"Avoid influenza, gargle daily"
“How to avoid influenza: Gargle Daily”

Every virus that infects a vertebrate, has to be able to deal with the vertebrate immune system. The virus’s ancestors that infected vertebrates must have been able to deal with the vertebrate immune system. Those viruses that couldn’t handle an immune response are extinct.

Some of the ways viruses handle immunity, we don’t think of as really “specific”. Rapid replication, for example, has benefits for the virus that extend past just beating the immune system to the punch. But just about every virus, even the smallest ones, also have some form of specific immune evasion gene — some way of blocking, dodging, diverting, or confusing the immune system.

In spite of this nearly universal presence, we don’t really have a good grasp of precisely what viral immune evasion genes do, as far as supporting viral pathogenesis. (For that matter, it’s only for a handful of viruses that we really have much understanding of the pathogenesis in general.) Some viruses have a huge number of genes that are clearly immune evasion genes, others apparently only have one or two. Sometimes you can knock out an immune evasion gene and virtually destroy the virus’s ability to infect; sometimes the knockout only has a modest effect; sometimes there’s no effect at all, or it may even make the virus more, rather than less, virulent.

Viruses are so different from each other1 that there are probably few if any general rules for immune evasion. Still, we’re not even at a point yet where we have non-general rules, so the more we learn the more likely we are to see patterns.

Physicians thank influenza (1803)
Physicians expressing their thanks to influenza.
Coloured etching attributed to Temple West, 1803.

Influenza, of course, has its own set of immune evasion genes. The most important one is the NS1 gene.2 NS1 blocks the interferon pathway, and to the extent that we can generalize, it seems that blocking interferon is one of the most critical things any virus can do. Almost every virus has some way of meddling with the interferon pathways, whether by preventing interferon from being triggered or inducing resistance to the effects of interferon. It’s been known for quite a while that NS1 does this — prevents interferon from being turned on — for influenza viruses, and it’s also been known that NS1 is very, very important to the virus. Mutant influenza viruses without NS1 are much, much less virulent than wild-type virus, and even targeting NS1 after an infection has started can help treat influenza.

(A flip side of this is that influenza viruses with a particularly effective NS1 may be more virulent. The 1918 pandemic influenza, which had a very high mortality rate,3 seems to have a particularly effective NS1 that can block interferon in several ways, and it’s been shown that swapping just the NS1 from the 1918 virus can make otherwise mild flu viruses more virulent. See my previous post about that.)

But there’s a bit of a paradox here. We know that NS1, the interferon blocker, is important to influenza virus. But we also know that interferon is very important in controlling influenza virus infections. For example, mice that can’t respond to interferons are much more susceptible to infection with avian influenza.4 So if NS1 works by blocking interferon, why does interferon still protect?

For that matter, one of the major explanations for why some influenza viruses (like avian flu and the 1918 flu) are so virulent, is the “cytokine storm” hypothesis.  (I talked about cytokine storms here and here.)  According to this concept, these viruses are especially lethal because they induce a huge release of cytokines, such as interferon. Yet at the same time the argument is made that these viruses are the ones with especially effective interferon blockers. If they’re really good at blocking interferon, then why do people die of having too much interferon?

It turns out that part of the answer may be timing. A recent paper from Thomas Moran’s group5 shows that in the very earliest stages of influenza virus infection, interferons are not being produced; then, a couple of days in, there’s a sudden big bang of cytokines. Knocking NS1 out of the virus changed this; interferons were produced from the beginning of the infection, and the virus was shut down. They call this phenomenon “stealth replication”:

Our data demonstrate that the initiation of lung inflammation does not begin until almost 2 full days after infection, when virus replication reaches its apex. The migration of lung DCs to lymph nodes and the subsequent priming of naive T cells are similarly subject to this delay. We demonstrate that the delay in the generation of immediate lung inflammation is mediated by the influenza NS1 protein. We propose that the virally encoded NS1 protein establishes a time-limited “stealth phase” during which the replicating influenza virus remains undetected, thus preventing the immediate initiation of innate and adaptive immunity. 5

They point out that in normal human influenza virus infection, symptoms take a couple of days to kick in, which fits because most of the “flu-like symptoms” we talk about are generic effects of cytokines. They also point out that a lot of virus transmission occurs before symptoms — i.e. in the first couple days of infection.

Thus, a stealth phase may also occur in humans and probably functions to maximize the probability of transmission before cytokines such as type I IFNs hamper the normal replicative cycle of influenza virus.5

This also helps make sense of the cytokine storm concept, I think. If avian or 1918 NS1 is especially good at preventing cytokines, then there might be a slightly longer stealth period, during which time the virus can replicate more. Then, when the immune system suddenly does become aware of an infection, there’s a huge amount of virus present, and the cytokine response would be correspondingly huge.

We might even be able to generalize to other viruses:

The stealth phase concept is not only applicable to influenza virus but can probably be extended to virtually all “real” human viral pathogens that have been shown to have an asymptomatic incubation time. For example, measles and varicella zoster viruses have a substantially prolonged evasion period that can last up to 2 wk. During this asymptomatic phase, these viruses also transmit to other susceptible hosts. Research aimed at interfering with the stealth phase may lead to the development of novel modulators as preventive treatments that target this early immune evasion mechanism. 5

I want to point to a previous post I made here, too, about herpes simplex virus. HSV has a wide range of immune evasion molecules, and we don’t have much understanding of what these things do in a natural infection.Frank Carbone’s group  did experiments with mouse infection that showed that HSV has a very narrow window (less than 24 hours) during which it can move from its original site of infection, in the skin, to neurons where it sets up a life-long infection. If the immune response can control HSV in this window, the virus can’t get into neurons and its life cycle is cut short. I speculated at the time that this might help explain immune evasion by HSV — it wouldn’t have to be super efficient, just keep things under control during that brief, early window. Seems quite similar to the influenza situation: Timing is critical, and perhaps immune evasion is one reason why.

  1. “Virus” isn’t a natural division; it groups together things with very different, and completely unconnected, evolutionary histories[]
  2. “NS” stands for “Non-structural”, meaning that the protein isn’t part of the virion that floats around and infects new cells — rather, the NS1 protein is produced anew in each cell after infection.[]
  3. As influenza infections go — not close to something like smallpox or ebola, but some 20 times higher than normal seasonal flu[]
  4. Szretter, K., Gangappa, S., Belser, J., Zeng, H., Chen, H., Matsuoka, Y., Sambhara, S., Swayne, D., Tumpey, T., & Katz, J. (2009). Early Control of H5N1 Influenza Virus Replication by the Type I Interferon Response in Mice Journal of Virology, 83 (11), 5825-5834 DOI: 10.1128/JVI.02144-08[]
  5. Moltedo, B., Lopez, C., Pazos, M., Becker, M., Hermesh, T., & Moran, T. (2009). Cutting Edge: Stealth Influenza Virus Replication Precedes the Initiation of Adaptive Immunity The Journal of Immunology, 183 (6), 3569-3573 DOI: 10.4049/jimmunol.0900091[][][][]