Though many people question how Covid-19 can "be deadly in one person but asymptomatic in the next," modern science suggests that for viruses, "a wide range of disease severity is the norm rather than the exception," Sarah Zhang writes for The Atlantic—an understanding that sheds light on how the coronavirus may mutate in the future.

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A 'delicate dance between pathogen and immune system'

Zhang explains that, while for much of human existence "we didn't know that viruses could infect us asymptomatically," modern science has demonstrated that "viruses are up to much more than making us sick"—which is why a range of illness severity is to be expected. 

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In fact, since viruses need a living host to survive or, at least, live long enough to infect others, the "viruses best adapted to humans have co-evolved over millions of years to infect but rarely sicken us," she writes. For instance, Zhang cites the human cytomegalovirus, a virus that so commonly presents asymptomatically "that it lives in obscurity despite infecting most of the world's population."

By comparison, the coronavirus that causes Covid-19 is far newer to humans, Zhang writes, and perhaps the best way to understand why it "makes some of us sick, and leaves others unscathed, requires an appreciation of the delicate dance between pathogen and immune system that begins each time the virus finds a new host."

A 'fire alarm and a sprinkler system'

Citing Angela Rasmussen, a virologist at Georgetown University's Center for Global Health Science and Security, Zhang explains that within "hours of a typical viral infection, the first infected cells begin secreting interferons, a group of molecules that acts as a 'fire alarm and sprinkler system in one.'"

Specifically, the "fire alarm" function "alerts the two main branches of the human immune system: the fast but nonspecific innate immune system, which causes inflammation and fever, and the adaptive immune system, which over a series of days will muster antibodies and T cells that more precisely target the invading virus," Zhang writes.  Meanwhile, the interferons' "sprinkler system" interferes "with the virus in a number of ways, such as degrading viral genes, preventing cells from taking up viral particles, suppressing the manufacturing of viral proteins, and causing infected cells to self-destruct"—actions that essentially slow viral replication and "buy time for the rest of the immune system." 

But, according to Zhang, this process unfolds in this way only "when everything goes right." And viruses, for their part, are constantly adopting new ways to evade "the body's defenses." In the case of Covid-19, for instance, several of the virus' genes "encode proteins that seem capable of blocking interferons," she writes, enabling the virus to "set fire after fire" by effectively disabling that dual fire alarm and sprinkler system.

And while the body's immune system can eventually detect and respond to those fires, it often starts to "gear up…too late," Zhang writes. "Without timely targeted strikes from the adaptive immune system’s antibodies and T cells, the powerful but blunt innate immune response ramps up and up, destroying healthy human cells in the process," she explains. In fact, this response "is one possible explanation for the immune overreaction observed in severe and fatal cases of Covid-19."

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For instance, Zhang cites one study that examined two sets of young, healthy brothers who fell severely ill with Covid-19. The study found that all four young men had genetic mutation that impairs interferon production. However, she cautions against extrapolating on the findings, noting that the brothers' "specific mutation is not common, and genetics are unlikely to completely explain the variation in Covid-19 cases."

Zhang also cites a study that examined the other side of the equation, asymptomatic patients. For that study, researchers monitored the immune system response of 478 workers in Singapore over six weeks. They found that among those workers who contracted Covid-19, "asymptomatic patients had more specific and coordinated T-cell responses with high levels of an antiviral molecule and another that regulates other T cells." In comparison, according to the researchers, patients who fell more severely ill "released a broader range of inflammatory molecules, suggesting that their immune system was less targeted," Zhang writes.

A spotlight on T cells

According to Zhang, "T cells are now emerging as key to fighting Covid-19." 

In fact, these T cells may be playing a critical role in patients with milder infections: "Depending on where in the world you look, some 28 to 50 percent of people have T cells that predate the pandemic but nevertheless react to the new virus," she writes, cells that "may be remnants of infections with related coronaviruses." As Zhang explains, at least one study has found that people who were relatively recently infected with other coronaviruses tended to have milder cases of Covid-19.

Conversely, researchers also suspect that the fact that T cell responses weaken with age "may help explain why Covid-19 is dramatically more deadly for the elderly." (Another factor, Zhang writes, could be the human cytomegalovirus, which demands ongoing attention from our T cells, thereby making us more vulnerable to new viruses.)

And while this coronavirus isn't yet as capable of hiding in the human body as the human cytomegalovirus, it's also quite new to humans, Zhang writes—over time, "it will have a chance to hone its strategy, probing for more weaknesses in the human immune system." But that doesn't necessarily mean it will become more fatal, she writes. In fact, it could behave much like the other four coronaviruses already in circulation, which typically cause only minor colds.

"As the virus continues to infect humans over the coming years, decades, and maybe even millennia, it will keep changing—and our immune systems will keep learning new ways to fight back," she concludes. "We're at the very beginning of our relationship with this coronavirus" (Zhang, The Atlantic, 4/7).