February 3, 2022 – The great mystery of infectious disease: Why are some people not seemingly affected by a disease that harms others? During COVID-19 pandemic, we saw this show over and over again when whole families got sick except one or two happy family members. And at so-called superspreader events that infect many, a few lucky ones usually go intact. Has the virus never entered their bodies? Or do some people have a natural resistance to pathogens they have never been exposed to before that are encoded in their genes?
Resistance to infectious diseases is much more than scientific curiosity, and studying how it works can be a way to combat future outbreaks.
“In case we can identify what makes some people resilient, it immediately opens the way for therapies we could apply to all those people suffering from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York. York City.
Spaan is part of an international effort to identify genetic variations that save people from infection SARS-CoV-2, the virus that causes COVID-19.
There is much more research on what triggers the susceptibility to infectious diseases than on resistance to them. But several researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases they have already translated those insights into treatments.
Perhaps the strongest example of how unusual genes can trigger treatments that will help many comes from research into the human immunodeficiency virus (HIV), a virus that causes acquired immune deficiency syndrome (AIDS).
In the mid-1990s, several groups of researchers independently identified a mutation in the so-called gene CCR5 associated with resistance to HIV infection.
The gene encodes a protein on the surface of some white blood cells that helps establish the movement of other immune cells to fight infections. Meanwhile, HIV benefits CCR5 a protein that will help it get into white blood cells to infect.
The mutation, known as delta 32, results in a shorter-than-normal protein that does not reach the cell surface. People wearing two copies of the delta shape 32 CCR5 I don’t 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 1997 that people with two copies of the mutation were unusually common among a group of men who were at particularly high risk of exposure to HIV but never contracted the virus. And of the more than 700 HIV-positive people, none wore two copies CCR5 delta 32.
Pharmaceutical companies have used these insights to develop blocking drugs CCR5 and delay the development of AIDS. For example, medicine maraviroksold by Pfizer, was approved for use in HIV-positive people in 2007.
So far, only a few examples of this type of innate, genetically determined complete resistance to infection have been heard. They all include molecules on the cell surface that are believed to help a virus or other pathogen enter the cell.
“The first step for any intracellular pathogen is to enter the cell. And if you miss the door, then the virus can’t reach the first step in its life cycle,” says Murphy. “Getting inside is fundamental.”
Changes in molecules on the cell surface can also increase the likelihood that someone will have an infection or severe illness. One such group of molecules on the cell surface that is associated with increasing and decreasing the risk of various infections are histo-blood group antigens. The best known members of this group are the molecules that define blood groups A, B and O.
Scientists have also identified one example of complete resistance to infection involving these molecules. Researchers in 2003 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 norovirus families that cause diseases of the digestive tract.
Gene FUT2 encodes an enzyme that determines whether blood group antigens are found in a person 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 didn’t have that first enzyme, they didn’t get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina at Chapel Hill.
Norwalk is a relatively rare species of norovirus. But FUT2 the deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have occasionally spread around the world over the last quarter of a century. These diseases are particularly severe in children in developing countries, causing malnutrition and contributing children’s and the death of children.
But progress in translating this knowledge of genetic resistance into drugs or other things that could reduce the burden of norovirus has been slow.
“The biggest hurdle here is the lack of ability to study viruses outside of humans,” says Lindesmith.
Noroviruses are very difficult to grow in the laboratory, “and there is no small animal model of gastrointestinal disease caused by viruses.”
It’s clear we’re taking huge steps to improve those skills, “says Lindesmith.” But we’re just not quite there yet. “
In the years before the advent of COVID-19, tuberculosis, or TB, is responsible for the largest number of annual deaths in the world from infectious diseases. It is a lung disease caused by bacteria Mycobacterium tuberculosisand it has been a pandemic for thousands of years.
Some 85% -95% of people with an intact immune system who are infected with tuberculosis control the infection and never get active lung disease. And some people who are intensely, continuously exposed to the bacterium, which is spread by droplets and aerosols from people with active lung disease, apparently never become infected at all.
Understanding the ways 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 difficult to study is the fact that there is no gold standard for measuring infection,” she says. “So what we’re doing is a conclusion about an infection from two different types of tests” – a skin test and a blood test that measure different types of immune responses to bacteria molecules.
Kroon and other researchers studied resistance to infection by monitoring people living in the same household with those with active lung disease or people living and working in overcrowded conditions in high-risk communities. But not all such studies they used the same definition of so-called resistors, documented exposure in the same way, or monitored to ensure that people continued with a negative test over the long term.
The best clue that has emerged from previous studies resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Dr. Marlo Möller, a professor in the TB Host Genetics Research Group at Stellenbosch University.
“It always seems to appear everywhere. But the rest is not so obvious,” she says. “Many studies don’t find the same thing. It’s different in different populations,” which may be the result of a 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 contagious disease, but teasing how it contributes to both severe disease and resistance to infection remains a major challenge.
Early in the pandemic, research from The human genetic effort of COVID, an international consortium of which Spaan is a part, linked COVID-19 severe pneumonia to a lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy those molecules. Together, these mechanisms explain approximately one-fifth of the severe cases of COVID-19, scientists say reported in 2021.
Several studies of other groups have investigated resistance to COVID-19 infection, suggesting that the reduced risk of virus infection is related to certain blood group factors. People with blood type O appear to be at a slightly reduced risk of infection, for example.
But studies to date have been designed to find common genetic variations, which generally have little effect on resistance. Now genetic researchers are starting effort identify factors of genetic resistance with great effect, even if they are very rare.
The group recruits people who did not become infected with COVID-19 despite high exposure, such as those living in households where all other members became ill or people who were exposed to a super-spread event but did not become ill. As with tuberculosis, being sure someone is not infected with the virus can be inconvenient, but the team uses several blood tests to find people who are most likely to have escaped the infection.
They plan to sequence the genomes of these people to identify things that strongly affect the risk of infection, and then conduct more laboratory studies to try to discover the means of resistance.
Their work is inspired by earlier efforts to detect innate resistance to infections, Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. These earlier efforts occurred in the “second era,” before rapid sequencing technologies existed, Spaan says.
“Now we have modern technology to do it more systematically.”
The emergence of viral variants such as Delta and Omicron COVID strains raises the stakes in the work, he continues.
“The need to unravel these innate COVID resistance mechanisms has become even more important because of these new variants and the expectation that we will have COVID with us for years to come.”