During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?
Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.
“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.
Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.
There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.
Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
A genetic quirk
In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.
The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.
The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.
Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.
Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.
Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.