When we get the flu, we feel miserable. We swallow pain relievers, drink lots of tea, slurp down chicken soup. None of these treatments actually eradicates the flu virus itself; our immune system eventually takes care of that. Instead, these remedies make us feel better by alleviating the symptoms: inflammation, dehydration and congestion. “Most of what makes us sick is actually inflammation — the immune response — not the pathogen itself,” said Ruslan Medzhitov, an immunologist at Yale University.
Yet while scientists have carefully chronicled the damage that the immune system can wreak on the body, they have paid much less attention to the mechanisms in place to repair it. “We spend a lot of our time figuring out how to stop the disease, but the real problem is how to get better, how to recover,” said David Schneider, an immunologist at Stanford University. “It’s possible that getting better is a different thing, not just the reverse of getting sick.”
Schneider and others have begun to study the recovery process on its own, arguing that it is just as essential a component of the immune system as the body’s attempts to eradicate foreign pathogens. They have divided the immune response into two basic categories: the traditional part, dubbed resistance, which fights the pathogen itself; and the less-studied part, called tolerance, which aims to curb or repair the damage inflicted by the pathogen or by resistance mechanisms. The research that they have published in the last few years hints that tolerance may be a crucial factor in whether individuals will survive infections such as malaria, cholera and sepsis.
In a paper published in April, Schneider and collaborators used physiological measurements of tolerance to predict whether malaria-infected mice would live or die. Schneider hopes that a similar approach will one day help predict whether a patient infected with the malaria parasite or another microbe will get better with moderate treatment or get worse and need more aggressive treatment. “It’s a completely different way of perceiving how a pathogen causes disease,” said Miguel Soares, an immunologist at the Gulbenkian Institute of Science in Portugal. “I think it will have huge implications for how we treat disease.”
When a malaria-infected mosquito bites someone, the parasite enters the bloodstream and infects the liver and eventually red blood cells. Hidden from the immune system within its host cell, the parasite multiplies, ultimately rupturing its cellular refuge. That releases a toxic molecule, damaging surrounding tissue. To recover from malaria, the immune system has to both kill the parasite and repair the damage caused by the parasite and the immune system’s attack on the parasite. In severe cases, people suffer kidney failure, anemia and brain injury.
A 2007 study examining how mice respond to malaria infection was among the first to explore the role of tolerance in this disease. Andrew Read, a biologist at Pennsylvania State University, and collaborators infected various genetic strains of mice with malaria. They found that the same level of infection — the same type and number of parasites — could cause very different effects in different mouse strains. One might look healthy while another looked very sick. “It was a tipping point for people like me,” Medzhitov said, who thought that tolerance “is a fundamental and overlooked concept.”
In 2011, Soares and collaborators showed that mice with a sickle-cell mutation, a gene variant that creates oddly shaped blood cells, had increased tolerance to malaria. The work helps to explain why people living in regions of Africa with high malaria rates are more likely to carry the sickle-cell trait as well. For a long time, scientists assumed that the trait enhanced resistance — that people with the variant were better at fighting infection by the malaria parasite. But people and animals with the sickle-cell trait have to break down and detoxify misshapen red blood cells their entire lives. So when they’re infected with malaria, the molecular machinery for cleaning up the mess is already in place.
If the sickle-cell trait is so helpful, why doesn’t everyone have it? Having one copy of the protective gene boosts tolerance. But possessing two versions is harmful, leading to sickle-cell anemia, a life-threatening condition. The fact that the gene variant persists despite the potential danger suggests that, when it comes to malaria, tolerance is an important means of protection.
The Recovery Loop
Genetics isn’t the only factor that influences tolerance against malaria. In the lab, about 20 percent of a genetically identical group of mice will die if infected with malaria. The rest recover, a phenomenon that has long puzzled scientists. In their April paper, Schneider and collaborators took the first step in solving this puzzle. They showed that as soon as the animals were infected, they could predict which would die.
The researchers envisioned the journey from infection to illness to recovery as a loop. Some infected animals appear outwardly healthy, develop signs of the illness, then recover to their initial healthy state. In others, a failure to complete the loop results in death. To create a malaria-specific loop, the researchers tracked the health of mice during the course of a malaria infection, measuring several factors, including the number of parasites and different immune cells. They then tried plotting many of these variables against one another, to see which pair of them best resembled the recovery loop the researchers had envisioned.
When they plotted the number of red blood cells against the number of immature red blood cells, they found that animals had a loop that took them from health to illness and back to health. Animals that recovered quickly had tight loops within this plot; those that did poorly had wide loops. The animals whose loops veered off course died. The plots of the doomed mice, for instance, looked different right from the beginning, with a unique ratio of red blood cells to immature red blood cells. Schneider said they don’t yet know why this ratio varies from animal to animal, but he speculates it was in place before the infection — the mouse equivalent of a pre-existing condition.
“It illustrates the power of analyzing the entire trajectory of disease going from the normal healthy state through recovery and back to health,” said Medzhitov, who was not involved in the study. “It’s a very original and valuable way to look at it.”
The loop approach is quite different from standard immunology studies, which look at single variables such as the number of parasites over time. The most powerful aspect of the loop model is that it recreates the time taken by the course of an infection, even though scientists don’t explicitly include time in the analysis. That’s especially important for translating the research into clinical practice. People suffering from malaria probably won’t know exactly when they were bitten by an infected mosquito. For physicians to predict whether a patient will likely recover with standard treatment or need a more aggressive approach, they need to have a predictive measure independent of time, such as the blood-cell ratio.
Schneider’s team validated the model in humans, analyzing published data from children infected with malaria. Children with the sickle-cell trait, who are more resilient to the infection, have ratios of red blood cells that mimic those of the resilient mice.
In June, the researchers launched a new study to map how genetically diverse strains of mice respond to malaria. The goal of the three-year project, funded by the Defense Advanced Research Projects Agency, or DARPA, is to identify additional genetic factors that drive tolerance.
Schneider and collaborators are also trying to better understand the cycle of infection. They want to figure out if there is a certain spot in the recovery loop that represents a point of no return, a threshold where treatment given beforehand prevents illness but is useless if given afterward.
In one preliminary experiment, scientists treated mice with drugs to kill parasites. If given early in an infection, the animals never got sick. But if the researchers held off treatment until a certain point, all the animals fell ill. “What happens to make that change?” Schneider asked.
Life in Balance
The sickle-cell trait boosts tolerance to malaria by enhancing the body’s existing tools for dealing with stress. Though the details likely vary from infection to infection, scientists theorize that tolerance mechanisms tend to fall under this general umbrella. They co-opt the repair machinery that evolved to deal with other insults.
Soares and others hope that by better understanding these tolerance mechanisms, we can figure out new ways to enhance them. Indeed, the researchers have found that studying tolerance can point to quite unexpected avenues for drug development.
Do Mosquitoes Get Malaria?
Scientists once thought that mosquitoes were immune to the malaria parasite’s effects, but we now know that those with the infection do pay a price. Still, the insects have largely evolved to live with the microbe, just as we can tolerate the many thousands of microbes that live on and inside us. The mosquitoes represent the extreme end of the tolerance spectrum.
Which microbes qualify as tolerable and which are harmful varies from species to species. Even the same microbe can oscillate between harmless and dangerous. C. difficile, for example, is a member of our gut microbial community that is tolerable in low numbers but can trigger severe abdominal pain and diarrhea if its population spirals out of control.
Sepsis, for example, is a potentially deadly complication from infection. It develops when the immune system spirals out of control and releases a flood of inflammatory cytokine molecules. That flood damages blood vessels and other tissues, which can lead to organ failure. “The immune reaction is so strong that people die,” Soares said. The fatality rate for severe sepsis, in fact, is a startling 28 to 50 percent. “It seems to us and others to be a clear case of disrupted tolerance that can’t be solved with antibiotics.”
In 2013, Luis Moita, an immunologist at the Gulbenkian Institute of Science, and Soares and collaborators showed how drugs might be used to boost tolerance rather than resistance. The researchers searched for drugs that could stem the flood of cytokines that the body releases in response to infection. They then induced sepsis in mice and treated them with different compounds. Drugs known as anthracyclines, which trigger DNA damage and are sometimes used in chemotherapy for cancer, were found to prevent the sepsis from becoming severe. “This was totally unexpected,” said Dominique Ferrandon, a geneticist in France at CNRS, the national center for scientific research.
Scientists theorize that the drugs work by triggering a mild stress that protects against a later, potentially lethal stress, a concept called hormesis. “Our interpretation is that by using a low dose of a DNA-damaging drug, we trigger a DNA-damage response, which might, in addition to repairing DNA, protect the organism against the tissue damage,” Moita said.
The mice still had the same number of pathogens, suggesting that the drugs boost tolerance rather than resistance. “Perhaps we can now screen for drugs that specifically target these kinds of mechanisms,” Soares said.
Malaria faces a similar challenge. Pharmaceutical companies are looking for drugs that kill the malaria pathogen. “But thousands of people die despite the fact that they can kill the pathogen,” Soares said. A complementary approach might be to look for drugs that help infected people survive. Soares has identified the chemical pathway that helps people with the sickle-cell trait tolerate malaria. Drugs exist that target molecules in this pathway, but Soares said he’s unaware of clinical trials testing them for malaria.
This article was reprinted on TheAtlantic.com.