Viruses are microscopic agents that must enter a host cell to replicate. This entry is governed by a specific interaction, often described using a “lock and key” analogy, where a protein on the virus’s surface acts as a “key” shaped to fit a specific receptor protein—the “lock”—on a human cell. Unless this key fits the lock, the virus cannot get inside.
The scientific process of identifying which cellular locks a virus uses is known as viral receptor mapping. Pinpointing this molecular doorway is the first step in understanding an infection and provides a clear target for medical intervention.
The Mechanism of Viral Entry
The entry of a virus into a host cell begins when a protein on its outer layer, like the Spike protein of coronaviruses, binds to a receptor on a human cell. For SARS-CoV-2, the virus that causes COVID-19, this receptor is angiotensin-converting enzyme 2 (ACE2). This binding is a highly specific attachment that initiates the infection process.
Once attached, the binding event triggers changes in the cell’s membrane. The membrane may fold inward to engulf the virus in a process called endocytosis, or it can fuse directly with the viral envelope. Either action allows the virus to deliver its genetic material into the cell, where it hijacks the cellular machinery to produce thousands of new viral copies.
This need for a specific receptor explains viral “tropism”—the tendency of a virus to infect only certain cell types. For example, respiratory viruses primarily infect cells in the lungs and airways because those cells are rich in the required receptors. The distribution of these receptors throughout the body dictates the pattern of infection and the resulting symptoms.
Methods for Identifying Viral Receptors
One powerful method is the CRISPR-based genetic screen. Researchers use the CRISPR-Cas9 gene-editing tool to systematically turn off, or “knock out,” one gene at a time across millions of host cells. This creates a vast library of cells, with each one missing a different gene. This population of cells is then exposed to the virus.
Most cells, still having the necessary receptor, are infected and die. However, cells that had the specific receptor gene knocked out survive because the virus cannot infect them. By sequencing the genes of these survivors, scientists can identify which gene was turned off, thereby revealing the receptor’s identity.
Another widely used technique is Affinity Purification-Mass Spectrometry (AP-MS), which acts as a molecular “fishing” expedition. In this method, scientists use the virus’s surface protein as “bait” and mix it with all the proteins from a host cell. The viral bait will only bind to its specific partner, the receptor protein.
Scientists then “pull” the bait out of the mixture, bringing the attached receptor with it. The captured protein is then identified using mass spectrometry, which determines its precise molecular composition. This method was used to identify dipeptidyl peptidase 4 (DPP4) as the receptor for MERS-CoV.
An older method uses genomic libraries. In this approach, scientists introduce individual human genes one by one into cells that a virus cannot normally infect. If a specific gene makes the cell susceptible to infection, that gene is identified as coding for the receptor protein.
Applications in Drug and Vaccine Development
Identifying a viral receptor has direct applications in developing antiviral drugs. Once the specific “lock” is known, a primary strategy is to develop “receptor blockers.” These are small-molecule drugs designed to fit into the receptor protein on the host cell, effectively plugging the lock so the virus’s key cannot gain entry. This approach is exemplified by the drug Maraviroc, which blocks the CCR5 receptor on human T-cells, preventing HIV from using it to infect these immune cells.
Another application is the development of therapeutic antibodies. These lab-engineered antibodies target and bind to the virus’s surface protein. By coating the viral “key,” these antibodies prevent it from interacting with the host cell’s receptor, neutralizing the virus. This strategy has been used to create treatments for COVID-19, where monoclonal antibodies targeting the Spike protein can reduce viral load in patients.
Receptor knowledge is also foundational to modern vaccine design. Many of today’s vaccines, including the mRNA vaccines for COVID-19, work by teaching the immune system to recognize the virus’s surface protein. The vaccines deliver instructions that cause our own cells to produce a harmless version of this protein, such as the SARS-CoV-2 Spike protein. The immune system then generates antibodies, preparing it to block the actual virus from binding to its receptors during a future infection.
Preparing for Future Viral Threats
Technologies from viral receptor mapping are being used to proactively prepare for future viral threats. Scientists are working to create a comprehensive “atlas” of all proteins on the surface of human cells that could be used as viral receptors. This initiative aims to identify the likely doorways that new viruses could exploit before they emerge.
This receptor atlas is a form of preparedness for “Virus X”—a placeholder for a novel, unknown pathogen with pandemic potential. By understanding the landscape of potential receptors, scientists can respond much faster when a new virus appears. If a new virus’s surface protein is similar to a known one, researchers can immediately test if it uses the same receptor, accelerating research.
Methods like CRISPR screens are also being developed into rapid-response platforms. When a new pathogen is isolated, these technologies can be deployed to find its receptor in weeks or months, not years. This rapid identification shortens the timeline for developing countermeasures like drugs and vaccines. Building this foundational knowledge and technology helps the scientific community prepare to neutralize future pandemic threats.