Influenza is an acute respiratory illness caused by infection with an influenza virus. These viruses are categorized into three main types—A, B, and C—with Type A and B responsible for the annual epidemics that affect humans. The disease begins when the virus enters the body and targets specific host cells within the respiratory system to initiate replication. Understanding which cells the virus infects reveals the biological mechanisms that lead to the characteristic symptoms and potential complications of the flu.
The Molecular Gateway to Infection
The influenza virus particle is enveloped and studded with two primary glycoproteins: Hemagglutinin (HA) and Neuraminidase (NA). Infection is initiated when HA binds to specific sugar molecules on the surface of host cells called sialic acid receptors. Human-adapted influenza strains, such as seasonal H1N1 and H3N2, preferentially bind to sialic acid linked via an alpha 2,6 linkage, which dictates their cellular preference within the respiratory tract.
Once HA is attached to the sialic acid receptor, the host cell internalizes the virus through endocytosis. Inside the cell, the virus sheds its outer layer, releasing its genetic material to take over the cell’s machinery. Neuraminidase (NA) plays a role later in the infection cycle by cleaving the sialic acid receptors.
This enzyme activity prevents newly formed virus particles from sticking to the infected cell or aggregating. By cleaving the sialic acid, NA ensures the release of viral progeny, allowing them to spread and infect neighboring cells. The balance between the binding activity of HA and the cleaving activity of NA is necessary for successful viral replication and spread.
Primary Cellular Targets in the Respiratory Tract
The primary cellular targets of influenza infection are the epithelial cells lining the entire respiratory tract, from the nose down to the bronchi. These cells are targeted because they possess a high density of the alpha 2,6-linked sialic acid receptors preferred by human influenza strains. Infection of these cells directly causes the initial respiratory symptoms of the flu.
The most heavily targeted cells are the ciliated epithelial cells, which are responsible for the sweeping motion of the mucociliary escalator. When the influenza virus infects and destroys these cells, the natural defense mechanism of the airways is impaired. The loss of ciliated function leads to a buildup of mucus and cellular debris, contributing to symptoms like coughing and congestion.
Goblet cells, which produce the protective mucus layer, can also be infected. While human strains prefer ciliated cells, avian strains often prefer the alpha 2,3-linked sialic acid, found more abundantly on goblet cells and in the lower respiratory tract. Infection of these cells can disrupt mucus production, further compromising airway defense.
The underlying layer of the respiratory epithelium contains basal cells, which function as progenitor cells for other epithelial types. These basal cells are often spared from infection, which is important for the repair and regeneration of the damaged ciliated and goblet cell layers after the infection is cleared. The sparing of the basal cells explains why the respiratory epithelium is able to recover following a typical influenza infection.
Beyond the Airways: Systemic and Secondary Cellular Involvement
While upper airway epithelial cells are the main site of initial infection, the virus can also target cells deeper in the lungs or cause systemic effects in severe cases. In the lower respiratory tract, the virus can infect alveolar cells, specifically Type II pneumocytes, which produce surfactant and regenerate the alveolar lining. Infection of these cells, which often express the alpha 2,3-linked sialic acid preferred by pathogenic strains, can lead to viral pneumonia.
The immune system’s cells can become involved, either by direct infection or functional impairment. Alveolar macrophages are sentinel immune cells in the lungs that attempt to engulf and clear the virus. Influenza infection can impair their ability to function, which increases the host’s vulnerability to secondary bacterial infections.
In severe infections, the virus can also affect the endothelial cells lining the blood vessels. Although influenza rarely establishes a productive infection in these cells, their interaction with the virus or infected epithelial cells can trigger a release of pro-inflammatory signaling molecules. This intense inflammatory response, sometimes called a “cytokine storm,” contributes to systemic symptoms and tissue damage. Damage to the primary epithelial barrier also provides an opportunity for secondary bacterial pathogens, such as Streptococcus pneumoniae, to invade compromised tissues and cause bacterial pneumonia.