The influenza virus, a member of the Orthomyxoviridae family, is responsible for the infectious disease commonly known as the flu. This pathogen causes widespread illness each year, leading to seasonal epidemics globally. The continuous circulation of the virus in human and animal populations also poses the constant threat of occasional, more severe pandemics. Understanding the mechanisms by which this virus functions is necessary to combat its persistent impact on public health.
Anatomy of the Influenza Virus
The influenza virion is an enveloped particle encased in a lipid membrane stolen from the host cell. This viral envelope is studded with protein spikes that dictate the virus’s ability to infect and spread. The viral genetic material is composed of a segmented, negative-sense, single-stranded RNA genome.
Influenza A and B viruses typically contain eight distinct RNA segments, each wrapped in nucleoprotein to form ribonucleoprotein complexes (RNPs). The segmentation of the genome is a defining characteristic that contributes to the virus’s ability to adapt and evolve. The two most prominent surface glycoproteins are Hemagglutinin (HA) and Neuraminidase (NA), which protrude from the lipid envelope.
Hemagglutinin acts as the molecular key, binding the virus to the host cell surface to initiate infection. It specifically targets sialic acid receptors found on the membranes of respiratory epithelial cells. Neuraminidase is a viral enzyme responsible for cleaving these sialic acid bonds. This function enables newly formed viral particles to detach and escape from the infected cell surface, preventing self-aggregation.
A third protein, the M2 ion channel, also traverses the viral envelope. The M2 protein forms a proton-selective channel that is a target for certain antiviral medications. Beneath the envelope lies a layer of Matrix protein (M1), which provides structural stability and links the envelope to the internal RNPs.
Cellular Invasion and Fusion
The infectious cycle begins with the Hemagglutinin protein attaching to the sialic acid receptors on the host cell membrane. The cell then internalizes the entire virion through receptor-mediated endocytosis, enclosing the virus within a membrane-bound vesicle known as an endosome.
As the endosome moves deeper into the cell, proton pumps acidify the vesicle’s interior. This lowering of the pH triggers a conformational change in the bound Hemagglutinin protein. The change causes the HA protein to unfold and expose a fusion peptide, which inserts itself into the endosomal membrane.
Simultaneously, the acidic environment activates the M2 ion channel embedded in the viral envelope. This channel pumps protons from the endosome into the interior of the viral particle. The resulting acidification inside the virion weakens the interaction between the M1 matrix protein and the internal ribonucleoprotein complexes (RNPs). This uncoating mechanism allows the viral RNPs to dissociate from the M1 shell and be released into the cytoplasm following the fusion of the viral and endosomal membranes. The RNPs, containing the viral genome, are then actively transported to the host cell nucleus.
Viral Reproduction Cycle
Upon entering the host cell nucleus, the influenza virus begins its reproductive cycle, a process unique among most negative-sense RNA viruses. The viral RNA-dependent RNA polymerase complex, part of the RNP, initiates transcription of the negative-sense genomic RNA. This transcription uses “cap snatching,” where the viral polymerase steals the 5′ cap from host messenger RNA molecules to prime its own mRNA synthesis.
The resulting viral mRNA is exported to the cytoplasm, where host ribosomes translate it into viral proteins. These proteins include structural components (HA, NA, and M2) and components necessary for further replication (polymerase subunits). The structural proteins are trafficked through the endoplasmic reticulum and Golgi apparatus to the cell membrane for assembly.
In the nucleus, the viral polymerase also synthesizes positive-sense complementary RNA (cRNA) from the genomic RNA template. This cRNA intermediate serves as the template for the synthesis of new, full-length, negative-sense genomic RNA segments. These newly replicated genomic segments are then packaged into RNPs, ready for export from the nucleus.
The progeny RNPs are exported to the cell membrane, where the viral structural proteins have gathered. The M1 protein forms a layer beneath the host membrane, and the eight viral RNPs are incorporated into the budding particle. The virion buds from the host cell membrane, acquiring its new lipid envelope. Finally, the Neuraminidase protein cleaves the sialic acid bonds tethering the new virion to the host cell surface, ensuring the release of the infectious progeny.
Immune System Manipulation
The persistent threat of influenza is largely due to its ability to evade the host immune system through changes in its surface proteins. The virus accomplishes this through two distinct evolutionary processes: antigenic drift and antigenic shift. Antigenic drift involves minor, gradual changes in the Hemagglutinin and Neuraminidase surface proteins.
These changes are caused by point mutations that accumulate during the replication of the viral RNA genome. Because the viral polymerase lacks proofreading ability, it introduces errors frequently, leading to small alterations in the antigenic sites of HA and NA. This allows the virus to escape recognition by existing antibodies produced from previous infections or vaccinations. Antigenic drift is the primary reason why seasonal influenza epidemics occur and why the flu vaccine must be updated annually.
Antigenic shift is an abrupt and major change that results in a completely novel subtype of influenza A virus. This is possible because the segmented influenza genome allows for reassortment. If a host cell is simultaneously infected by two different influenza A strains, the eight RNA segments from each virus can mix and match.
The resulting progeny virions incorporate a new combination of segments, potentially leading to a virus type that has never circulated in the human population. This lack of pre-existing immunity often triggers a pandemic. Antigenic shift is largely restricted to Influenza A viruses because they can infect multiple species, such as birds and pigs, providing a mixing vessel for reassortment.