When a cell feels that it has been infected by a virus, it generally knows that it is doomed. Soon, it will be destroyed by the body’s immune patrol or detonated by the invader itself. So the dying cell plays its trump card: it lets out microscopic shrieks that danger is near.
These intercellular messages, carried by molecules called interferons, serve as a warning signal to nearby cells: “’You’re about to get infected; it’s time for you to establish an antiviral state,’” says Juliet Morrison, an immunologist at UC Riverside. The receptor cells begin to batten down the hatches, turning on hundreds of genes that help them pump out sets of defensive proteins. Strong, forceful interferon responses are essential for early viral control, acting as a “first line of defense” that kicks in within minutes to hours, says Mario Santiago, an immunologist at the University of Colorado Anschutz Medical Campus. At best, interferons can contain the infection so quickly that the rest of the immune system hardly needs to intervene.
Viruses, of course, are not content to let that happen. Virtually all of them, SARS-CoV-2 included, are very good at affecting interferon signaling or finding their way around virus-blocking shields that cells put up after heeding those molecular calls. And as new strains of coronaviruses emerge, they may steadily improve their ability to withstand the hit of interferons, perhaps making it easier for microbes to spread within and between bodies, or causing more severe illness.
This development may sound a bit familiar: As the coronavirus has evolved, one of its main moves has been to repeatedly dodge antibodies generated by past infections and vaccines. But there is a key difference. Although antibodies are powerful, most are capable of recognizing and attaching to only a super specific portion of the body of a single pathogen. Meanwhile, interferons are the ultimate generalists, a set of general burglar alarms. Even if the body has never seen a particular pathogen before and there are no relevant antibodies, cells will produce interferons as soon as they realize there is a virus – “any and all viruses,” says Eleanor Fish, an immunologist at the University from Toronto. . “It doesn’t matter what the virus is, it doesn’t matter where it comes from.”
Once warned, the interferonized cells spring into action. They will reinforce your exteriors; sharpen the molecular scissors that can cut the microbe into pieces, should it enter; and conjure up sticky substances that can prevent the progeny of the virus from getting out. All of this gives the immune system time to wake up, again with the help of interferons, more precise fighters, like B cells and T cells.
But this system is not infallible. Some viruses will hide their guts from cellular sensors, so the relevant alarm wires will never go off. Others destroy the gears that make the interferon system work, so the warning signals are never sent. Particularly resistant viruses may not even care if interferon messages are emitted, because they can fortify themselves against the many defenses that the molecules mount in other cells. Strategies like these are pretty ubiquitous because they are crucial to the success of pathogens. “I challenge you to identify any virus that doesn’t have factors in its genome to block the interferon response,” Fish told me.
This, from our perspective, is not ideal. They derail these early responses and “there’s a domino effect,” says Vineet Menachery, a coronavirologist at the University of Texas Medical Branch. More cells are infected; Antibody and T cell responses are delayed, even as viral particles continue to spread. Eventually the body can become wise and try to catch up. But by then, it may be too late. The worst of viral replication may be over, leaving the immune frenzy to divert much of its ravages to our own tissues.
Interferons, then, can make or break a host’s fate. Researchers have found that people whose interferons are weak or slow after contracting the coronavirus are much more likely to get seriously ill. Others experience similar problems when their immune systems make the wrong antibodies that attack and destroy interferons as they try to transmit messages between cells. Interferons also play a very dramatic role in counteracting the viruses that cause dengue and yellow fever. Those pathogens are quickly mopped up by rodent interferons and never make those animals sick, Morrison told me. In people, however, microbes have invented ways to silence the molecules, one of the main reasons they cause such debilitating and deadly diseases.
Coronaviruses in general are pros at interferon sabotage. Among the most powerful is MERS, which “just shuts everything down” on the interferon assembly line, says Susan Weiss, a coronavirologist at the University of Pennsylvania. Basically, that ensures that almost no interferons are released, even when there are lots of viruses going around, a dismantling of defenses that likely contributes to MERS’s substantial mortality rate. Weiss doesn’t think SARS-CoV-2 is likely to copy her cousin in that regard any time soon. The virus has some ability to shut down interferon production, but it would take much more, she told me, to silence the system as MERS has.
Still, SARS-CoV-2 appears to be taking its own small, tentative steps toward interferon censorship. For months, several groups of researchers, including CU Anschutz’s Santiago, have been studying how well the virus can invade and replicate inside cells that have been exposed to interferons. They found that recent variants like Delta and Omicron appear to be better at infiltrating those hardened cells compared to some versions that preceded them, a hint that this resistance could be helping new iterations of the virus spread across the globe and cause repeated rounds. of illness
The increase in SARS-CoV-2 resilience doesn’t appear to be huge, more “on the margins” of improving infectious success, Menachery told me. Antibody evasion, for example, could be playing a more dominant role in helping the virus spread and make more people sick. Still, the pattern that’s unfolding raises a disturbing question, Santiago told me. The potency of interferons against the virus already appears to be slowly but surely being undermined; “What if at some point in the future, the virus becomes much more resistant?” The challenge of managing COVID, whether through vaccines or antivirals, could be disproportionately increased. And unlike antibody evasion, with interferon resistance, “there’s nothing we can do to vaccinate against this,” Menachery told me.
Still, there is probably a ceiling to how resistant to interferon the coronavirus can become. Eventually, repeated attempts to disarm our alarm systems may “take a toll” on the infectious potential of the virus, or the speed at which it spreads, Morrison told me. Interferons are also extremely diverse and have redundancies between them. If one pathogen confounds one flavor, another is likely to help fill in the gaps.
Many researchers, like Fish, are also testing interferon-based treatments in people who have recently been infected or exposed to the coronavirus. Several of these trials have produced mixed or disappointing results. Still, “I think there’s every reason to think that interferons will still be effective” in some form, once scientists figure out the timing, recipe and dosage, says Eric Poeschla, Santiago’s collaborator at CU Anschutz. The molecules are, after all, nature’s homemade antivirals.
However, for such a gamble to pay off, viral evolution, and therefore viral transmission, will need to be kept in check. SARS-CoV-2 has a huge wiggle room in its genome; Giving him less practice in infecting us is one of the easiest ways to stop his self-improvement urge. “Each replication cycle is an opportunity,” Menachery told me, for the virus to fine-tune its MO further.
Source: www.theatlantic.com