Hemagglutinin is a protein found on the surface of certain viruses, most notably influenza. It acts as a bridge, allowing the virus to connect with and enter host cells. Understanding this protein is important for comprehending how these viruses cause infection and how our bodies develop immunity. Its structure and function are central to the recurring challenges posed by viral illnesses like the flu.
What is Hemagglutinin
Hemagglutinin (HA) is a glycoprotein, a protein with attached sugar chains, located on the outer surface of influenza viruses. It is one of the two main surface proteins, alongside neuraminidase (NA), that define influenza A and B viruses. The name “hemagglutinin” originates from its ability to cause red blood cells to clump together in laboratory settings.
The presence of hemagglutinin is fundamental to the virus’s ability to infect host cells. It serves as a molecular “key” that recognizes and binds to specific receptors on the surface of target cells, such as those found in the human respiratory tract. This binding is the initial step, allowing the virus to attach to the host cell.
Anatomy of Hemagglutinin
Hemagglutinin presents as a trimer, composed of three identical protein units forming an elongated, cylindrical shape that extends from the viral surface. Each unit is initially synthesized as a single polypeptide chain (HA0), which host enzymes cleave to become active. This cleavage results in two smaller subunits, HA1 and HA2, linked by a disulfide bond.
The HA1 subunit forms a large globular “head” domain at the outermost tip of the molecule. This head contains the receptor-binding site, responsible for recognizing and attaching to host cells. The HA2 subunit, along with parts of HA1, forms a more conserved “stalk” or stem domain that anchors the protein to the viral membrane. This stalk region is largely alpha-helical, providing a stable core.
How Structure Drives Infection
The precise structure of hemagglutinin directly dictates its role in initiating viral infection. The first step involves the attachment of the influenza virus to a host cell, mediated by the HA1 subunit’s globular head. The receptor-binding site within this head binds to sialic acid molecules, sugar-containing receptors on host cell surfaces, particularly in the upper respiratory tract. This binding allows the virus to adhere to the cell for entry.
Following attachment, the virus is taken into the host cell through endocytosis, enclosed within an endosome. Inside the endosome, the environment becomes acidic (pH 5.0-6.0). This pH change triggers a significant conformational change in the hemagglutinin protein, particularly within the HA2 stalk domain. This rearrangement exposes a hydrophobic “fusion peptide” at the N-terminus of HA2.
The exposed fusion peptide then inserts into the endosomal membrane, bridging the viral and host cell membranes. Subsequent refolding of the HA2 subunit pulls these membranes closer, causing them to fuse. This fusion creates a pore, allowing viral genetic material to enter the host cell’s cytoplasm.
Structural Changes and Immune Challenges
The structure of hemagglutinin, particularly its surface-exposed head domain, constantly changes, challenging the host immune system and vaccine development. Minor mutations in HA genes lead to subtle structural alterations, known as antigenic drift. These changes result in new influenza strains unrecognized by existing antibodies, necessitating annual flu vaccine updates.
Antigenic shift, a more dramatic change, occurs when entirely new combinations of HA (and neuraminidase, NA) proteins emerge, often through the reassortment of genetic material from different influenza virus strains infecting the same cell. This can lead to novel influenza A virus subtypes for which the human population has little to no pre-existing immunity, raising the potential for widespread epidemics or pandemics. There are 18 known HA subtypes (H1-H18) and 11 NA subtypes (N1-N11), with influenza A viruses classified by their specific HA and NA combinations, such as H1N1 or H3N2.
Historically, human influenza pandemics have been caused by H1, H2, and H3 HA subtypes, including the 2009 H1N1 pandemic from swine. Other HA subtypes, like H5 and H7, primarily circulate in avian populations but have caused severe human infections with high mortality rates. This prompts concern about their pandemic potential if they acquire efficient human-to-human transmission. Hemagglutinin’s variability highlights the ongoing challenge influenza viruses pose to immune systems.