Since the beginning of the pandemic, once-esoteric scientific terms have become common parlance—spike protein, PCR, mRNA.

Pathogenesis is not one of them. Yet, when it comes to understanding COVID-19, this may well be the most important word that has yet to make its way into the mainstream lexicon.

Pathogenesis—or “origin of disease”—is the study of the processes that give rise to physiologic dysfunction and illness. In the case of COVID-19, it is the study of virus-induced mischief—how SARS-CoV-2 interacts with various cells, tissues, and organs to cause COVID-19.

As the world inches along on its journey through this ever-evolving pandemic, understanding the “how” of COVID-19 could be the most important question of all.

The question has motivated the research of  Galit Alter and David Knipe over the last year. The two co-lead the pathogenesis research group of the Massachusetts Consortium on Pathogen Readiness (MassCPR), a multi-institutional, cross-disciplinary, international research effort established on March 2, 2020, at Harvard Medical School to help combat the current pandemic and set the stage for fighting future ones.Alter is a professor of medicine at HMS and an investigator at the Ragon Institute of MGH, MIT, and Harvard. Knipe is a professor of microbiology and molecular genetics in the Blavatnik Institute at HMS.

A year after the World Health Organization declared COVID-19 a global pandemic, Alter and Knipe discussed what they have learned about the disease-fueling interplay between the SARS-CoV-2 and its human host and their ongoing efforts to understand the shifting landscape of COVID-19.

A triad of disease

The archetypal triad of infectious diseases involves a host, a pathogen, and the interaction between the two. To understand the mechanisms of infection, neither the human host nor the pathogen can be studied in isolation—a disease is invariably a function of the interplay between the two.

• The pathogen—the structure and behavior of the virus and how it evolves over time under various pressures around it.
• The host—the underlying individual factors—genetics, differences in immune response, overall health, age—determine how and why a virus might affect one person differently from another to cause a range of disease manifestations.

COVID-19 has demonstrated a stunning versatility in not only in the range of its severity—from asymptomatic to deadly—but also in range of organs and organ systems it can affect.

• The interplay—the host and pathogen are engaged in an ongoing battle. The field where this battle unfolds is the immune system. The host immune response powerfully modifies how the virus behaves once inside the body, the magnitude of the infection, the severity of the disease, and the risk for organ damage and complications.

Yet, understanding COVID-19, or any complex disease for that matter, is not a simple equation of summing up the individual parts. Each of the three variables carries multiple unknowns within itself. In a way, understanding the pathogenesis of COVID-19 is akin to solving a three-body problem, a notorious challenge in classical mechanics.

“The study of pathogenesis is essentially puzzle-solving,” Knipe said. “It’s a systems approach to studying a disease, so one of the roles of our group is to put together the pieces of knowledge from areas of study to explain the system.”

Alter and Knipe emphasize that a comprehensive understanding of COVID-19 pathogenesis should go beyond how the virus behaves inside the human host. That classic view may be limiting. Alter points out that the host-pathogen interaction is but one link in a long chain of biologic events.

“We are trying to ask every single question about this virus—how it infects, how it causes disease, how it affects the world around us but also how the virus survives in nature so that we can be prepared for the next coronavirus,” Alter said. “We are focused on everything that the pathogen can interact with, what allows it to survive and persist, and that’s a much bigger scope of inquiry.”

To be sure, that scope is staggering, but scientists have also generated immense knowledge about an entirely new human virus causing an entirely new human disease, and they have done so at a pace never before achieved in the history of science and medicine.

This growing knowledge has defined the contours of the disease and filled in many critical blanks. Here are some of the key insights gleaned by researchers from MassCPR’s pathogenesis working group.

The pathogen: survival of the wiliest

The structure of SARS-CoV-2 was elucidated early in the pandemic, and the virus’s genome was sequenced and published in early January 2020—mere weeks after the first reports out of Wuhan, China.

The pathogen’s behavior has posed more of a challenge. One critical blind spot early in the pandemic was asymptomatic and pre-symptomatic viral transmission, which posed a major hurdle in halting the spread of the virus.

Another behavioral quirk of SARS-CoV-2 is how quickly it has changed. Researchers anticipated that the virus would mutate. They knew that new SARS-CoV-2 variants would emerge eventually. What blindsided them was the extent to which some of the viral mutants could dodge antibody defenses.

Another baffling observation was that some mutations were arising in geographically remote parts of the world. The virus, the researchers realized, was developing natural evolutionary workarounds against host immune defenses.

In the early months of the pandemic, the assumption—and hope—was that SARS-CoV-2 would not change too fast because, unlike most of its fellow RNA viruses, it has a “proofreading” protein whose job is to prevent too many changes to the viral genome.

But the virus did change, and researchers worry that if vaccine rollout remains sluggish, the viral changes may outpace our ability to keep up with them.

Know thine enemy

A microbe has only one goal—to survive and propagate. To achieve this, a virus must change in response to its environment. These adaptive changes occur through mutation. Mutations are a normal part of the life cycle of a virus and happen every time a virus makes copies of itself.

Some mutations are of no consequence, others can harm the virus itself, and still others can become advantageous to the microbe, allowing it to propagate more easily from host to host or to dodge the host’s immune defenses. If a mutation gives a virus an evolutionary advantage, this fitter variant can gradually outcompete others and become the dominant one.

On a basic level, to survive long-term, any organism must engage in a delicate balancing act between safeguarding its genome against too many mutations and introducing new adaptive mutations that render it better adapted to survive in its environment.

“The whole viral evolution story has been puzzling,” Knipe said. “We thought initially the virus was pretty stable genetically, but the variants with the same multiple changes have arisen in several geographic areas. This not a gradual evolution.”

Rather, Knipe added, recent studies suggest that viral recombination—or shuffling of segments of the viral RNA—may lead to new, more infectious genetic combinations of mutations.

In the case of SARS-CoV-2, most mutations emerge simply as a consequence of adapting to a new host. Best current evidence suggests that SARS-CoV-2 made its way into people from bats, a transition that compels the virus to get better and better at invading the cells of its new host.

Other mutations to SARS-CoV-2 appear to arise in response to pressure from the host’s immune system. To ensure its survival inside the human host, the virus comes up with workarounds—escape mutations—that allow it to dodge immune defenses.

The most common, and best understood, immune defense is neutralizing antibodies, immune proteins that block the virus from entering and infecting cells. To prevent SARS-CoV-2 from entering human cells, antibodies latch onto an area of the virus called the receptor-binding domain (RBD). Logic would dictate that the virus would first develop escape-enabling mutations in this vulnerable part of its structure but, to the researchers’ surprise, mutations are now appearing on other parts of the virus as well.

“The virus is not changing only where the antibodies attack,” Knipe said. “It’s changing throughout the genome. Why is it changing so much all the way through?”

The question is also a clue.

This observation raises an interesting hypothesis. It suggests that the virus may be experiencing immune pressure elsewhere on its genome and that such pressure does not arise from the antibody response. This indicates that antibodies are not the only troops deployed by our immune system to disable the enemy, Knipe said.

The emergence of viral variants that appear to be more transmissible points to the ability of the virus to shapeshift rapidly in response to immune pressure. This, in turn, highlights the importance of immunizing large swaths of the population, thereby reducing the number of hosts for the virus to infect and the number of opportunities to mutate.

Understanding viral behavior mandates aggressive genomic surveillance of SARS-CoV-2 but, just as importantly, research into how coronaviruses, in general, and other viruses replicate, Knipe said. The information derived from studying viral behavior, he added, can help scientists guess the pathogen’s next moves, such as the appearance of novel mutations, and factor them into the design of broadly acting therapies and vaccines that target multiple sites of vulnerability on the virus.

Lines of defense  

Traditionally, scientists who study infectious diseases have paid more attention to the pathogen than the host. But COVID-19, perhaps more so than other infectious diseases, has pointed to the importance of host-specific factors.

“What’s really amazing with this particular infection is the crazy battle between the host and the pathogen,” Alter said. “It’s fascinating to see how the immune response can grab hold of this virus.”

Broadly, our defense against microbes arises from two branches of the immune system. Innate immunity comprises various protective mechanisms we are born with. Adaptive, or acquired, immunity is a form of continuing education for the immune system. As it encounters new pathogens, it learns how to deal with them.

Once the immune system meets a pathogen, it must recognize it as a foreign and retain a memory of it. Upon subsequent encounters, our immune defenses recognize the pathogen as a familiar foe and mount a rapid defense, often triggering minimal symptoms or no symptoms at all.

Broadly speaking, adaptive immunity uses two forms of defense: antibodies, the so-called humoral immunity, and T cells, also known as cellular immunity.

The role of the different types of immunity in COVID-19 has not been fully elucidated. Of the two arms, however, adaptive immunity has been the main focus of research efforts.

Does the dose make the poison?

How the immune system responds early during infection could help scientists forecast disease trajectory and survival. The search for telltale clues—or biomarkers—to predict who will get severe disease and who will not is one of the more fundamental challenges right now.

One fairly straightforward predictor of disease severity is the amount of circulating virus in the blood, or the viral load. Research led by MassCPR member Jonathan Li compared viral loads and disease severity among infected people who were either hospitalized with serious illness or had mild disease and recovered at home.

Compared with people who had mild disease, those with illness serious enough to require hospitalization not only had greater viral loads but also increased markers of inflammation, worse respiratory illness and a dip in infection-fighting white blood cells. People with higher viral loads tended to have more severe disease and greater risk of dying.

The findings suggest that viral load profiles could be helpful predictors in who might get severely sick, but beyond risk stratification, the observations hint at a possible mechanism underlying the different disease trajectories.

It suggests that people exposed to a higher initial dose of the virus are more prone to severe disease and that these people’s immune systems may not be able to control and minimize viral replication. As a result, the virus may escape the lungs, invade the blood and seed infection in other organs, fueling widespread inflammation and illness.

Antibodies: Quality over quantity

Antibodies, proteins made by the immune system in response to pathogens, are a well-established hallmark of immune function. Traditionally, higher levels of antibodies, or titers, have been thought to portend a more robust immune response.

But emerging evidence suggests that when it comes to antibodies in COVID-19, antibody accuracy and precision may be more important than levels of antibodies produced. Research by Alter and colleagues found that COVID-19 patients who recovered and those who succumbed to the disease exhibited differences in the types of antibodies they made. The key difference, the study showed, was the part of the virus that antibodies glommed onto.For example, people who developed antibodies mostly targeting the spike protein—the structure that SARS-CoV-2 uses to enter human cells—were more likely to survive than people who developed antibodies primarily targeting another part of the virus, known as the nucleocapsid.

In other words, Alter says, producing antibodies may not be enough. What matters is whether these antibodies home in on the right target. The research also showed that antibodies able to “recruit” the immune system to fight the infection evolved rapidly in individuals who survived, but their evolution was blunted among those who ultimately died.

Yet another newly published study led by Alter also reinforced the notion that the type of antibodies rather than merely their levels may be important in creating immune memory against SARS-CoV-2 following initial infection.

The work demonstrates that when it comes to rendering people immune to subsequent encounters with SARS-CoV-2 what may be more important is whether an individual has developed robust levels of antibodies against specific parts of the virus.

Another small study of 113 patients led by MassCPR researcher Alejandro Balazs offers a similarly intriguing observation: that the quality of antibodies may matter more than their quantity. Patients who went on to develop severe illness or died of COVID-19 did not necessarily have fewer antibodies. Their antibodies, however, appeared to be less fit and less capable of blocking the virus.

Memories from encounters past

One important question about the host-pathogen interaction has been whether some people may have partial immunity to SARS-CoV-2 from previous exposure to viruses from the same family.

Understanding such cross-immunity offers one possible explanation behind the observation that people with similar risk profiles, such as age or underlying conditions, may experience SARS-CoV-2 infection differently: Their preexisting immunity dampens disease severity.

A study led by Manish Sagar and Joseph Mizgerd, MassCPR members at Boston University, suggests that people whose immune systems bore markers of recent infections with other coronaviruses—less virulent cousins of SARS-CoV-2—were not protected from SARS-CoV-2 but when infected with it, they tended to have milder disease.

Understanding variations in immune response to different coronaviruses, could help scientists identify dents in the pathogen’s armor and build therapies that target those areas of vulnerability.

A study led by MassCPR member and HMS geneticist Stephen Elledge mapped the footprints of human antibody responses made against seven coronaviruses, including common cold viruses and SARS-CoV-2.

The analysis revealed differences in the antibody responses of patients who had different outcomes, ranging from mild infection to critical illness. The insights identify vulnerable spots on the virus that could serve as targets of immune defense and inform the design of antibody-based therapies and vaccines.

“Data suggest that cross-reactive immune responses somehow confer natural immunity against the new virus, and if we could understand how this happens, we could get a better handle on designing vaccines against this specific virus, but also against any coronavirus that pops up in the future,” Alter said.

Cellular defenses

Thus far, the role of cellular immunity in SARS-CoV-2 infection remains poorly understood.

Rapidly growing evidence over the past several months has pointed to the critical role of T cells in COVID-19. But there remain key unknowns: How soon after infection do T cells get activated to halt the spread of the virus? Does the strength of the response vary from individual to individual and, if so, what factors underlie such variations? Are T cell and antibody responses related to one another and, if so, how do they modulate each other? How long do T cells retain memory of SARS-CoV-2?

The answers to these questions have therapeutic implications. Designing treatments and vaccines that stimulate antibody and cellular responses would be an important goal, not only for reining in SARS-CoV-2 but also for dealing with novel coronaviruses that are likely to emerge in the future.

Knipe and Alter said that traditionally vaccine developers have focused on designing vaccines that marshal neutralizing antibodies. But as our understanding of the interplay between the immune system and SARS-CoV-2 grows, the two researchers added, it will be important to go beyond neutralizing antibodies and to design vaccines that stimulate other forms of defense.

These include T cell immunity or opsonization and phagocytosis, the process of coating microbes with sticky proteins, encapsulating them and devouring them.

“Developers design vaccines with antibody-based protection as an end goal in mind, but what we have learned over the years from many clinically approved vaccines is that they can work through mechanisms other than neutralizing antibodies,” Alter said.

Hints of such mechanisms abound, Alter and Knipe said. For example, evidence points to partial immunity following the first dose of mRNA vaccines before the second booster shot. During this short window there are no neutralizing antibodies in the blood, yet the existence of partial protection suggests that the immune system is finding other ways to create protection.

“What this tells us is that there are other players, not only antibodies—the innate immune system, the adaptive immune system, cellular immune response—and collectively, acting together, these various defenses can respond to the virus,” Alter said.

Too much of a good thing

COVID-19 infection unfolds in two phases: An acute phase—lasting 5 to 7 days on average—is marked by the virus hijacking cells inside the body and by rapid replication.

This phase is followed by an inflammatory phase (day 7-14 days in), which is marked by the activation of multiple immune-signaling pathways that produce inflammatory molecules against the virus as well as against virus-infected human cells.

If misguided or too strong, this otherwise protective response can inflict serious collateral damage to cells, tissues and organs. At its most extreme, inflammation gone awry can unleash a so-called cytokine storm that overwhelms the body, damages organs and, at times, leads to death.

One area of active interest is mapping the precise steps and cascade of inflammatory mediators that directly or indirectly promote disease. Such knowledge could inform the design of precision-targeted anti-inflammatory treatments that target specific pathways.

Currently, the exuberant inflammation of COVID-19 is managed with an old-school immune-modulating drug, dexamethasone, a corticosteroid that suppresses overall immunity.

Research has shown that the drug can prevent death among those with severe lung disease caused by COVID-19. Yet, the therapy carries the traditional risks of corticosteroids, such as elevations in blood pressure, cholesterol and blood sugar, and must be used with caution in patients who have weakened immune systems because it could severely suppress their ability to fight infection.

Identifying the cascade of biochemical events that culminate in a cytokine storm is critical to designing more finely tuned therapies that do not dampen overall immunity.

Defining the right window for timing of treatment is an evolving question.

“Timing is very important in that if you give it too soon, you’re going to block the antiviral response,” Knipe said. “If you don’t give it soon enough, you won’t block the immunopathology or the inflammatory response.”

“This is the whole issue that we’ve been grappling with in pathogenesis—the complexity of the host immune response and the acute respiratory distress and the virus,” Knipe added. “How do we toggle and finetune the treatment so precisely that we eliminate the immunopathology but still allow the immune response to control the virus.”

In addition to inflicting damage on cells and organs, severe inflammation may interfere with the body’s ability to establish long-term immune memory, according to research led by MassCPR member Shiv Pillai. His work shows that people with COVID-19 who experience cytokine storms may also end up making fewer antibody-producing B cells, which are so critical to creating sustained immune memory.

The root of dysfunction, the study shows, is one particular cytokine, TNF, which appears to interfere with the formation of germinal centers—areas in the lymph nodes and spleen where antibody-producing B cells grow and proliferate. The findings offer one possible explanation for the non-durable immunity seen in COVID-19.

How long does immune memory last?

Two of the most critical questions since the start of the pandemic have been: How long does the human immune system retain memory of SARS-CoV-2? Does the immune memory vary from person to person and, if so, what drives this variation in immune longevity?

Research led by MassCPR scientist Duane Wesemann offers some answers. The work shows that while antibodies against SARS-CoV-2 declined in most individuals after disease resolution, a subset of patients sustained antibody production for several months following infection.

These antibody “sustainers” also had shorter disease course, suggesting that those who overcame the disease faster also mounted more lasting immunity to the virus. The samples used in the study, however, were obtained from people with mild to moderate disease and excluded individuals at the two extremes of the illness spectrum—asymptomatic infections and those withs severe disease.

Another study, led by MassCPR member Richelle Charles, an infectious disease expert at Mass General, explored the question of immune memory in a group that consisted mostly of individuals with severe infections.

The work showed that one type of antibody, IgG, persisted for at least three months following infection, offering a window into the longevity of immune protection after infection. By contrast, two other types of antibodies IgA and IgM decayed within two and half months or less after infection.

Re-infection vs. persistent shedding

Scientists have learned that a small number of people may become re-infected with the virus. Why such reinfections occur remains to be elucidated. Yet another subset of individuals appear to never clear the virus but instead subdue its replication to chronically low levels.

Telling the two groups apart has been challenging. The question often arises when clinicians encounter patients with documented prior COVID-19 and subsequently test positive by PCR, a test that viral RNA.

The U.S. Centers for Disease Control and Prevention defines reinfection as having a positive PCR test and symptoms suggestive of COVID-19 at least 45 days following an original diagnosis of COVID-19. An individual who has a second positive PCR, even without symptoms, 90 days or longer after an initial positive PCR test is also considered re-infected.

“We see this a lot, but we do not know whether it’s a new infection, chronic infection or lingering shedding from the prior infection,” said Charles during a recent session of the pathogenesis working group.

“The question we’re interested in is how the immune response in persistent shedders or chronically infected individuals may be different from individuals who are able to clear the virus, and what factors make individuals susceptible to reinfection,” Charles added. She is conducting ongoing research in an effort provide some answers.

Charles and colleagues are working to analyze the antibody immune profiles of patients across the spectrum of infections. The study will track immune-marker changes over time to glean telltale differences between persistent shedders, chronically infected individuals, and those who clear the virus quickly. The work could also help identify immune markers associated with risk for re-infection.

One important aspect of chronic infection is that it increases the risk for introducing new mutations. Chronically infected people thus are reservoirs of ongoing viral replication and may contribute to the development of new, fitter viral variants.

Twists to the plot

One of the greatest surprises about the host-pathogen interaction, Alter said, was the realization that when it comes to immune response, location matters. In SARS-CoV-2, the body appears to deploy different immune mechanisms that limit viral replication and infection in the upper airways versus the lungs.

“We really don’t have a good handle on this even though we’ve been studying flu and tuberculosis and so many other respiratory pathogens for a long time,” Alter said. “It really kind of opened our eyes to the importance of understanding the lung-specific immune response.”

This difference was borne out in the vaccine data, which showed different markers of immunity that suggest the virus is controlled differently in the upper airway (nose and pharynx) than in the lower airway (trachea, bronchi and lungs).

“This really draws our attention to the idea that maybe people with asymptomatic or mild infections are able to resist through completely different mechanisms than people in whom the virus gets into the lungs, that they have this entirely different immune repertoire that they can leverage to fight the disease,” Alter said.

Not just small adults

How the pathogen affects people of various ages has yielded some of the most tantalizing observations and greatest surprises in the pandemic. How children respond to the virus has been on such surprise that may offer valuable clues beyond the pediatric population.

Typically, respiratory pathogens—such as those causing flu, whooping cough, TB, RSV—lead to worse disease in children. The opposite is true with SARS-CoV-2—children have been largely spared serious illness.

One explanation could be that children tend to do better because they may have been more recently exposed to other corona viruses and have some cross-over immunity against this class of viruses. Yet another possibility arises from age-related cellular differences.

SARS-CoV-2 invades human cells through the ACE-2 receptor on the surface of cells, the gateway for viral invasion. Children have fewer such receptors on their cells, an observation that provides a plausible explanation for lack of severe disease in the vast majority of children. In any case, Alter said, the story is likely more complicated than the presence or absence of ACE2 receptors, begging the question of which immune-protective mechanisms may be at play.

The difference may arise from a more “naïve” immune response that may shield children from the aberrant immune-fueled inflammation seen in adult severe disease.

“It could be that children’s immune systems do not respond so powerfully to the spike protein, which adults have seen in the past and which can trigger a more aberrant immune response, leading to severe inflammation and worse disease,” Knipe said.

Nonetheless, a small subset of previously healthy children infected with SARS-CoV-2 can mount a powerful immune response and develop a serious, at times life-threatening, condition known as multi-system inflammatory syndrome in children (MIS-C).

The condition, which resembles Kawasaki disease and toxic shock syndrome and could affect several organs including the heart, typically emerges about a month after infection with SARS-CoV-2.

MassCPR member Adrienne Randolph, a critical-care specialist and immuno-biologist at Boston Children’s Hospital and a principal investigator of a multicenter national trial of COVID-19 in children and young adults, described the development of this illness in previously healthy children and adolescents infected with SARS-CoV-2.

A newly published study led by Randolph sheds light on the different ways in which the virus can affect children and adolescents, drawing a clear immunologic distinction between youngsters who develop serious COVID-19 and those who develop MIS-C.

This pediatric condition is reminiscent of certain inflammatory syndromes seen in adults, a similarity that may point to a common immune profile or immune phenotype, Alter said, with the two conditions being merely the pediatric and adult versions of the same physiologic phenomenon.

“I think the jury’s still out on why kids are somehow protected against this respiratory pathogen and not others,” Alter said. “That to me is like a big black box. If we could understand that, maybe that would allow us to think through how we can make better vaccines against other respiratory pathogens too.”

The heart of COVID-19

Much has been said and written about the spectrum of severity of COVID-19 and its ability to affect people with varying degrees of virulence. But another just as confounding aspect of the illness is the variability in the type of organ damage it can inflict.

For one person it could be the heart, for another the kidneys, for yet another the brain or the lungs. One of the greatest uncertainties is whether there exists an underlying mechanism that unifies these disparate manifestations.

Case in point—the heart. That COVID-19 can affect the heart is indisputable. How it does so remains an evolving mystery. Scientists have hypothesized that there may be several mechanisms, yet much is unclear. One question looms large: Is SARS-CoV-2 a mere amplifier of preexisting heart problems, direct cause of cardiac muscle demise or an indirect driver of myocardial injury?

It is this question that has dominated the efforts and focus of pathogenesis working group member Christopher Newton-Cheh, a transplant cardiologist and cardiovascular geneticist at Mass General and assistant professor of medicine at HMS.

Many hospitalized patients with COVID-19 experience elevations in troponin, a protein that increases during acute heart muscle injury and is commonly used to diagnose damage to the heart.

Yet, what is not known is whether such spikes in troponin arise directly from COVID-19 or whether they are a marker of the overall systemic stress that infection can impose on people’s cardiovascular systems, Newton-Cheh said during a recent pathogenesis group meeting.

COVID-19 could be damaging the heart in several ways, both direct and indirect. For example, it could be the proverbial straw that breaks the camel’s back and causes cardiac damage in those with underlying, even if unrecognized, heart disease.

Or it could be causing heart injury by damaging the blood vessels and causing blood clots, a known complication of COVID-19. It may also be causing the heart to work harder leading the muscle’s demand for oxygen to outstrip supply. And the widespread inflammation of COVID-19 could also cause collateral damage to the heart, as well as other tissues.

Yet, another possibility is that the virus may infiltrate the cells of the heart muscle and damage them directly, thus injuring the heart. However, Newton-Cheh notes, emerging pathology reports from biopsies and autopsies suggest this is not a common route of heart damage. Complicating matters further could be that the mechanism of heart damage likely varies from person to person.

Understanding how heart injury occurs could help cardiologists decide whether they need to focus on treating the heart specifically during COVID-19 illness or whether nonspecific inflammatory control would be sufficient to shield the organ from the ravages of COVID-19.

Newton-Cheh noted that the lung as a source of systemic inflammation could be sufficient to compromise the work of the left ventricle of the heart, the organ’s main pumping chamber, which sends blood throughout the body.

In addition, heart disturbances are commonly seen in critically ill patients, regardless of the cause, he noted. This observation suggests that systemic inflammation and respiratory distress could fuel cardiac dysfunction, but it does not mean that COVID-19 is, by itself, a unique driver of cardiac injury.

“There’s always a challenge in understanding whether the presence of small amounts of virus in the cells of the heart muscle is directly causing their destruction or whether their destruction is more of an autoimmune phenomenon,” Newton-Cheh said. “I do not think this has been resolved despite decades of research since the 1990s documenting the presence of viral genomes in cardiac cells in the setting of myocarditis.”

Thus, even though it is well-known by now that SARS-CoV-2 infection can trigger cardiac complications, it is not yet known how it does so, whether these complications are transient or long-lasting and whether they represent direct viral damage to the heart muscle. One encouraging indicator, albeit anecdotal, is that people seem to recover.

“I am following people who had severe systolic dysfunction during their illness who have normal function a few months later,” Newton-Cheh said.

The long game of pathogenesis research

The accumulation of knowledge over the past year, coupled with a realistic understanding of the limitations of human nature, has yielded a new realization: The notion that SARS-CoV-2 will one day vanish may be magical thinking, Alter and Knipe said.

Many experts now agree that the virus is here to stay and that our best chance for a return to some semblance of normality may be to subdue, rather than eradicate, the virus by achieving a level of herd immunity, preferably through a vaccine rather than natural infection.For pathogenesis research there is really no endgame.

“Even when you have a vaccine, even when you have a therapy, even when you have a diagnostic test, pathogenesis doesn’t end. Ever. Because we know this virus is not going to completely go away anytime soon,” Alter said.

“Human behavior dictates that, unless everybody accepts the vaccine, the virus is not going to go away. On top of which, we know that there are other coronaviruses lingering in nature that are waiting to have their chance.”

It's a point that Knipe returns to again and again.

“History teaches us that we just don’t know where the next pathogen might come from, so we can’t take our eyes off the ball. We have to use what we have learned about SARS-CoV-2 and use this knowledge to continue basic science research into other pathogens.”

But there is an even more fundamental reason for the work to continue, Alter and Knipe said: To sustain this never-before-seen intellectual collaboration sparked by the journey to understand the mechanisms of COVID-19 and to maintain the intellectual interactions with fellow scientists from both academia and industry and from disciplines as diverse as systems biology and computational biomedicine, pediatrics and epidemiology, genetics, cardiology, radiology, neurology, endocrinology and more.

“MassCPR had this vision of bringing together epidemiology, therapeutics, diagnostics, clinical medicine, and more to create these pillars of fighting a disease,” Alter said. “Now, imagine if we did the same for every other disease. Imagine doing this for breast cancer, for Parkinson’s. Just think about what we could accomplish if we could form these Manhattan projects.”