Genes and bird flu are being talked about again. A WHO study is "stating" some kind of genetic factor may be at work, but it appears it is only an observation that in the notorious Indonesian Karo cluster of eight family members, only those "related by blood" were affected by the human-to-human spread:
Only blood relatives were infected in the Karo district of North Sumatra, the largest cluster known to date worldwide, "despite multiple opportunities for the virus to spread to spouses or into the general community," it added.The theory - which it said merited further study - was contained in WHO's report from a closed-door meeting of 35 scientific experts held in late September. (NineMSN)
Maybe. Maybe not. This is an observation, not a "study." As WHO says, it deserves further inquiry. This idea was broached at the time of the cluster, but it seems to us the genetic predisposition, if it exists, would have to be very specific (not multifactorial) since the supposed blood relationships of these extended family members would not be so strong as to completely determine host competence for infection. It is a gigantic leap from this observation to the conclusion that one's genes determine infectivity.
It would not be at all surprising, however, for there to be modulating heritable factors that interact with environmental ones (here meaning host resistance from other than genetic causes like co-morbidities, temperature, routes of transmission, dose response, etc.). Animal studies are one way to isolate the genetic factors. A study presented at the American Physiological Society meetings this week provides some interesting clues as to how genetic factors might affect host response.
Experiments investigated how genetic factors in mice might explain why some mouse strains are much more severely affected than others. Here it is not a question of being infected or not, but of how serious the infection is. Researchers at Southern Illinois University looked at two inbred strains of mice, one of which was lethally affected by H5N1 infection, the other of which suffered illness but only mild mortality rates.
[Rita] Trammell and [Linda] Toth infected two strains of laboratory mice with an Influenza A virus. "Our previous studies established that if you give the same dose of influenza A virus to both strains of mice, about half of the BALB/cByJ (Type B) mice will die, compared to about 10% of the C57BL/6J (Type C) mice," Trammell said.
The researchers studied the early immune response by examining the lung tissues of mice 30 hours after they were infected. They measured the amount of virus, cytokines and myeloperoxidase that was present in the lungs.
Cytokines and myeloperoxidase are proteins that function in the immune response. Some cytokines are pro-inflammatory, that is, they cause inflammation that helps to eliminate the pathogen. In a well-orchestrated immune response, pro-inflammatory cytokines act first and then recede once the virus is eliminated. Anti-inflammatory cytokines regulate the immune response to minimize damage to normal tissues. Myeloperoxidase is an enzyme that indicates the number of neutrophils -- a type of white blood cell -- present in the lung.
The researchers found the level of virus in the lungs of the two mouse strains did not differ significantly. However, all the pro-inflammatory cytokines, with one exception, were significantly higher in the Type B (disease susceptible) mice when compared to Type C (disease resistant) mice.
"Although viral titers are equivalent, B mice develop a much greater pro-inflammatory response during influenza infection than C mice, which may contribute to the differential mortality in these strains," the authors concluded. (Eurekalert)
To confirm the results Trammell and Toth collaborated with SIU colleague Ming Ding to show using microarrays that the genes for producing immune related proteins were expressed differently (mRNA levels) in the two mouse strains.
Like the other study, these researchers found no difference in the amount of virus in the lungs of the two mouse strains after influenza infection. But they were "amazed at the difference in immune-related mRNA levels between the two strains," Trammell said. When compared to uninfected control mice, the mRNA levels in Type B mice were on average 24 times higher, with some types of mRNA increasing more than 100 fold. In contrast, mRNA levels in Type C mice only increased less than 3-fold after infection.
"Both studies show clear and dramatic differences in the pulmonary inflammatory response of the Type B strain of mice, as compared with Type C strain, after infection with the same dose of influenza virus," Trammell said. "These distinctive responses to the identical virus challenge suggest that the genetic control of the inflammatory response differs between these two strains."
In other words, one mouse strain responded with a "cytokine storm," the other did not. The study, as reported, does not reveal what it is that is causing the abnormally regulated response. Finding that out could be an important clue to how H5N1 works, independently of the genetic susceptibility question.
These are both interesting data points regarding the role genes might play in human response to bird flu. The WHO observation is just that, an observation of a single cluster and a very limited observation at that. It suggests that whether someone is infected or not might have a genetic component. Could be. Whether this is true (it wouldn't be unreasonable) and more importantly, how determinative it is, remains unknown. It would be quite surprising to us if a single gene or gene variant made the difference between being able to be infected or not. Even if true, the significance of this, when the virus itself is constantly changing, is somewhat doubtful.
The animal studies are limited in a different way, being studies of mice, not humans. The mice in the experiment are inbred species, genetically homogeneous as a result of inbreeding. Humans are an outbred species. Thus the question is not how much humans are like mice, but which humans are like which mice, and how. These kinds of experiments are more important for what they tell us about the mechanism of H5N1's virulence.
There is much more to the question of genetic influence on H5N1 infection than the implied inference that the reason someone gets bird flu lies in their genes. Infectious disease is an interaction between a host, its environment and the agent. Isolating one element can provide important information but doesn't correspond to the real world.
I'm not sure the WHO observation follows this pattern. I would be wary of such simplistic formulations.
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Speculating aloud here...
Mice B are all identical to each other.
Mice C are all identical to each other.
Mice B and C are different to each other in the regulatory pathways governing inflammation. This may be a single or multi-gene difference between the strains.
Is there any follow up to determine from the RNA expression probes which gene expressions differ between the mice, and to find homologues in humans?
To me this is suggestive that people with allergies or atopic dermatitis are those more likely to be killed by the virus, as would anyone with frank rheumatological disorders.
If the case fatality rate remains high, do you give these people scarce drug, or are these the ones that get tagged 'dead' in triage.
If theories about inflammation and vascular disease are correct (and CRP levels suggest they are), then this bug could prove to be an evolutionary filter against genes that predispose one to heart and vascular disease.
A child watching a snake eat a rat was asked by his father, 'what do you think about that'. The child replied, 'good for the snake, bad for the rat.'
This pandemic may prove good for the survivors, bad for the dead.
(Okay, thats an admittedly feeble attempt both at humor and at trying to find something redeeming about a ghastly situation.)
Good humor as far as I am concerned Lisa. Very descriptive but pandemic is coming and we all know it. The phone will ring and with the level of preparedness in this country being what it is, I would suggest Chinese as the new language to be learning. Good for the snake.
A post pandemic world at the 80% rate would really only leave about 1 billion worldwide. It would give the survivors everything they needed to survive as resources but no way to implement them. Many of those survivors will be those who prepared but were unable to adapt beyond things out of the can. No more cans left. Have to go and get food.
Two things would go by the wayside really fast and first would be the economy, second would be our ability to produce food. So that 1 billion is really now down to about 650 million. On the other hand and this wouldnt be funny the stench would be terrible and contagion of other diseases rampant. So 650 million might get rounded down post an 80% event to about 20 million. Those people would be so hard core that eating a dog raw might not be out of the question and its your sisters dog.
Genetic predisposition to the disease? Maybe, post disposition to survival is my thing. Human die backs have happened throughout history and it may sound like pontification but someone is going to end up in charge and likely it wont be us. It is a terrible situation and every government on this planet seems to be lost in la la land to it. Straight forward adaptive mutation would leave this crap unchanged and frankly at pandemic plus one year at 80% its going to be primaevel in this country. We might have a government but not much of one.
Lisa: These papers have only been given orally so i don't know the details although the outlines are clear. As far as I can tell, they are part of a research agenda to tease out the parts of the regulatory path that is involved. What we will find when we do this I don't know. The microarray work should go som way towards this but more experiemnts will be needed. Then we'll know something -- about these mice.
Randy -
About that Chinese language instruction.
Just about any way the cookies crumble, the PRC is liable to get slammed much harder than we will.
Think about it. An aerosol-transmissible disease? A higher degree of crowding is going to produce a higher attack rate. Assume similar lethality, plug in China's population density, particularly in urban areas, and the simplest arithmetic hands you the rest.
It gets worse for the PRC if you factor in the way they've grown this last 40 years.
BTW, I don't see where your 80% estimate is coming from. Use the available numbers for a horseback guess, and here's what you get. Assume an attack rate of 25 to 33%, and a lethality of 50 to 60%. This gives you a dieback range of 12.5% (best case) to 20% (worst case). Mortality additional to this would be from collateral damage.
Of course, 12.5% of, say, 300 million, is going to be 37.5 million deaths. The worst catastrophe in American history? Yes, beyond any question. 1347-1349? No. Lethality in Britain from yersinia pestis pushed 50%. And they came out of it socially intact, albeit massively traumatized.
Have you people solved out the brain damage question yet? Is the encephalitis due to the virus itself damaging the brain or due to the "cytokine storm"?
Charles thanks. I have been running side numbers against our friends at the WHO. The are posting about a 67% for the last five years. If you take it against the last two it bumps up to about 73% depending on their ever changing numbers, and then for the last year about 80% which is varying each time they post a new casualty or ilness. China would suffer no doubt. Because though of sheer number of people they would come out of it far better than we. We are a fast food network in the US and many will starve because if McDonalds isnt open, a lot of people are going to go hungry at even an 8% rate. Our ability here to grow food is very factory farmed. But over there its very likely hard to get H5 standing in a rice paddy separated from family and friends by 80 to 100 feet as you are planting next season. As long as the PRC is in charge they will force that issue while they sit in their biowarfare masks.
AS for the PRC. China in a side venue could disintegrate into a warlord society replete with your own in home nukes. Once you get one, who is going to take it away from you? The Chinese have about 5000 rounds per man in the army now and its a big army. So the opportunities are quite large for a post flu party. Could the PRC possibly go as part of this? It could. But our ability in even an 8% event to help that along will be very limited. The cities in China will as you say become death houses from overcrowding. SARs proved that pretty well. If its a multiple wave event for all of us then all bets are off. IIf it went for five years and took 12.5% each time, we would be pretty much done in this country and everywhere else for that matter.
So many things to consider but we assume society will hold together. It will for a while. But its the what ifs that really make me wonder. Steve Buscemi's "Embrace the Horror" comes to mind. It remains to be seen if its in our genes. Biblical "chosen ones" if you will? There's the mystery for sure.
Back to Lisa the GP's question: this seems to suggest that perhaps people who already demonstrate a sensitive allergic response system might be predisposed to have a cytokine storm. Yes or no? I was thinking, as I read this, that maybe those people who seem to get frequent colds with lots of mucous production - deep chest congestion, runny nose etc - might be the type that are likely to have this serious inflammatory response. Any thoughts on that?
Any extended disruption of the food supply, whether it's closed restaurants or empty grocery stores, is going to result in starvation to some extent. The cities are going to be BAD, but even many rural areas will suffer. Because no one grows their own food anymore. I live in a rural area with 100 acres of corn/wheat fields across the road, many homes on 5+ acres and I've seen maybe two small gardens in this area (not counting my own). Most of my neighbors are city folk who have a few flower beds if anything. It's scary. And the thought of distribution centers handing out basic food stuffs is almost laughable - how many people would actually be able to cook something edible with a sack of flour, a bag of beans and a box of rice? People will panic when the food runs out. Of course we do have an abundance of cows out here, so providing we could find someone who actually knows how to butcher them.... free BBQ at city hall!
MiH: Yes, I have a response. It is you shouldn't reason like that. I addressed this in a previous post on cytokine storm. This speculation might be true but probably isn't. This is a complex system with a lot of moving parts and allergies are not in the same subsystem as the one we are talking about. Thinking that cytokine storm is an overactive immune system is wrong. It is one very special kind of a dysregulated immune system. It's like saying a car with a stuck accelerator is an over active car.
MRK and CR,
Looking forward to the impact a pandemic would have: on this eve of an interesting American election, wonder what would do better post-pandemic? Red state or blue state?
Revere, how do you see the role of cytokine storm in relation to the H5N1 encephalitis? Any new knowledge?
Thinlina: Encephlilitis is infection of neural cells with the virus. Cytokine storm is a systemic disease of a dysregulated immune system that can have CNS effects but is not primarily a CNS disease.
Yes, that's basics. Are you avoiding to answer my question?
Is it the cytokine storm that causes the signs and symptoms of an encephalitis? We all know that an encephalitis can be caused by viruses and it can be caused by bacteria. It can also be caused by larvae and even by autoimmune reactions e.g. partly multiple sclerosis. Can it be caused by a cytokine storm provoked by H5N1 virus?
Mary, encephalitis is the result here of H5N1 invading the brain via a different route of entry. There is no reason to suppose cytokine dysregulation is not involved, but whether it is involved to the same degree as other tissues remains an unknown.
Knowing that H5N1 is highly neurotropic what would lessen it's ability to provoke an immune storm?
thinlina: I think I am answering your question. Encephalitis is the infection of neural tissue. That means the virus is replicating in the nervous system. Cytokine storm is a dysregulation of the immune response resulting in a runaway inflammatory response in some tissue, usually the lung. That runaway response can have systmic effects, including on the brain but it is not a result of infection of the brain tissue. Encephalitis and cytokine storm can happen simultaneously but they are different ideas. They can also happen independently. Whether they can affect each other's risk is not known.
We hve no evidence at the moment that tissue tropism is related to cytokine storm. The recent NS1 paper doesn't suggest this, but there is much to learn. I appreciate your wanting to know the answers to certain questions, but you must also realize we don't know the answers to most of them.
I don´t specially *want* answers. I'm just trying to find them. As most of us, I guess.
Encephalitis is an inflammation of brain, not only infection. Or why is said "aseptic encephalitis"?
But anyways, what do you think, when there are news about H5N1 encephalitis, could they actually refer to an inflammation in barain? And if yes, could that inflammation mean inflammation provoked by H5N1 autoimmune cytokine storm?
Do we have any evidence of that those "H5N1 encephalitis" cases are really
1) degradation of brain tissue by viral infection of brain tissue
or
Could it be
2) inflammation of H5N1 viral infected brain tissue by a massive cytokine storm?
Sorry, English isn't my native language.