Pathogenicity and virulence of influenza

Abstract

Influenza viruses, including four major types (A, B, C, and D), can cause mild-to-severe and lethal diseases in humans and animals. Influenza viruses evolve rapidly through antigenic drift (mutation) and shift (reassortment of the segmented viral genome). New variants, strains, and subtypes have emerged frequently, causing epidemic, zoonotic, and pandemic infections, despite currently available vaccines and antiviral drugs. In recent years, avian influenza viruses, such as H5 and H7 subtypes, have caused hundreds to thousands of zoonotic infections in humans with high case fatality rates. The likelihood of these animal influenza viruses acquiring airborne transmission in humans through viral evolution poses great concern for the next pandemic. Severe influenza viral disease is caused by both direct viral cytopathic effects and exacerbated host immune response against high viral loads. Studies have identified various mutations in viral genes that increase viral replication and transmission, alter tissue tropism or species specificity, and evade antivirals or pre-existing immunity. 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. This review summarizes the current knowledge on viral determinants of influenza virulence and pathogenicity, protective and immunopathogenic aspects of host innate and adaptive immune responses, and antiviral and pro-viral roles of host factors and cellular signalling pathways. 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.

Keywords: host factors; immune responses; influenza virus; pathogenesis; virulence; virus-host interactions.

Figure 1.

Illustration of influenza virion components, genomic organization, and viral genes. (a) Influenza virus is an enveloped RNA virus, which has 3 envelope proteins (HA, NA, and M2) on the viral membrane, an M1-formed matrix layer, and eight vRnps. (b) Each vRNP consists of one vRNA segment wrapped with NP and associated with polymerase complex PB2/PB1/PA. (c) Each vRNA segment encodes 1–3 genes, through alternative splicing (NS2/NEP and M2) and frameshifting (such as PA-X and PB1-F2). Accessory proteins expressed through frameshifting are shown as filled dark green bars/boxes.

Figure 2.

Influenza virus evolution. Almost all IAV subtypes (H1 to H16, N1 to N9) have natural hosts in water birds, of which some have established infections in other species, such as H1N1, H2N2, and H3N2 in humans and pigs. Human influenza viruses have changed over the years mainly due to the emergence of four pandemic flu viruses. Currently, circulating influenza viruses include two IAV subtypes H1N1 and H3N2, and two IBV lineages (B/Yamagata and B/Victoria). Some animal IAVs, particularly bird and swine flu, can occasionally spill over to cause zoonotic infections in humans. In recent years, avian H5 and H7 viruses caused human infections with a high case fatality rate.

Figure 3.

Pro-viral host factors and host signalling pathways important for influenza viral replication. Host factors and cellular signalling pathways are hijacked by the influenza virus to promote viral replication at different steps of the viral life cycle. Host factors are listed inside light green boxes next to the specific step of viral replication. Receptor tyrosine kinases (EGFR, c-Met, TrkA) on plasma membranes are activated by influenza viral infection and function to promote viral replication. EGFR, c-Met, and PLC-γ1 enhance viral uptake. TrkA signalling is important for several steps of the viral life cycle: viral RNA synthesis, vRNP nuclear export, and viral budding and release. NF-κB signalling enhances viral RNA synthesis and induces the expression of proinflammatory genes. PI3K/Akt and Raf/MEK/ERK pathways also strongly increase viral replication.