respiratory epithelium — trachea, bronchi) is recognised by human H1N1 and H3N2 — explaining upper respiratory tract tropism and efficient human-to-human transmission. α-2,3 Sia (predominant in avian intestinal epithelium and human lower respiratory tract/alveolar AT2 cells) is recognised by avian H5N1 — explaining lower respiratory tract tropism, inability for efficient droplet transmission, and high-severity pneumonitis. A single amino acid substitution in HA can switch receptor specificity, enabling zoonotic adaptation.
2 · Endocytosis, M2 uncoating, and nuclear replication
After HA binding, IAV is endocytosed into clathrin-coated vesicles. Endosomal acidification (~pH 5.0) triggers two events: (1) HA conformational change exposes the fusion peptide, which inserts into the endosomal membrane, driving viral–endosomal membrane fusion; (2) M2 proton channel allows H³ influx into the virion interior, dissociating the M1–vRNP interaction, releasing vRNPs into the cytoplasm. vRNPs are imported into the nucleus via importin-α/β. The PB1–PB2–PA polymerase complex performs “cap-snatching” — PB2 binds host pre-mRNA caps while PA endonuclease cleaves the host mRNA 10–13 nt downstream — to prime viral mRNA synthesis. Eight viral mRNA species are produced; replication proceeds via cRNA antigenome intermediates.
3 · NS1 protein — primary interferon antagonist
NS1 is a multifunctional IFN antagonist central to immune evasion: it binds dsRNA (replication intermediates) directly, preventing RIG-I recognition and IRF3 phosphorylation, thereby blocking IFN-β induction; it binds and inactivates PKR (protein kinase R), preventing eIF2α phosphorylation and translational shutdown; it sequesters CPSF30 (cleavage and polyadenylation specificity factor), inhibiting 3′-end processing of cellular antiviral mRNAs. PA-X (alternative reading frame product of PA segment) degrades host mRNAs including antiviral transcripts (host shutoff). Together NS1 and PA-X create a permissive intracellular environment for viral replication.
4 · Antigenic drift and shift — immune evasion at the population level
Antigenic drift: IAV RdRp lacks proofreading (~10−³ errors/site/cycle); point mutations accumulate in HA and NA under antibody selection pressure, gradually altering antigenic surface epitopes. This continuous antigenic evolution means prior season’s antibodies become partially or fully non-protective — driving annual epidemic recurrence and necessitating yearly vaccine strain updates by the WHO Global Influenza Surveillance and Response System (GISRS). Antigenic shift: when two distinct IAV strains simultaneously infect the same cell (e.g., human and avian IAV in a pig), the 8 segments can reassort into novel combinations. If the resulting reassortant carries a novel HA (e.g., H2 or H3 in 1968) or NA subtype to which humans have no pre-existing immunity, pandemic emergence is possible. The 2009 H1N1pdm was a quadruple reassortant (human, avian, and two swine lineage segments).
5 · Virion assembly, budding, and NA-mediated release
New vRNPs export from the nucleus via NEP/NS2 in complex with M1. vRNPs traffic to the apical plasma membrane of polarised respiratory epithelial cells, guided by M1 and HA/NA membrane targeting signals. Segment packaging ensures incorporation of all 8 distinct vRNPs via specific packaging signals. Virions bud from the apical surface. NA cleaves sialic acid on newly released virions (which would otherwise re-attach to adjacent HA molecules on the same cell), enabling efficient spread. Oseltamivir (Tamiflu) and zanamivir (Relenza) competitively inhibit NA active site; H274Y (N1 numbering) is the primary oseltamivir resistance mutation, retaining zanamivir sensitivity.
Host Immune Response
Disease Spectrum
| Severity | Presentation | Pathology | Notes |
|---|---|---|---|
| Uncomplicated influenza (most common) | Abrupt onset fever (38–40°C), myalgia, headache, cough, rhinorrhoea, sore throat; 5–7 days duration | Tracheobronchitis; no parenchymal involvement; ciliated epithelial cell destruction | Infectious 1 day before symptoms to 5–7 days after onset |
| Primary viral pneumonia | Bilateral infiltrates, rapid progression, hypoxaemia; high fever; dyspnoea within 24–48 h | Diffuse alveolar damage: AT1 and AT2 cell death, hyaline membranes, alveolar haemorrhage | High-risk groups: elderly, pregnant, immunocompromised, cardiopulmonary disease |
| Secondary bacterial pneumonia | Clinical improvement followed by recurrence of fever and focal consolidation at days 5–10 | Focal bacterial pneumonia; S. aureus (including MRSA), S. pneumoniae, H. influenzae most common | High mortality; IAV-induced ciliary clearance loss + immune suppression predispose |
| ARDS | PaO₂/FiO₂ <200, bilateral infiltrates, rapid ventilatory failure | Extensive DAD; macrophage/neutrophil infiltration; flooding of alveolar space | ICU care required; mechanical ventilation; ECMO in refractory cases |
| Pandemic / avian strain (H5N1, 1918) | Often young adults; cytokine storm; multi-organ failure; W-shaped mortality curve (young adults, elderly, infants) in 1918 | Extensive bilateral pneumonitis; cytokine-driven DAD; lymphocyte apoptosis; α-2,3 Sia tropism drives lower respiratory tract tropism | Case fatality rate ~60% for H5N1 hospitalised cases; 50–100M deaths in 1918 |
Treatment & Prevention
| Oseltamivir (Tamiflu) | NA inhibitor; oral prodrug (phosphate); reduces symptom duration by ~1 day in uncomplicated influenza; reduces hospitalisations in high-risk groups when started within 48 h of symptom onset; H274Y (N1) mutation confers resistance while retaining zanamivir sensitivity |
| Zanamivir (Relenza) | NA inhibitor; inhaled powder; active against oseltamivir-resistant H274Y strains; less convenient route limits use; IV zanamivir available for severe hospitalised cases |
| Baloxavir marboxil (Xofluza) | Cap-dependent endonuclease (PA) inhibitor; single oral dose; blocks cap-snatching; I38T/M mutations in PA confer resistance; active against oseltamivir-resistant strains; approved for uncomplicated and high-risk influenza |
| Inactivated influenza vaccine (IIV) | Annually reformulated based on WHO GISRS strain selection to match predicted circulating strains; trivalent (2A + 1B) or quadrivalent (2A + 2B); adjuvanted for elderly (MF59, AS03); ~40–60% efficacy in well-matched seasons; standard recommendation for healthcare workers and high-risk groups |
| Live-attenuated influenza vaccine (LAIV) | Intranasal; cold-adapted temperature-sensitive strains; induces mucosal IgA and cellular immunity; approved for healthy non-pregnant individuals aged 2–49; preferred in some paediatric programmes; higher efficacy in children than IIV in some studies |
| mRNA influenza vaccines (pipeline) | mRNA-based seasonal and pandemic influenza vaccines (Moderna, Pfizer/BioNTech) in Phase 2–3 trials; potential for faster strain-matched production; head-to-head trials versus standard IIV ongoing |
Cross-Atlas Connections
References
- Palese P. Influenza: old and new threats. Nat Med. 2004;10(12 Suppl):S82-7. doi:10.1038/nm1141 · PubMed 15577936
- Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev. 1992;56(1):152-79. doi:10.1128/mr.56.1.152-179.1992 · PubMed 1579108
- Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis. 2006;12(1):15-22. doi:10.3201/eid1201.050979 · PubMed 16494711
- World Health Organization. Influenza (seasonal) Fact Sheet. WHO; 2023. who.int/news-room/fact-sheets/detail/influenza-(seasonal)
Contribute to the Pathogen Atlas
This entry covers IAV structure, sialic acid tropism, NS1 immune evasion, antigenic variation, and treatment. Avian H5N1 / H7N9 pandemic risk assessment, universal influenza vaccine targets (HA stalk, M2e, NP), and baloxavir resistance mechanisms are planned expansions. Every entry follows the same schema: structured frontmatter, peer-reviewed citations, and cross-atlas links.