• Alex Cloherty

The long arm of the immune system

Updated: Aug 12, 2020

When the cell came crashing down

And the virus turned around

It felt its future prospects grow dim

It stood face to face with the long arm of the immune system

{ to paraphrase Kenny Rogers }

Last week, we covered how the cellular soldiers of the immune system spring to action upon infiltration of your body by an enemy microbe. Innate immune cells like macrophages and dendritic cells lead the initial counter-attack, by literally eating up as many of the enemy microbes as possible. These cells then digest the enemy microbes, and actually display bits and pieces of the unlucky enemy microbes on their cell surface.

This gruesome armour, composed of the digested remains of enemy microbes, is not only a warning; it also acts as a messaging system to inform adaptive immune cells of what they need to look for. Adaptive immune cells, like T cells, which act as tanks and directly blow up the enemy, and B cells, which produce antibodies and thereby lay traps that can entangle the enemy, not only help with the current campaign against the enemy microbe, but they also have a memory. The memory of the adaptive immune cells means that, the next time the same enemy microbe tries to enter the kingdom of your body, the defense will already be lying in wait. The defensive forces now know exactly what that particular enemy looks like, which means that they can more quickly mount their defense.

But, as you might remember from the many excellent articles currently circulating about the novel coronavirus, some enemy microbes, like viruses, enter your cells pretty quickly. So quickly, in fact, that they can catch the innate and adaptive arms of the immune system unaware. Although these first two arms of the immune system are extremely effective, they do need to first detect the enemy before they can act. But if the enemy swiftly and sneakily infiltrates, like a thief in the night, the actors of the innate and adaptive immune systems can end up blissfully unaware of the danger until it's too late.

And that, my friend, is why we weird and wonderful eukaryotes (i.e. organisms composed of cells with multiple complex sub-compartments - like us humans) have evolved to further outsmart viruses. That is why we have a third arm of the immune system: cell-intrinsic immunity.

Unlike innate and adaptive immunity, which need to be 'turned on' by signs of the enemy, the components of cell-intrinsic immunity are constitutively expressed - or in other words, constantly 'on'. Unlike the cells of the innate and adaptive immune systems, the actors of cell-intrinsic immunity are proteins - and thereby more like machines than soldiers. And, these proteinaceous machines are within cells. To keep with the Star Wars analogy from last week, these proteinaceous machines resemble defense droids. They are "designed to defend their organic masters from hostiles", and are constantly on the lookout. As soon as a virus enters a cell, the proteinaceous defense droids will jump to action.

As in the Star Wars universe, there are many different types of proteinaceous defense droids, with many different strengths and abilities. However, they all have a single goal in common: to defend the cell.

For example, upon encountering a hostile microbe, many of these 'droids' trigger the production of a type of message called 'interferon' within their cell. This cellular message is well named: it interferes with the replication and infection cycles of the intruder. When a single infected cell starts producing interferon, both it and its neighbouring cells will start making and stockpiling additional proteinaceous machines that help with antiviral defense. Furthermore, when interferon is sent outside of the cell and out through the rest of your body, it calls the innate and adaptive arms of the immune system to action. It's a back-up mechanism to alert them to the microbial danger, in case they haven't sensed it already.

Other types of 'droids', which virologists call 'restriction factors', can directly target the hostile virus for imminent destruction. For example, my supervisor showed that a 'droid' called TRIM5α recognizes pieces of the HIV-1 virus, and targets the virus for destruction via the recycling system of the cell. In Star Wars terms, TRIM5α throws HIV-1 into the garbage compactor of the Death Star.

Of course, this additional cell-intrinsic defense system isn't foolproof. Over the course of capital-T Time, viruses and their hosts have been engaged in an unending battle. Both players are constantly evolving and counter-evolving to one-up the other. When we eukaryotes evolved cell-intrinsic immunity defense mechanisms, viruses evolved alongside us. As this paper beautifully put it,

In order to replicate and transmit, viruses need to counter and evade the multi-layered host restriction defense system... Viral antagonism against a host restriction factor also demonstrates the presence of this restriction in the context of in vivo viral infections, which have driven the selection and evolution of specific viral counter measures. Indeed, viral antagonistic strategies… illuminate the diversity of viral evolution in evading host restriction.

In one sense, it is a battle. In another sense, it is a dance. Together with our viruses, we are entangled in an evolutionary tango that will endure for as long as we dancers do.

Until next week,

Dance on.

~ Alex

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