Hemagglutinin is a protein found on the outer surface of several viruses, most notably influenza viruses. It is classified as a glycoprotein, a protein with attached carbohydrate molecules. Its name comes from its ability in lab settings to cause red blood cells to clump together, a process called agglutination. This clumping action, while giving the protein its name, is a side effect of its primary function. These proteins extend from the viral surface like spikes, each one composed of three identical subunits.
The Mechanism of Viral Entry
The main role of hemagglutinin is to allow a virus to gain entry into a host’s cells. This process is often compared to a “lock and key.” In this analogy, the hemagglutinin protein is the “key,” shaped to bind to molecules on our cell surfaces that act as the “lock.” These “locks” are a type of sugar called sialic acid.
When the virus comes into contact with a host cell, such as those lining the respiratory tract, the hemagglutinin “key” binds firmly to the sialic acid “lock.” Once attached, the cell membrane of the host is triggered to envelop the virus, pulling it inside through a process called endocytosis.
Inside the cell, the virus is contained within a compartment called an endosome. The environment within the endosome becomes more acidic, causing the hemagglutinin protein to change its shape. This change exposes a previously hidden part of the protein, which then inserts itself into the endosome’s membrane, fusing the viral envelope with the endosome’s membrane. This fusion creates an opening for the virus to release its genetic material into the cell, hijacking the cell’s machinery to create more copies of itself.
Classifying Influenza Viruses
The hemagglutinin protein is a feature used by scientists to categorize and name different strains of influenza A viruses. There are numerous subtypes of this protein, each with slight structural variations. At least 18 hemagglutinin subtypes have been identified and are designated by a number, such as H1, H5, or H7.
The classification system for influenza also includes another surface protein called neuraminidase (N). Neuraminidase also has multiple subtypes, which are similarly identified by numbers (e.g., N1, N2). The specific combination of a hemagglutinin subtype and a neuraminidase subtype gives an influenza virus its distinct name.
This naming convention, such as H1N1 or H5N1, provides a standard way to identify a specific strain. For example, the H1N1 virus has a type 1 hemagglutinin and a type 1 neuraminidase on its surface. This classification is used for tracking the circulation of different flu viruses globally and understanding their potential to infect different species.
The Target for the Immune System and Vaccines
Located on the exterior of the influenza virus, hemagglutinin is highly visible to the immune system, making it a primary target for the body’s defensive response. When the immune system detects a virus, it produces proteins called antibodies. These antibodies are designed to recognize and bind to specific foreign invaders, known as antigens, and hemagglutinin is a major antigen for the influenza virus.
Antibodies from an influenza infection target the hemagglutinin protein. They function by binding to the head of the HA protein, which is the part that attaches to the host cell’s sialic acid receptors. This action blocks the “key” from fitting into the “lock,” a process known as neutralization.
This interaction is the principle behind seasonal flu vaccines. Flu shots are designed to introduce a harmless form or component of the virus, specifically its hemagglutinin protein, to the immune system. This exposure prompts the body to produce neutralizing antibodies against the HA proteins of the influenza strains predicted to be most common. If a vaccinated person is later exposed to the virus, their immune system is prepared with antibodies to neutralize it.
Viral Evolution and Public Health
Hemagglutinin’s tendency to change over time has consequences for public health, as it allows the influenza virus to evade the human immune system. This evolution occurs through two mechanisms: antigenic drift and antigenic shift.
Antigenic drift refers to the small, gradual mutations in the genes that code for the hemagglutinin protein. These minor changes alter the shape of the HA protein’s head over time. Consequently, antibodies created from a past infection or vaccination may no longer recognize the newer, slightly different version of the virus as effectively. This steady accumulation of changes is the reason why the flu virus varies from one year to the next and why annual vaccination is recommended to keep up with the evolving strains.
A more abrupt change is known as antigenic shift. This event happens when different influenza A viruses, for instance, a strain that infects birds and one that infects humans, infect the same host cell simultaneously. Inside the cell, their genetic material can mix and get re-sorted, potentially creating a virus with a completely novel hemagglutinin subtype that has never circulated in the human population. Because humans would have little to no pre-existing immunity against this new HA protein, the virus can spread rapidly and cause a widespread outbreak, or pandemic.