A new study by a team of researchers from the

National Emerging Infectious Diseases Laboratories

(NEIDL) of Boston University and Princeton University, in the United States, on the

Covid-19

virus in the lung suggests that there are

11 genes

that define protection against infection, which would answer why some people get sicker than others from

Covid-19

, and, more importantly, could help many avoid the worst symptoms.

Covid-19

vaccines

have saved at least a million lives in the United States alone, but for many people, one lingering fear remains: If, or when, they are hit by the coronavirus, how serious will it be?

Will they get by with little more than a sore throat, or will it saddle them with long-term complications, perhaps even bring them to the brink of death?

Since

SARS-CoV-2

began in early 2020,

COVID-19

has claimed six million lives and counting, according to the

World Health Organization

, which estimates it has directly or indirectly caused more than 15 million death.

And yet, the vast majority of people who have contracted

Covid-19

, around 99 percent of the more than 500 million confirmed cases, have survived their contact with the disease.

So why are some people so severely affected by

Covid-19

when it hardly hurts many?

Age and other health conditions increase the risk of severe illness, but a new study suggests that those who escape the worst symptoms may also have the

right balance of a type of immune cell called macrophages

.

White blood cells found in all tissues, macrophages, part of a group of cells called myeloid cells, the protectors of the immune system, are healers.

They are crucial in wound repair as they are transmitted to an injury to help the body repair itself.

They also attack invaders,

engulfing and digesting anything that doesn't seem to belong in the body

, from dead cells to harmful bacteria.

That mode of attack helps us stay healthy, but it also appears to be a factor in severe cases of

Covid-19

.

Evidence has been mounting that many

Covid-19

deaths are caused by

a hyperimmune response

: rampaging macrophages that attack not only the virus, but also our bodies, causing excessive inflammation and damaging heart and lung tissue.

The study, published in 'Cell Reports, looked at why that was the case and examined the impact of

Covid-19

on who gets dangerously sick and who doesn't.

Studying lungs that seem to easily deflect

SARS-CoV-2

or recover quickly from infection, they found a set of genes that determine whether immune cells mount a robust defense or go rogue and put someone on a ventilator.

The findings could help efforts to develop new drugs that better prepare immune systems to fight the virus.

"If you can understand why most people are protected against

Covid-19

and how their body protects them, then you could harness this knowledge to develop therapies and other advances," explains

Florian Douam

, assistant professor of microbiology at the Faculty of Medicine.

Medicine of the BU that coordinated the study.

Why are some lungs protected against Covid?

After two years of illness and testing, scientists know a lot about how

SARS-CoV-2

is transmitted and how our bodies react when we contract it, but there's also a lot they don't understand.

Take the lungs: We know that

Covid-19

can leave the lungs fluid-filled and inflamed, sometimes scarred by sepsis.

But most of what is known about

Covid-19

in the lungs is based on samples taken from those who died of the disease, not those who survived it.

"The lung is only accessible when the patient dies. Obviously, you can't get someone who had mild disease and say, 'Oh, give me your lung.' Unlike lung autopsy samples from diseased patients, lungs of milder or asymptomatic patients are much more difficult to access. When you have a diseased lung, you get a snapshot of end-stage disease," says Douam, who works at NEIDL.

To overcome this challenge,

Douam

and the research team developed a new model, a mouse grafted with human lung tissue and boosted with a stem cell-derived human immune system, to monitor the different stages of

SARS-CoV-2

infection and

Covid-19

.

19 disease.

Douam says that mice with human lung tissue, but without the human immune system, do not react well to infection: lung tissues are damaged in a similar way to people with a severe case of the disease.

But when they studied mice that also had a humanized immune system, it was different.

"We hardly ever saw viruses in the lungs. The lung was protected. So we asked the question, 'Why is the lung protected?'

And this is where we find the macrophages."

According to Devin Kenney, a doctoral student in Douam's lab and lead author of the latest paper, one feature of the lungs that was most severely affected by

Covid-19

was a lack of macrophage diversity.

They were dominated by a proinflammatory macrophage, the cells that generally respond to viruses and bacteria, called M1.

"It seems to drive this hyperinflammatory response, and it leads to a more severe disease state," explains Kenney (MED'27).

In contrast, immune systems that mixed in more cells that normally aid in wound repair (M2, or regulatory macrophages) fared better.

"If you have a more diverse population of

macrophages

that you have regulatory and inflammatory macrophages, you can more effectively regulate the signals that drive antiviral responses, turning them off when appropriate. Then the immune system can clear the virus very quickly and protect tissue. "

", he points out.

The researchers linked this positive antiviral response to a set of

11 genes they called "protection-defining genes

. "

In cases of effective resistance, these genes worked harder, or what is known as upregulation.

"We now know that macrophages can not only promote protection in lung tissue. We also know the key set of genes that these macrophages need to express to protect the lung," he explains.

What they don't yet know is why some people can put a diverse mix of macrophages to work while others can't.

That is a goal for future studies.

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