Antigenic variation is a strategy infectious agents use to alter their surface molecules, thereby avoiding the host’s immune system. Pathogens like viruses, bacteria, and parasites have surface antigens, which are molecules the immune system recognizes to mount a defense. By changing these antigens, a pathogen becomes unrecognizable to immune cells that have “memorized” a previous version. This process allows the pathogen to cause chronic or recurring infections and is why immunity to one infection may not protect against another from the same pathogen.
Fundamental Mechanisms of Antigenic Variation
Pathogens use several genetic strategies for antigenic variation:
- Gene conversion is a process where a pathogen copies DNA from a silent gene into an active expression site. This replaces the current antigen gene with a new version, creating a different surface protein. For example, African trypanosomes possess a library of over 1,000 silent genes, allowing for many potential surface coats.
- Point mutations are small, random changes in the DNA of an antigen-coding gene. The influenza virus undergoes this process, known as antigenic drift. These gradual mutations alter its surface proteins over time, making the immune system’s memory from a previous flu season less effective and leading to new flu strains.
- Transcriptional control, or phase variation, involves turning different antigen genes on or off without altering the DNA sequence. This on-off switching allows a pathogen to rapidly change its surface protein expression, ensuring a part of its population can evade the immune response.
- Site-specific DNA inversions occur when a segment of DNA containing an antigen gene is flipped. This inversion changes which gene is read or how it is read, leading to a different protein. This recombination allows for a rapid and reversible switch between antigenic states.
Examples of Pathogens Utilizing Antigenic Variation
The influenza virus uses both gradual point mutations (antigenic drift) and the reassortment of gene segments (antigenic shift) to create new strains. Human Immunodeficiency Virus (HIV) also has a high mutation rate to constantly change its surface proteins, making it a persistent challenge for the immune system.
Among bacteria, Neisseria gonorrhoeae (gonorrhea) uses gene conversion to alter its pili, preventing the immune system from developing lasting memory. Borrelia burgdorferi (Lyme disease) shuffles its surface lipoprotein genes to create new variants, contributing to the persistent nature of the illness.
Protozoan parasites like Plasmodium falciparum (malaria) express a family of proteins called PfEMP1 on infected red blood cells. By switching which PfEMP1 gene is active, the parasite avoids clearance and maintains a chronic infection. African trypanosomes (sleeping sickness) use a dense coat of variant surface glycoproteins (VSGs) and switch the expressed VSG gene to thrive in the bloodstream.
Consequences for Host Immune Evasion
When the immune system first encounters a pathogen, it produces antibodies and memory cells tailored to its surface antigens, providing long-term immunity. When the pathogen alters these antigens, the existing antibodies and memory cells can no longer bind to and neutralize the invader.
This evasion forces the immune system to mount a new primary response against the novel antigens. This cycle of recognition, response, and pathogen escape leads to waves of infection. The pathogen population rises until the immune system responds, only for a new antigenic variant to emerge and restart the cycle.
The need to constantly respond to new variants can exhaust the immune system and prevent the pathogen’s complete clearance. This leads to chronic infections that persist for years, as the pathogen stays one step ahead of host defenses. This continuous immune activation can also contribute to tissue damage and symptoms of chronic disease.
Difficulties in Developing Vaccines and Treatments
Antigenic variation presents a major obstacle to developing effective vaccines. Most vaccines work by introducing a stable antigen to the immune system to build lasting memory. This approach is ineffective against pathogens that can change their antigens, as a vaccine for one variant will not protect against new ones.
The seasonal influenza vaccine illustrates this challenge. Scientists must predict which strains will be most prevalent each year and create a new vaccine. This is necessary because of the virus’s rapid antigenic drift, which makes previous vaccines less effective. For pathogens with more extensive variation, like HIV or Plasmodium falciparum, creating a broadly protective vaccine is very difficult.
Researchers are exploring new strategies to overcome this. One approach is developing “universal vaccines” that target conserved regions of a pathogen that do not change between variants. Another strategy involves creating multivalent vaccines that include antigens from many different strains to provide broader coverage. These efforts aim to outmaneuver the pathogen’s adaptive capabilities.