Asymptomatic Infection Is a Deep Biological Mystery

The coronavirus that causes COVID-19 is much newer to humans, and severe cases have justifiably gotten the most attention during the pandemic. Scientists have made dramatic advances in understanding this virus and how to treat it. But unraveling 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.

Let’s begin where a COVID-19 infection begins, when virus meets cell. The initial infectious dose—the number of virus particles that enter the body—may influence the course of infection. The more particles that land in your nose, for example, the closer the virus is to overwhelming your immune system, leading in some cases to more severe illness.

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,” says Angela Rasmussen, a virologist at Georgetown’s Center for Global Health Science and Security. The fire alarm 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.

Interferons also “interfere” 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. By slowing replication of the virus , interferons buy time for the rest of the immune system.

This is what happens when everything goes right. But every successful virus has to develop ways of evading the body’s defenses, and the coronavirus that causes COVID-19 is very good at a devilish trick: Several of its genes encode proteins that seem capable of blocking interferons. By quieting the body’s fire alarm and disarming its sprinkler system, the coronavirus can set fire after fire. In the race between virus and immune system, the immune system falls behind. The virus proliferates. Lung cells die.

Eventually, so many viral particles are infecting so many cells that the immune system knows something must be wrong. It begins to gear up—but too late. 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. This is one possible explanation for the immune overreaction observed in severe and fatal cases of COVID-19.

This delayed interferon response, Rasmussen told me, reminds her of Ebola, which she studied before our current pandemic. Ebola is a very different virus with a much higher fatality rate, but deadly cases of Ebola are also characterized by uncontrolled inflammation in the body following a delayed interferon response. And Ebola is asymptomatic in some people too—as many as a quarter of all those infected, according to one estimate. Surveys in outbreak areas have found many people with antibodies against Ebola but no recollection of illness.


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