A journey inside the human body as it goes to war with COVID-19

Why is all this stuff so hard to pin down?

Headache. Fatigue. Chest pain. Problems sleeping. Depression. Dizziness. Fever. Shortness of breath. No single symptom defines long-haul COVID-19, and while some studies offer glimpses into who might experience them, the whys and the hows remain elusive.

It’s not even clear yet whether every long-haul patient suffers from the same kind of disease. The culprit could be a lingering viral infection, tissues damaged by the coronavirus, an autoimmune response in the wake of an infection – or a combination.

Changed by COVID: For millions, COVID-19 won’t quit

Sorting that out is key to diagnosis and treatment, and it’s complicated. This essay traces the knots scientists are trying to untangle.

It begins with the immune system, already among the body’s most complex functions – a web of protein sensors, cellular signals and cell types. It’s part of your skin and your digestive system, your lymph nodes and a diffuse family of circulating cells all communicating through chemical signals.

Each participant in this body-wide cross-talk is capable of changing how the conversation flows. Some immune cells tell others to ramp up the aggression, while others calm and soothe. Some parts of the body, like the eyes and central nervous system, dampen the immune system, preventing runaway inflammation from damaging delicate tissues.

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Those chemical signals and cells are in constant conversation across your body. A whiff of death or decay, a taste of invasion or war draws reinforcements out of neighboring tissues and distant lymph nodes. Hints of severe infections echo through the body like gunshots in a canyon.

Undergirding it all is your body’s sense of self – each cell signaling to the immune system that it is part of you. As if in a choir of affirmation, every cell is part of the whole.

Typically, the immune system does its job well. It encounters billions of foreign microbes and viruses every day. Most days you don’t get sick.

In part that’s because the overwhelming majority of microbes and viruses aren’t interested in infecting you. They may not even be able to. The most common viruses on earth are those that infect bacteria, numbering in the trillions in every drop of water.

Most infections are opportunistic, striking only when defenses are weakened. But some microbes and viruses have learned to manipulate the immune system. Many live benignly in or on other animals, learning to communicate with the host immune system.

CHANGED BY COVID

Day one of a weeklong USA TODAY Network series exploring long-haul COVID-19, the people who’ve suffered and the experts trying to help them. If you don’t want to miss future stories in this series, sign up for our COVID-19 newsletter here.

SARS-CoV-2, the coronavirus that causes COVID-19, is thought to have hopped species from bats to humans. In bats it is benign. In humans, the communication strategy the coronavirus uses to work with the bat immune system is weaponized and out of balance. Like other coronaviruses, it promotes the wrong immune response while suppressing the parts that work to clear them out.

This is a common path to becoming a human disease, hopping species, changing context. Whether a disease ever reaches benign equilibrium with a new host is a matter of time, environmental pressure and luck.

COVID-19 also can infect many organs, including the heart, lungs, gastrointestinal tract and nervous system. Immunologically this is a bit like setting a bunch of small fires across a wide forest. Smoke rises from everywhere. The fires burn hot or smolder. Embers carried on the wind bring fire to less accessible areas.

There’s one big difference from a real fire, though: The immune system – the fire fighters – track fire by scent, not sight. And this fire is actively trying to hide.

This is thought to be part of why COVID-19 causes a “cytokine storm,” where the infection touches off an immune system wildfire. Targeted inflammation is like a controlled burn, but COVID-19 infects systemically, setting unhelpful immune reactions off everywhere. Inflammatory proteins race through your bloodstream and wreak havoc, killing tissue and damaging organs.

Your immune system vs. COVID-19

Immunity has evolved over millions of years to provide defense in layers of increasing specificity. Barriers, like skin, keep the environment out.

The next layer is the innate immune system, an ancient assembly of cells, clotting factors, antimicrobial peptides and a repertoire of chemical sensors. It is called innate because its constituent parts are encoded into the human genome. Every human has approximately the same innate immune system.

The innate system is one part community watch group, one part defense force, one part cleanup crew and one part army. It does what you think the immune system does, fight disease, clear infection, look for injury.

In most living things, innate immunity is all there is. If you happen to be a crab and you get sick, that’s your only line of defense. In vertebrates, the innate immune system can do one more thing: It can call in the big guns by turning on the adaptive immune system.

The adaptive immune system is the final layer for vertebrates, whether they are humans, chimpanzees, geckos or zebrafish. It changes throughout life as the immune system encounters new infections.

Humans use vaccines to train the adaptive system.

Adaptive immune cells wait for the innate immune system to show them a protein fragment that matches their individual signature from an invading disease.

Think of this as if each detective on “Law & Order” was capable of recognizing the image of only a single suspect generated at random from a pool of facial features.

Imagine millions of slightly different versions of Detective Olivia Benson milling around a precinct. When one of them recognizes the crook – the illness – of the week, that one Benson becomes an army of Bensons. Some Detective Bensons stay behind to make antibodies, the body’s wanted posters. Others go out, coordinate the search and attack the illness.

During that attack, adaptive immune cells mutate further, refining and adapting to better target the infection.

The adaptive immune system has a superpower: it remembers past infections so that they can’t infect you in the future. Vaccines stimulate this memory function, training the adaptive immune system to recognize a disease before it arrives.

The adaptive immune system also is responsible for causing autoimmune diseases, where the immune system accidentally attacks the body. The superpower of remembering and adapting to new illnesses can flag parts of the body as invaders.

And autoimmune disease in turn is a potential cause of long-haul COVID-19.

Chasing viral ghosts

Viral infection can cause the immune system to accidentally attack the body, most famously with reactive or viral arthritis in hepatitis patients and inflammation of the central nervous system in HIV patients.

These infections induce the adaptive immune system to attack the body. Some viral proteins are mimics that resemble those of the host tissues, fooling the immune system into seeing “self” as “foreign” and attacking the wrong targets.

To expand the “Law & Order” metaphor, imagine if some of the army of Detective Bensons Clones started to attack random bystanders because they happened to look like a suspect.

Early research shows that SARS-CoV-2 also can induce such autoimmunity. A study from Yale University of COVID-19 patients identified circulating auto-antibodies that targeted an array of tissue types and immune-signaling molecules – noise that disrupts the immune system, and the body, but leaves the coronavirus unscathed.

Echoes of this might be responsible for some of COVID-19’s legacy of longer-term suffering.

Viruses like Epstein-Barr, cytomegalovirus and various herpes viruses can leave behind symptoms like those of long-term COVID-19. Evidence of viral infection and chronic inflammation has been detected in some chronic fatigue and fibromyalgia patients, too. Other autoimmune diseases like autoimmune myocarditis – a condition in which the immune system inflames heart tissues – are associated with mild viral infections.

These connections to viruses, and the diseases themselves, have historically been controversial because not every patient can clearly identify an infection in their past. That makes it hard to pin down the cause and effect of their lingering symptoms.

Some scientists spend their careers chasing elusive viral ghosts, the haunted echoes of infection, without success. The trigger for Type 1 diabetes has long been thought by some scientists to be viral, but decades of research have yielded confusing, often contradictory, results.

While SARS-CoV-2 causes illness on an incredible spectrum from asymptomatic and mild to life-threateningly severe, tests during infection and antibody tests after give the infection a timeframe and a name – one clue in an otherwise perplexing illness.

The collective paper trail of those tests will help medical researchers determine whether long-haul COVID-19 has a long-term autoimmune component and, in time, find ways to treat it.

Vincent Gabrielle is a science journalist at the Knoxville News Sentinel. Before he became a journalist he studied mucosal immunology and new vaccination technology. He has a master’s degree in immunology and microbial disease from Albany Medical College.

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This article originally appeared on USA TODAY: How the immune system goes to battle with many COVID-19 symptoms