One of the tragic ironies of disease-causing infections is that, in many cases, it’s not the offending virus or bacteria that kills. At least not directly. It’s the immune system’s response to a pathogen — or, more accurately, its over-response — that ultimately causes internal destruction and death.

The novel coronavirus seems to play by these rules. One of the defining features of life-threatening and life-ending Covid-19 disease is the now-infamous “cytokine storm,” a surge of inflammation-summoning molecules that, in an attempt to eradicate the infection, ends up mutilating the tissues of the lungs, heart, kidneys, or other organs. Like burning down a house to rid it of rats, the immune system’s remedy can be worse than the threat.

So far, SARS-CoV-2 has sickened more than 30 million people worldwide. Its death toll has exceeded 1 million. But a large percentage of those infected — by most estimates, somewhere around 40% to 45% of carriers — seem to endure the virus without symptoms or lingering effects.

Unlike “disease resistance,” which refers to all of the body’s methods of killing and expunging a threat, disease tolerance describes a host’s ability to put up with or even accommodate an intruder.

It’s often assumed that these people possess immune systems that are more adept at killing or clearing the germ. But that doesn’t seem to be the whole story.

Studies on people with Covid-19 have found that viral load, or the amount of virus detectable in the body, usually peaks during the first week of symptoms and steadily declines thereafter, regardless of whether a person quickly recovers or grows critically ill. There also doesn’t seem to be a correlation between maximum viral load and disease severity; asymptomatic carriers appear to be walking around with just as much of the virus in their body as sick carriers.

These sorts of findings have prompted some researchers to ask whether attempts to help the immune system attack and drive out the novel coronavirus are always the best approach to managing the disease. “People normally try to explain [asymptomatic carriers] as their immune systems must be better at destroying the virus or preventing it from getting down into the lungs,” says Janelle Ayres, PhD, a professor and principal investigator at the Salk Institute for Biological Studies in California. “But an alternative or complementary way to think about them is that maybe they’re better at tolerating the disease.”

Ayres is a pioneering researcher in an emerging field known as “disease tolerance.” Unlike “disease resistance,” which refers to all of the body’s methods of killing and expunging a threat, disease tolerance describes a host’s ability to put up with or even accommodate an intruder. “While killing a pathogen is important, clearly there are examples where these mechanisms can’t fully explain variations in disease severity,” Ayres says.

“There are other ways to deal with a pathogen, and that includes cooperating with it.”

Any time there are huge disparities in patient outcomes despite comparable infection exposures, which seems to be the case for SARS-CoV-2, she says that disease tolerance mechanisms are likely at play. She and others in her field believe that a deeper understanding of these mechanisms could open up new avenues of treatment — and not just for Covid-19.

“Our traditional approach [to infectious diseases] reflects a general mentality that humankind has whenever there’s a problem, which is that we have to annihilate it,” she says. “But there are other ways to deal with a pathogen, and that includes cooperating with it.”

A life-saving compromise

Tuberculosis is an ancient killer. Genetic studies have found that Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis, has been with us for at least 35,000 years and that it descends from a species that is up to 3 million years old.

“We’ve found its footprint in mummies, so it’s a very old disease,” says Maziar Divangahi, PhD, a tuberculosis expert and the Strauss chair in respiratory diseases at McGill University in Canada.

Despite medical science’s concerted efforts to eradicate it, tuberculosis remains one of the deadliest infectious diseases on Earth. In 2018 alone, it killed 1.5 million people and was among the top-10 leading causes of death worldwide. Unlike milder respiratory infections, which the body’s defenses often neutralize while still in the upper respiratory tract, Mtb has “an incredible ability to reach down into the lower airways of the lungs,” Divangahi says. Once there, the infection can trigger a pronounced immune response that can cause damaging inflammation, dysfunction, and death. Other severe respiratory infections, including SARS-CoV-2, are also associated with this kind of lower-airway incursion and perilous immune-system response.

But while an Mtb infection can be deadly, the World Health Organization estimates that, globally, 1.7 billion people — or more than one in five individuals — are currently infected with the bacteria. While some of those people eventually become ill, roughly 90% to 95% of them never develop any symptoms.

“We have to become more creative in thinking about how we treat disease. We need to think about the whole immune system and all the tissues that are impacted.”

What stops Mtb from sickening and killing more of its hosts? Divangahi says that, once the pathogen spreads to the lower airways, one of two scenarios plays out: “Either the bacteria will be eliminated during the early phase of the infection, or the host will wall off Mtb by forming granulomas.” Granulomas are little pods of immune cells that encapsulate the pathogen and sequester it in the exterior tissues of the lung — almost like moving boxes being tucked away in a storage unit. Mtb can survive inside these granulomas, but its host is henceforth asymptomatic and noninfectious. It’s as if, after an initial dustup, the person and the pathogen agree to a truce.

“We’ve developed very successful mechanisms that allow us to live with [Mtb],” Divangahi says, referring to the body’s ability to safely manage the infection. “Rather than trying to eliminate the bug, we basically keep it in check.”

The human body’s accommodation of Mtb is an example of innate disease tolerance. Researchers have identified other examples, including blood-based factors that undercut malaria, and reactions in the lining of the gut that protect some people from cholera. Along with these natural forms of disease tolerance, the concept also encompasses drugs or treatments that help the body withstand a pathogen in ways that don’t involve killing it.

“Tolerance is not about targeting the virus — it’s about targeting the overall health of the individual,” says Andrew Olive, PhD, an assistant professor and disease tolerance researcher in the department of microbiology and molecular genetics at Michigan State University.

Olive points out that dexamethasone — one of the very few drugs that helps people survive severe Covid-19 disease — is an anti-inflammatory steroid that turns down the immune system’s assault, rather than turning it up. “The fact that you can target inflammation, not the virus, and better the outcome of the disease tells me it’s more these inflammation pathways that are really driving severe Covid-19,” he says.

Despite this finding, the vast majority of infectious-disease treatment research today — both for Covid-19 and for many other infectious diseases — is aimed at helping the immune system kill the offending pathogen. But Olive says that this approach is often too myopic — too obsessively fixated on extermination rather than harm mitigation. “We have to become more creative in thinking about how we treat disease,” he says. “We need to think about the whole immune system and all the tissues that are impacted.”

Apart from informing more effective treatments, a greater emphasis on tolerance mechanisms might also help prevent the unintended and sometimes catastrophic consequences of too-aggressive attempts to kill a pathogen.

Perhaps the best example of this is the growing threat of antibiotic-resistant bacteria — those pathogens that, in response to our often-overzealous attempts to kill them, have evolved in ways that render our drugs useless. “This is one example of how killing a virus or bacteria may not always be such an effective approach,” Olive says.

How disease tolerance could improve Covid-19 care

For reasons that medical scientists don’t yet understand, some healthy people develop life-threatening reactions to SARS-CoV-2. But these cases seem to be the exceptions, not the rule. The majority of severe Covid-19 cases have occurred in those who are in some way compromised, either due to old age or an existing medical condition.

This suggests that a healthy body already possesses built-in qualities that help it handle the novel coronavirus. (It also suggests that healthy behaviors — eating right, exercising, getting enough sleep — may provide a measure of protection from a severe infection.) By identifying how healthy bodies manage to tolerate the virus, researchers may be able to develop focused Covid-19 treatments that limit the disease’s damage.

“With different infectious disease models, including respiratory diseases, we’re finding that the metabolic state of the host seems to be important if they’re going to be healthy or survive, versus those that die,” says the Salk Institute’s Ayres. Some of her work has explored how metabolic health may be a crucial variable when it comes to SARS-CoV-2, and it could reveal steps a person could take — alone, or with medical help — to better tolerate the virus.

In this context, “metabolism” refers to all of the life-sustaining chemical processes that take place in the human body. Ayres says that diseases of metabolic dysfunction — including obesity and Type 2 diabetes — seem to be among the greatest risk factors for a life-threatening SARS-CoV-2 infection. It’s possible that a closer examination of the metabolic processes that occur in asymptomatic SARS-CoV-2 carriers could inform the development of therapies that replicate those helpful processes and therefore protect people with metabolic disease from the virus.

For example, she says that, among people with Covid-19, there’s an association between control of blood glucose and improved outcomes. “The traditional way to think about how glucose influences susceptibility to infection is that elevated blood glucose impairs the ability of the host to control the virus,” she says. “However, we are finding that changes in the levels of glucose in the blood can also contribute to disease tolerance by regulating tissue susceptibility to damage.” This insight could help researchers create therapies that safeguard tissues from damage.

This is just one example of how disease tolerance could inform Covid-19 care. “In theory, you could make disease-tolerance drugs that target pathways in the lungs to remove the fluid that can build up in the air sacs, which interfere with proper gas exchange,” Ayres says. In cases where the virus threatens other organs, similar targeted therapies could prove helpful.

Ayres is quick to add that disease-tolerance mechanisms alone aren’t the answer. “Killing and clearing the infection — that approach makes sense,” she says. Especially during the early stages of an infection, the old “resistance” game plan is often the most effective one. But when early attempts to repel the virus fail, she says that “having strategies beyond supportive care to promote cooperation with the pathogen so that you’re able to stay healthy even when it’s present is sort of an uncharted area for us — it’s something we’re not used to thinking about.”

Others in her field say that, especially when a new pathogen emerges, tolerance-based therapies can be the fastest route to improved care. “If you’re facing something where you can’t stop the actual infectious agent — like a new virus — then what you are left with is changing the way the disease is caused or the body responds. And that’s tolerance,” says David Schneider, PhD, a professor and chair of microbiology and immunology at Stanford University.

Schneider agrees that vaccines and other resistance approaches have their place. “I don’t think we should just do tolerance in the absence of resistance,” he says. “We should do both.” But the fact that so many people seem to weather a SARS-CoV-2 infection without serious ill effects indicates that there are ways to help the body manage the novel coronavirus short of killing it.

“It’s worth putting in a lot of effort to figure out what’s different in these people who don’t become ill with Covid-19,” he says. Not only could this help us come up with better treatments for the current pandemic, he says, but it could also help us better prepare for the next one.