Could disabling one protein cure the common cold? | Science News for Students

Could disabling one protein cure the common cold?

Cold viruses don’t reproduce in mice and human cells lacking this protein
Oct 29, 2019 — 6:45 am EST
rhinoviruses

Rhinoviruses (shown in this drawing) are behind most cases of the common cold. New research suggests a way to stop them, and others, from spreading in people.

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Scientists may be one step closer to a cure for the common cold. They aren’t fighting the viruses that cause the infection. Instead they’re looking to make human cells — the hotel rooms in which viruses reproduce — an unwelcome place.

Viruses can’t reproduce on their own. They must hijack the machinery in cells to do that. So they temporarily infect those cells to make more of themselves. Then they explode open their host cell. This releases huge quantities of new infectious viruses.

Researchers have now identified a key protein that some viruses need to multiply inside human cells. Disabling that protein might stop a cold virus dead in its tracks. Or that’s the idea described September 16 in Nature Microbiology. Jan Carette is a microbiologist in California at the Stanford University School of Medicine. His team has just shown that in mice and human cells engineered to lack this protein, the viruses couldn’t replicate. No replication, no spread.

“It’s not quite a cure for the common cold,” says Ellen Foxman. She’s an immunologist at Yale School of Medicine in New Haven, Conn., who was not involved in the study. Still, she finds, the new work is “an interesting step forward.”

Colds are our most common infectious disease. On average, adults catch two or three  each year. Children may get even more. Any one of a few hundred viruses, including rhinoviruses (RY-no-vy-russ-es), can cause these infections. That’s one thing that has made it so hard to find a cure for the cold. But there’s a second challenge, too. These viruses mutate — undergo spontaneous genetic changes — quickly. One or more of those changes may eventually leave them able to resist almost any drug thrown at them.

That’s why Carette’s group focused on the human host. The team wanted to see if it could identify the human proteins that many viruses use to replicate. Genes make a cell’s proteins. So these researchers hunted down the gene behind the protein that viruses take over.

Carette and his colleagues started by using a molecular scissor — the gene-editing tool CRISPR — to systematically snip out chunks of DNA from human cells growing in lab dishes. In the process, they built a library of altered cells, each one missing a single protein-making gene. The researchers then infected these altered cells with two types of viruses. One type causes colds. The other has been linked to nerve-related diseases.

Then the scientists used different viral proteins like hooks. They dipped them into the stuff inside human cells to see which proteins these viral hooks latched onto and pulled out. That let the team identify which human proteins were interacting with viral ones. This was a sign that the virus needed those human proteins to hijack a cell’s replicating machinery.

The viruses repeatedly fished out one particular protein. Known as SETD3, tests showed that the viruses needed it to take over a cell. Scientists knew this protein could affect actin proteins — ones that help muscles contract. That it might also aid viral infections came as a big surprise.

Tests show the anti-viral tactic has promise

To test the importance of SETD3, the researchers injected viruses into mice that had been engineered to lack a working version of that gene. And sure enough, no mice got sick. Human lung cells that also lacked the gene also remained healthy. (Lung cells are often used in these types of studies because they are especially susceptible to many cold-triggering rhinoviruses.)

Especially exciting: Running similar tests with other, potentially more serious, viruses suggested the approach may thwart more than just the common cold.

Engineered human cells didn’t become infected when they were exposed to viruses that cause hand, foot and mouth disease and a polio-like spinal-cord disease called acute flaccid myelitis (Flaa-sid My-eh-LY-tis). And when mice were exposed to these viruses, the rodents without a working SETD3 gene were much more likely to survive than those with a working gene.

“We have identified an excellent target,” says Carette, of SETD3. Still, it’s not clear whether disabling that gene and its protein might cause new problems. The engineered mice survived, appeared healthy and were fertile. They could not, however, push their pups out of the womb during birth. Says Carette, this might be due to the protein’s role in muscle contractions.

Scientists don’t fully understand what this gene does in people, so getting rid of it might have some nasty side-effects, notes Vincent Racaniello. He’s a virus expert at Columbia University in New York City who wasn’t involved in the work. “The authors show that mice lacking the gene for SETD3 are viable and resistant to infection. However,” he says, “this observation does not mean that SETD3 in humans is [not needed].”

Instead, the researchers think their best bet is to search for a drug that makes it seem like the gene isn’t working. The drug might block the human protein and its viral counterparts from interacting. Or, it might destroy the SETD3 protein — but only when it is interacting with the viruses.

Such drugs are still a long way off. “The question is always ‘When can I buy it over the counter?’” Carette says. The challenge, he notes: “Drug development takes time.”

Power Words

(more about Power Words)

actin     A protein that can form long chains in cells. In muscle cells, these chains help the muscle contract. Actin chains also help cells move.

acute     An adjective to describe conditions, such as an illness (or its symptoms, including pain), that typically are short in duration but severe.

acute flaccid myelitis     An illness first identified in 2014. It triggers an inflammation of the spinal cord, damaging nerves that run through it. This weakens or paralyzes muscles in the arms and/or legs. The condition most often afflicts children.

average     (in science) A term for the arithmetic mean, which is the sum of a group of numbers that is then divided by the size of the group.

cell     The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

colleague     Someone who works with another; a co-worker or team member.

contract     To activate muscle by allowing filaments in the muscle cells to connect. The muscle becomes more rigid as a result.

CRISPR     An abbreviation — pronounced crisper — for the term “clustered regularly interspaced short palindromic repeats.” These are pieces of RNA, an information-carrying molecule. They are copied from the genetic material of viruses that infect bacteria. When a bacterium encounters a virus that it was previously exposed to, it produces an RNA copy of the CRISPR that contains that virus’ genetic information. The RNA then guides an enzyme, called Cas9, to cut up the virus and make it harmless. Scientists are now building their own versions of CRISPR RNAs. These lab-made RNAs guide the enzyme to cut specific genes in other organisms. Scientists use them, like a genetic scissors, to edit — or alter — specific genes so that they can then study how the gene works, repair damage to broken genes, insert new genes or disable harmful ones.

development     (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape.

DNA     (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. It is built on a backbone of phosphorus, oxygen, and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

fertile     Old enough and able to reproduce.

flaccid     Weak or limp; lacking strength.

foot and mouth disease     Sometimes known as hoof and mouth disease, it’s a highly contagious viral disease that affects cattle and a number of other livestock species (such as sheep and goats) and deer. Affected animals develop fevers and blisters around the mouth, tongue, hooves and mammary glands. They find it hard to eat, so they lose weaken and lose weight. Pregnant animals may abort their fetuses or give birth to stillborn young. The virus can persist in the breath, saliva, urine and other things excreted by infected animals. Once in the environment (such as soil or barn surfaces), it can persist for up to months.

gene     (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

genetic     Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.

host      (in biology and medicine) The organism (or environment) in which some other thing resides. Humans may be a temporary host for food-poisoning germs or other infective agents.

immunologist     A doctor or scientist who works in the field of biomedicine that deals with the immune system.

infect     (adj. infectious) To spread a disease from one organism to another. This usually involves introducing some sort of disease-causing germ to an individual.

infection     A disease that can spread from one organism to another. It’s usually caused by some type of germ.

microbiology     The study of microorganisms, principally bacteria, fungi and viruses. Scientists who study microbes and the infections they can cause or ways that they can interact with their environment are known as microbiologists.

muscle     A type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in protein, which is why predatory species seek prey containing lots of this tissue.

nerve     A long, delicate fiber that transmits signals across the body of an animal. An animal’s backbone contains many nerves, some of which control the movement of its legs or fins, and some of which convey sensations such as hot, cold or pain.

polio     An infectious viral disease that affects the central nervous system and can cause temporary or permanent paralysis.

protein     A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.

pup     A term given to the young of many animals, from dogs and mice to seals.

replicate     (in biology) To copy something. When viruses make new copies of themselves — essentially reproducing — this process is called replication.

rhinovirus     One of the most common viruses that causes the common cold.

rodent     A mammal of the order Rodentia, a group that includes mice, rats, squirrels, guinea pigs, hamsters and porcupines.

tactic     An action or plan of action to accomplish a particular feat.

viable     Able to live and survive. (in biology) Able to survive and/or live a normal lifespan. (in engineering) Something that should work or operate according to plan, as in a “viable concept.”

virus     Tiny infectious particles consisting of RNA or DNA surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as live or dead, in fact no virus is truly alive. It doesn’t eat like animals do, or make its own food the way plants do. It must hijack the cellular machinery of a living cell in order to survive.

womb     Another name for the uterus, the organ in mammals in which a fetus grows and matures in preparation for birth.

Citation

Journal:​ ​​ J. Diep et al. Enterovirus pathogenesis requires the host methyltransferase SETD3. Nature Microbiology. Published online September 16, 2019. doi:10.1038/s41564-019-0551-1.