Lawrence Steinman is a professor of pediatrics and neurologic sciences at Stanford University and has served as chair of the Interdepartmental Program in Immunology. He is an elected member of the National Academy of Sciences and the National Academy of Medicine USA.
As we shelter in place during the COVID-19 pandemic, military metaphors have been rampant. And why not? We haven’t faced an enemy quite like this in more than a century, and so anything that can provide context and framing during a time of great uncertainty is instructive.
But if the fight against COVID-19 is a war, then we have to understand it’s a biological attack – and we must also understand the processes that our personal departments of defence have in place to protect us.
Any good defence system begins with its warning mechanisms – whether it’s sentries posted along fortifications or Paul Revere, racing through the night on his horse to warn that the British were coming. More recently, as of 1957, the United States and Canada collaborated on a “distant early warning system,” or the DEW Line, which was intended to alert the allies of any Soviet air or land attack. Operations of the DEW Line continue under the North American Aerospace Defense Command, a joint Canadian and U.S. military effort. And satellites contribute to the alarm systems we have in place.
The immune system has its own version of an early defence line – namely, fever. One of the chemicals produced when the immune system senses danger is called interleukin-1 (IL-1), which allows communication between our immune forces via the brain’s command-and-control centre. Once IL-1 enters the brain through a special window in the blood-brain barrier – causing fever as a side effect – it gains access to a master command-and-control station in a region on the underside of the brain, the hypothalamus. IL-1 overtakes the control systems in the brain responsible for body temperature, eating and sleeping.
Imagine IL-1 as a Special Forces team, gaining access to a key control system in the brain and then using it to launch a warning that the enemy is coming. IL-1 triggers an increase in temperature via the control centre in the hypothalamus, and fever sends a co-ordinated alarm to the immune system.
The rise in temperature slows certain chemicals needed for viral replication. Other immune chemicals in the first line of defence, our cytokines, bearing names such as interleukin-6 and cachexin (also known as “tumor necrosis factor”), are then called into action. These cytokines are weapons of war themselves, directed against the invading virus.
Fever drives a desire to sleep, which then saves energy for the intense immune warfare that will follow in the next few days. It also causes muscles to ache, which makes us slow down, again conserving energy for immune defence. At least one of these chemicals, cachexin, causes us to avoid eating. Though we might prefer not to “march on an empty stomach,” being hungry may provide another energy-saving benefit, as digestion requires us to expend energy better saved for immune-system combat.
The history of the military has also taught us that defence lines need to be mobile. France’s Maginot Line exemplified the pitfalls of static defence. Built in the 1930s to prevent a German invasion, this deep line of fortifications and turrets – all of which were impervious to aerial bombings, tank fire and other forms of attack – was the next big thing in trench warfare, the First World War standard. But in the Second World War, the Germans overran the Maginot Line by entering France through Belgium and the Ardennes Forest, and the stationary fortresses were rendered useless.
Fortunately, our immune forces are highly mobile and they have powerful weapons at their disposal. The first are circulating white blood cells, including some that immunologists have descriptively named “natural killer cells.” These cells attack the virus in organs that have been infected early after exposure. Fever, along with these mobile natural killer cells, are key components of the first-line defence, or the “innate immune response.”
Within the next 24 hours, the body launches an adaptive immune response that is capable of deploying an arsenal of precision weapons that efficiently target and kill viruses. One of these “smart bombs” is a specialized type of white blood cell, known as a plasma cell. These produce antibodies, which are carried in the blood, disperse throughout the body and latch on with laser-like precision to the viral foe.
These antibodies have a warhead that recognizes the enemy and a tail that activates a variety of “cluster bombs.” Among the blood-borne armaments are molecules known as complement proteins, with a molecular design that can perforate viral shells – reminiscent of “bunker bombs.” Within a few days, we generate antibodies called immunoglobulin M (IgM). In about a week, the immune system generates stronger antibodies, known as immunoglobulin G (IgG), which bind more tightly to the virus.
In the case of the novel coronavirus, antibodies with remarkable specificity neutralize the virus’s targets, including on the spike proteins in its “crown.” Then, IgG can neutralize COVID-19. Laboratory kits that can be widely distributed will enable us to know, even with home testing, who has generated these protective antibodies.
The immune system has another white blood cell type with a precision armament: T cells. These have receptors that are designed like antibodies, giving them high specificity for COVID-19 as it invades the respiratory tract. Once the T cells encounter and recognize the viral enemy, they release a deadly arsenal of chemical toxins with names such as perforin – appropriately named because it can pierce through viral walls, just as anti-tank weaponry can shred heavy armour. Between the immune system’s antibodies and its T cells, our precision weaponry can deliver powerful chemical payloads that destroy COVID-19.
One of the remarkable aspects of these specific weapons – the antibodies and the T cells – is their capacity to provide immunologic protection for long periods should there be subsequent waves of attack. For many viruses, immunity gained in the first encounter or through a one-time vaccination produces long-lasting and even lifelong protection. For other viruses that mutate rapidly, we need to develop seasonal vaccines, as we do for influenza. We will need to learn the duration of our immunity to COVID-19 and whether future vaccines will require seasonal “boosters."
It should be emphasized that the weapons of war are often double-edged swords. The same chemicals that mediate fever can, like all munitions, be dangerous if not handled correctly. One of the presumed causes of death for those whose disease has progressed to require a ventilator is a dreaded “cytokine storm." In this scenario, IL-1, IL-6 and cachexin all explode like a stray bomb in an arms depot, unleashing a conflagration that kills our own immune forces and damages the territories where they’re most needed and most concentrated – in this case, the lungs. This kind of immune injury is akin to lethal “bystander damage.” On very rare occasions, the immune system targets our own tissues in a deadly act of friendly fire, mistaking them for a similar molecular structure in a virus. There can also be other enemies that follow the devastation of the first attack: After the 1918 influenza pandemic, there was an outbreak of Parkinson’s disease, and after the 1976 swine flu pandemic, there was an increase in a rare paralytic neurologic disease. (These events have not been detected at this time with COVID-19.)
In this war, our immune defence forces are quite formidable, but there is still a lot we have to learn. Clearly, maintaining a state of readiness is key. But while underlying diseases, including diabetes and hypertension – and even aging itself – appear to decrease the efficacy of our immune defence forces, a wonderful surprise is how well children are handling exposure to COVID-19.
Thinking of the immune system as a highly co-ordinated military provides a framework for us to understand how our own body responds and fights in case of infection during this continuing biological war. We are armed and ready – and with our own defence systems working at full force, we will win.
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