Infecting monkeys with 1918 pandemic flu virus

It may not be the most comforting headline, but it certainly is of interest to flu watchers: Rebuilt 1918 Flu Infects Monkeys, May Assist Research (John Lauerman, Bloomberg). It's also a pretty accurate headline. Nice to see. So what's it all about?

Most people who come here know that the 1918 "Spanish flu" virus has been reconstituted, using information frm fragments of the viral genetic material dug up from frozen corpses in Alaska, Siberia and pathology samples kept in archives. Once the entire sequence was pieced together the actual genetic material could be constructed and allowed to make a whole virus. This work was done years ago and so far the actual virus only exists in two places, under high containment. Some people are disturbed that this was done at all, and we agree it is a potentially risky venture, but it also has potential for substantial payoff, so in our estimation it is a risk worth taking. What have we learned and what more can we learn that is of more than historical importance?

We see two main questions. The first is whether the current pandemic threat from H5N1 is similar to 1918, and if so in what ways. The current descendants of that H1N1 virus are very unlike their deadly forbearer. In a paper in Nature (first paragraph only unless you have a subscription), the subject of Lauerman's article, the reconstituted 1918 virus was used for the first time to infect non-human primates (macaque monkeys) and compared with a later strain of H1N1 typical of seasonal influenza. As it has in mice and ferrets, the 1918 virus produced a rapidly fatal respiratory distress syndrome with all the hallmarks of the clinical cases described in the 1918 pandemic. Significantly the monkeys were inoculated with both viruses intranasally, that is, in the upper respiratory tract. Symptoms appeared within 24 hours. The animals infected with the contemporary H1N1 suffered only mild disease.

The 1918 virus infected tissues at high titers in both the upper and lower tracts through day 8 or until being euthanized. The contemporary virus was present in high titer only in the upper tract and was mostly gone by day 8 with no evidence of pathology in the lung. By contrast the 1918 virus produced severe lesions in 60% to 90% of the lung and virus was recovered from heart and spleen of some animals. The 1918 virus replicated at high level in many different types of cells in the respiratory tract, upper and lower.

The part of the paper that has attracted most attention, however, was the (by ow expected) dysregulation of the innate immune system. This is an intricate signaling system used by the body to respond immediately and in a fairly non-specific fashion to some kind of invasion by a foreign organism like a virus. The system involves chemical signals sent out both locally and systemically to call for help from other kinds of immune cells. Infected cells sense the presence of a foreign invader and sound alarms of various kinds, some of which tell immune cells to get ready to fight, some of which open the gates to the battle area, some of which prepare the ground for the cavalry to gain a foothold at the scene, and some of which issue orders for some of the battalions to stop and let others take over.

Sometimes the signaling systems break down and anarchy results. It's as if all sorts of different police forces and fire departments from various localities using different weapons were to descend on the scene at once with no overall coordination and no signal to stop. We've seen how this can happen in much simpler situations. Historical social events that come to mind are the Democratic Convention in Chicago in 1968 (described by the later Kerner Commission as a "police riot") or the LA riots in the wake of the Rodney King episode. When things spiral out of control, more damage can result. When this happens in the lung as a result of an H5N1 or 1918 H1N1 infection, it is called a cytokine storm (a bit of misnomer, since it is a dysregulation and involves also chemokines).

It is common to jump to what we believe is an incorrect interpretation: the damage is being done by an "overactive immune system." That is a bit like saying the Chicago Convention violence was caused by an "over active police department." In truth, the problem was a lack of discipline, permitted by a series of political decisions by Mayor Daley's administration. I use this analogy not for political purposes but to provide a vivid illustration that is easier to understand, whether you blame Daley or not. The point is that the police were allowed or induced to "be inappropriately active," not that they were inherently over active or "too strong." Another analogy would be a car whose accelerator gets stuck or whose brakes fail, or both, although this makes it sound too simple. The innate immune system, like a police force, is a complicated series of interlocking parts that have to work together. If they fail in a specific way, a police riot ensues. Somehow the 1918 and H5N1 viruses are able to do the same kind of thing to the immune system. It is this lack of coordination and discipline that is the problem, not its "overactivity."

This paper provides valuable new information on what parts of the innate system are out of kilter in comparison to the more benign contemporary H1N1 virus. We are a long way from deciphering how this system works and what goes wrong, however. A recent paper by La Gruta et al. in Immunology and Cell Biology (2007, pp 1 - 8) reviews the immunopathology of influenza infection in some detail and observes that many of the dysregulated cyto/chemokines have both positive and negative effects:

Immunity to the influenza A viruses is multifaceted and highly complex, involving different arms of the host response, all of which appear to be required for efficient virus clearance. However, exacerbation of any one or more of these response element can result in severe immunopathological damage. While the studies reviewed here provide strong indications that such immune-mediated pathology can occur, we do not yet have sufficient understanding of such effects to suggest possible mechanisms for clinical intervention. . . . Any therapeutic dampening of influenza-specific immune responses wish agents such as steroids would thus need to be done with a high degree of precision to balance the immune system's positive and negative effects."

The second major question we can answer from the 1918 virus regards transmissibility. Fortunately we do not as yet have an easily transmissible version of H5N1 but we do have an easily transmissible 1918 virus. The pandemic of 1918 is proof. From a news article in Nature:

A team at the Mount Sinai School of Medicine has already started to investigate. Peter Palese is working with Adolfo Garcia-Sastre and Jeffery Taubenberger, who first reconstructed the virus, to find out how it spreads. Working with ferrets, they have found that a change of only one or two amino acids in the flu sequence is enough to stop transmission. They will publish the result in Science. Identifying which sections of the genome are responsible for transmission "has huge predictive value for whether strains will become pandemic or not", says Guus Rimmelzwaan at the World Health Organization's National Influenza Centre in Rotterdam, the Netherlands. (Kerri Smith, Nature)

This is the second thing we can learn from the 1918 virus. It is a pretty Big Thing, too. The same two amino acids that stop 1918 from transmitting may shed important light on what it might take to make H5N1 transmissible. We eagerly await Palese, Garcia-Sastre and Taubenberger's article.

Is reconstituting the 1918 virus and using it to infect animals a risk? Yes. In our view, however, the risk is plausibly worth it. There is a greater risk in not obtaining the information.

More like this

Adolfo Garcia-Sastre, a Mount Sinai microbiology professor who conducted some of the earlier mouse work, said it may be a mistake to focus so heavily on immune system response. The 1918 flu virus "induces an overwhelming and probably damaging immune response system" but it is largely because the virus grows so much, he said.

In mice, when the overactive immune response was eliminated, mice died because of high viral levels.

"It's like a vicious circle, you get more viruses, you get more immune response and this results in damage," Garcia-Sastre said
--from the AP story

Would pharmacological downregulation of the innate immune system be a treatment?

This is consistent with the La Gruta review. However how the virus is able to reach such sustained and high viral titers is a question of the immune system, too. It may involve NS interaction with interferon workings, on the one hand (the alternate reading frame product) and recruitment of more macrophages, on the other by the regualr reading frame of NS. The idea that the tissue damage is secondary to viral load is consistent with other data, but why high viral loads continue is related to the other factors. This is a complicated interacting system and IMO trying to pick the element that is primary at this point is not possible. We may someday get to the point where we understand it well enough to do that but I don't think we are there yet.

sparc: It might be but it might also create havoc. We are not at the point where we can say what will work and what won't. Research like this is important to unraveling this intricate mechanism, which is why I think it is worth the risks. But it will take a great deal more effort to limn this system.

You are of course right about the fact that it is a risk worth taking.

However as the following news item shows, the labs handling dangerous viruses need to be monitored by the powers-that-be and more importantly, full public disclosure is needed from the said labs.

The The following news item, is from "Life Style Extra" of UK, headed "Lab accident sparks bird flu outbreak fear".

Apparently, a near-miss with the modified bird flu virus, happened last April, at the University of Texas and has only just now been exposed, mainly due to the efforts of Mr Ed Hammond, director of the Sunshine Project, an Austin-based pressure group.

He said that the incident only came to light because he demanded to see the university safety committee's records.

Full article here: http://www.lse.co.uk/ShowStory.asp?story=FC1733116X

JM

TBBFBT: I know Ed and have been following this story for about a week. I am trying to get some more info from another source.

The news item posted above, is in fact from the issue 2587 of New Scientist magazine, 20 January 2007, page 14.

This item is on our site, under the heading "Hybrid flu virus in near-miss escape" by NewScientist.com.

JM

Makes you want to run right out and watch the movie outbreak again. Would they do a state capitol? Dunno, but I think they should have double blind security and safety measures in place. This would make me as nervous as a cat if I was an insurer for a University. Protocols not followed, state run institution, flu breaks out... does sound like a movie plot. Fact is that when this kind of stuff happens the first thing that a government institution does is to clam up... wrong answer. The fact that its covered up is conspiracy in most states and about 80% of Federal statutes.

By M. Randolph Kruger (not verified) on 18 Jan 2007 #permalink

From the incident at UT, it sounds like people might want to turn their worried eyes towards people working with H5N1. No, H5N1 is not (yet) as contagious as the reconstructed 1918 H1N1... but only two labs have the latter, and it sounds like they're being very judicious both in handling it (Level 4 Laboratory, limited number of people with access) and in sharing it with other labs (they haven't, so far).

Besides, if the 1918 H1N1 got loose again, wouldn't it less destruction than it did in 1918? If there is widespread exposure amongst humans to its seasonal flu descendents.

Meanwhile, we have who knows how many labs doing who knows how many experiments doing who knows what with H5N1. Even with appropriate safety precautions and well-trained personnel, the chance of something going horribly wrong, while probably infintesimal, is multipled by the number of labs it's in.

It puts a little caution into our continued hopes that more research be done.

The key is to inhibit the pro-inflammatory cyokines while bootsing the anti-inflammatory ones until they come into more of a balance. Tough to do as some switch roles during the course of an infection.

The notion that it is "worth the risk" to resurrect one of the most deadly most virulent diseases ever encountered may be the best example of hubris I've yet seen from the bioscience community.

Estimates of deaths from the 1918/19 outbreak range from 20 to 100 million people.

The 1918 Spanish influenza was essentually extinct. Now its not. The Chinese or Russian or Iranian government will not want to be caught in a virus gap. The liklihood of proliferation of the virus has now jumped from virtually nil to something much greater. (Have I read correctly that the genetic code of the virus has actually been published?)

The notion that the virus will be studied only in BSL-4 labs is no reason to feel comforted. As the Canadian company that builds these labs in Canada and the U.S. has explained, these labs are now as safe as the space shuttle.

No one who has actually taken the time to look into the safety record of BSL-3 and -4 labs can believe that an accident is unlikely; its a near certainty.

I would characterize the resurrection of an extinct virus known to be so deadly as a crime against humanity. No sane person could find this a good thing. Worth the risk? With today's jet travel, spread of this virus would be much faster than in 1918. This is nuts.

It is likely that the monkeys used in this experiment (or demonstration, to my mind) died a hideous death. It is likely that more will be similarly used.

The bioscience community can't be trusted to self-police, they seem to have few moral constraints, and the regulations that should be keeping their behavior in check are little more than window dressing.

This is hubris run amok.

Can you say Andromeda Strain? How about The Stand?

Rick: Since I feel the way you do about smallpox (the virus should be destoryed) I don't think we are dealing with hubris but judgment. I understand your point. I just have reached a different conclusion in this particular case and we disagree.

Hubris is pandemic.

The bioscience community, at least the civilian part, does show some signs of partial immunity.

I disagree that it's hubris. Hubris would be doing it because they can, to demonstrate how smart they are, or to satisfy some wonkish curiosity, with no real consideration given to possible consequences.

There is some non-zero chance of a containment breach leading to a re-release of the virus. But there is also a much larger risk of a pandemic with a virus that shows eerie similarities to the 1918 virus. They're hoping that by studying the later, they might save lives from the former. This sounds like a calculated risk. It might, or might not, be good judgement.

Personally, I find the fact of a containment issue at a lab combining seasonal flu with H5N1 far more unnerving that the resurrection of the 1918 virus. (Revere, would a resurrected 1918 pandemic virus be as deadly as it was then? Since H1N1 is no longer a novel virus to humans.) Do we even know how many labs are tinkering with H5N1 in such ways, or what their biosecurity measures are like?

P.S.

It is likely that the monkeys used in this experiment (or demonstration, to my mind) died a hideous death.

Actually, they were euthanized after eight days to end their suffering.

As the Canadian company that builds these labs in Canada and the U.S. has explained, these labs are now as safe as the space shuttle.

Do you have a link?

Not so fast on destroying the smallpox just yet Revere. It is well known that you can get smallpox from the graves of those who have died. Talk about a mean bastard bug this is it. So you have to have the bug to build the vaccine. Vektor in Russia was rumored to have built a super variant too so unless you know a way to get rid of it completely we need to have it on hand.

The above on people working with H5N1 is well taken. The Chinese in all of their transparency and cooperation offered up H5N1 samples to the world last week or the week before. That means Fedex or someone is going to transport it. Sure they use some safeguards but if you have never been to a hub and see how sometimes, for no apparent reason it takes everything on the belt and tries to run it thru the belt. Their first inclination is to stop the belt, clear the jam and then find out what it was that went thru it. Then there are the people who actually get and use it. Could H5N1 be used as a bioweapon? Yeah, but yeaks you lose the battle, the war and the whole potato if you do. Are there people out their that think that GOD will save them because they are the chosen ones if they do unleash it? Yep.

Whatever you do, dont let PETA know where the samples go to be used on monkeys.

By M. Randolph Kruger (not verified) on 19 Jan 2007 #permalink

As the Canadian company that builds these labs in Canada and the U.S. has explained, these labs are now as safe as the space shuttle.

i too would like to see some evidence of this. if true, it seems quite unacceptable, and quite hard to believe --- a microbiology lab should be easy to make far more secure than the shuttle is, or even than the shuttle was ever meant to be.

By Nomen Nescio (not verified) on 23 Jan 2007 #permalink