Feb. 3, 2022 -- It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? 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 City.
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.
Locking Out Illness
"The first step for any intracellular pathogen is getting inside the cell. And if you're missing the doorway, then the virus can't accomplish the first step in its life cycle," Murphy says. "Getting inside is fundamental."
Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.
Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.
The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person's saliva and other body fluids as well as on their red blood cells.
"It didn't matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected," says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.
But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.
"The biggest barrier here is lack of ability to study the virus outside of humans," Lindesmith says.
Noroviruses are very difficult to grow in the lab, "and there's no small animal model of gastrointestinal illness caused by the viruses."
We are clearly making giant strides in improving those skills," says Lindesmith. "But we are just not quite there yet."
In the years before COVID-19 emerged, tuberculosis, or TB, was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.
Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.
"What makes it particularly hard to study is the fact that there is no gold standard to measure infection," she says. "So, what we do is infer infection from two different types of tests" -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.
Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.
The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.
"That always seems to pop up everywhere. But the rest is not so obvious," she says. "A lot of the studies don't find the same thing. It's different in different populations," which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.
COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.
A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.
But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.
The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.
They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.
Their work is inspired by earlier efforts to uncover inborn resistance to infections, Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in "a different epoch," before there were rapid sequencing technologies, Spaan says.
"Now we have modern technologies to do this more systematically."
The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.
"The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years."