Makings of a Killer

NS1 protein binding to RNA

The first line of our triple firewall against infection is our barrier defense. Once this wall is breached, we have to rely on an array of nonspecific defenses known as the “innate” arm of our immune system. These are typified by Pacman-like roving cells called macrophages (literally from the Greek for “big eaters”), which roam the body chewing up any pathogens they can catch. In this way, any viruses caught outside our cells can get gobbled up. Once viruses invade our cells, however, they are effectively hidden from our roaming defenses. This is where our interferon system comes in.

Interferon is one of the body’s many cytokines, inflammatory messenger proteins produced by cells under attack that can warn neighboring cells of an impending viral assault.¹⁷⁶ Interferon acts as an early warning system, communicating the viral threat and activating in the cell a complex self-destruct mechanism should nearby cells find themselves infected. Interferon instructs cells to kill themselves at the first sign of infection and take the virus down with them. They should take one for the team and jump on a grenade to protect the rest of the body. This order is not taken lightly; false alarms could be devastating to the body. Interferon pulls the pin, but the cell doesn’t drop the grenade unless it’s absolutely sure it’s infected.

This is how it works. When scientists sit down and try to create a new antibiotic (anti- bios, “against life”), they must find some difference to exploit between our living cells and the pathogen in question. It’s like trying to formulate chemotherapy to kill the cancer cells but leave normal cells alone. There is no doubt that bleach and formaldehyde are supremely effective at destroying bacteria and viruses, but the reason we don’t chug them at the first sign of a cold is they are toxic to us as well.

Most antibiotics, like penicillin, target the bacterial cell wall. Since animal cells don’t have cell walls, these drugs can wipe out bacteria and leave us still standing. Pathogenic fungi don’t have bacterial cell walls, but they do have unique fatty compounds in their cell membranes that our antifungals can target and destroy. Viruses have neither cell walls nor fungal compounds, and therefore these antibiotics and antifungals don’t work against viruses. There’s not much to a virus to single out and attack. There’s the viral RNA or DNA, of course, but that’s the same genetic material as in our cells.

Human DNA is double-stranded (the famous spiral “double helix”), whereas human RNA is predominantly single-stranded.¹⁷⁷ To copy its RNA genome to repackage into new viruses, the influenza virus carries along an enzyme that travels the length of the viral RNA to make a duplicate strand. For a split second, there are two intertwined RNA strands. That’s the body’s signal that something is awry. When a virus is detected, interferon tells neighboring cells to start making a suicide enzyme called PKR that shuts down all protein synthesis in the cell, stopping the virus, but also killing the cell in the process.¹⁷⁸ To start this deadly cascade, PKR must first be activated. PKR is activated by double-stranded RNA.¹⁷⁹

What interferon does is prime the cells of the body for viral attack. Cells preemptively build up PKR to be ready for the virus. An ever-vigilant sentry, PKR continuously scans cells for the presence of double-stranded RNA. As soon as the PKR detects that characteristic signal of viral invasion, the PKR kills the cell and hopes to take down the virus with it. Our cells die, but they go down fighting. This defense strategy is so effective in blunting a viral onslaught that biotech companies are now trying to genetically engineer double-stranded RNA to be taken in pill form during a viral attack in hopes of accelerating this process.¹⁸⁰

Cytokines like interferon have beneficial systemic actions as well. Interferon release leads to many of the other symptoms we associate with the flu, such as high fever, fatigue, and muscle aches.¹⁸¹ The fever is valuable since viruses like influenza tend to replicate poorly at high temperatures. Some like it hot, but not the influenza virus. The achy malaise encourages us to rest so our bodies can shift energies to mounting a more effective immune response.¹⁸² On a population level, these intentional side effects may also limit the spread of the virus by limiting the spread of the host, who may feel too lousy to go out and socialize. Cytokine side effects are our body’s way of telling us to call in sick.

Normally when you pretreat cells in the lab with powerful antivirals like interferon, the cells are forewarned and forearmed, and viral replication is effectively blocked.¹⁸³ Not so with H5N1, the deadly bird flu virus spreading out of Asia. Somehow this new influenza threat is counteracting the body’s antiviral defenses, but how?

Viruses have evolved a blinding array of ways to counter our body’s finest attempts at control. The smallpox virus, for example, actually produces what are called “decoy receptors” to bind up the body’s cytokines so that less of them make it out to other cells.¹⁸⁴ “I am in awe of these minute creatures,” declared a Stanford microbiologist. “They know more about the biology of the human cell than most cell biologists. They know how to tweak it and how to exploit it.”¹⁸⁵

How does H5N1 block interferon’s interference? After all, the virus can’t stop replicating its RNA. The H5N1 virus carries a trick up its sleeve called NS1 (for “Non-Structural” protein). If interferon is the body’s antiviral warhead, then the NS1 protein is the H5N1’s antiballistic missile.¹⁸⁶ NS1 itself binds to the virus’s own double-stranded RNA, effectively hiding it from the cell’s PKR cyanide pill, preventing activation of the self-destruct sequence. Interferon can pull the pin, but the cell can’t let go of the grenade. NS1 essentially foils the body’s attempt by covering up the virus’s tracks. Influenza viruses have been called a “showcase for viral cleverness.”¹⁸⁷

All influenza viruses have NS1 proteins, but H5N1 carries a mutated NS1 with enhanced interferon-blocking abilities. The H5N1’s viral countermove isn’t perfect. The virus just needs to buy itself enough time to spew out new virus. Then it doesn’t care if the cell goes down in flames—in fact, the virus prefers it, because the cell’s death may trigger more coughing. “This is a really nasty trick that this virus has learnt: to bypass all the innate mechanisms that cells have for shutting down the virus,” laments the chief researcher who first unearthed H5N1’s deadly secret. “It is the first time this mechanism has shown up and we wonder if it was not a similar mechanism that made the 1918 influenza virus so enormously pathogenic.”¹⁸⁸

Now that researchers actually had the 1918 virus in hand, it was one of the first things they tested in hopes of understanding why the apocalyptic pandemic was so extraordinarily deadly. They tested the virus in a tissue culture of human lung cells, and, indeed, the 1918 virus was using the same NS1 trick to undermine the interferon system.1¹⁸⁹ As the University of Minnesota’s Osterholm told Oprah Winfrey, H5N1 is a “kissing cousin of the 1918 virus.”¹⁹⁰ H5N1 may come to mean 1918 all over again.