Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

[Giuseppe]

[Source: Nature, Scientific Report, full page: (LINK). Abstract, edited.]


doi: 10.1038/srep02318 - pmid: 23897131 / (OPEN ACCESS)

Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

Yongbo Wang 1*, Zhangyan Dai 2*, Han Cheng 1*, Zexian Liu 1*, Zhicheng Pan 1*, Wankun Deng 1*, Tianshun Gao 1, Xiaotong Li 1, Yuangen Yao 1, Jian Ren 3 & Yu Xue 1


1)Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China, 2)School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4027, Australia, 3)State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.


Abstract

Recently, a highly dangerous bird flu has infected over 130 patients in China, and the outbreak was attributed to a novel avian-origin H7N9 virus. Here, we performed a systematic analysis of the virus. We clarified the controversial viewpoint on neuraminidase (NA) origin and confirmed it was reassorted from Korean wild birds with higher confidence, whereas common ancestors of pathogenic H7N9 genes existed only one or two years ago. Further analysis of NA sequences suggested that most variations are not drug resistant and current drugs are still effective for the therapy. We also identified a potentially optimal 9-mer epitope, which can be helpful for vaccine development. The interaction of hemagglutinin (HA) and human receptor analog was confirmed by structural modeling, while NA might influence cellular processes through a PDZ-binding motif. A simplified virus infection model was proposed. Taken together, our studies provide a better understanding of the newly reassorted H7N9 viruses.


SUBJECT AREAS: DATA MINING. PHYLOGENY. PROTEIN FUNCTION, PREDICTIONS, PROTEIN STRUCTURE, PREDICTIONS

Received 14 May 2013 / Accepted 15 July 2013 / Published 30 July 2013

Correspondence and requests for materials should be addressed to Y.X. (xueyu@hust.edu.cn)

* These authors contributed equally to this work.


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[gsgs]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

I'm no native English speaker either, but this paper looks to me
like a bad translation from Chinese.


-----------------------------------------------
> Thus, a more rigorous surveillance will be helpful for further
> preventing the pandemic outbreak.

yes, but don't count on that. Surveillance alone is not sufficient

> In addition, the phylogenetic analysis is not helpful for calibrating
> a more precisely reassortant model,
> because the time scale is too short that the reassortment started
> around November 2012 (the data that A/brambling/Beijing/16/
> 2012 was sequenced) and ended in February 2013.

how long does a reassortment take ? Just one replication cycle, ~8 hours.

> (Fig. 7): 1) The reassortment of six internal genes
> might occur in the Yangtze river delta, start before 11/2012 and still
> not finalize after the date, because A/brambling/Beijing/16/2012 was
> sequenced in November 2012 (From its annotation information);


>2) HA of H7N3 subtype was reassorted with six genes of H9N2 subtype
> in Zhejiang Province after November 2012, because H7N9 subtype
> HA was not reassorted from A/brambling/Beijing/16/2012;

the brambling had just a related virus, it needn't be (and unlikely is) the direct
ancester of H7N9 in any segment

> 3) The reassortment of NA from H7N9 virus in Korean wild bird occurred
> in Shanghai before 19/02/2013, the date when the first Shanghai
> patient was infected.

sure.

> Our results can?t fully exclude the probability
> of other models, if new data was reported. For example, Liu et al.
> argued that NS might have at least two origins based on newly
> released sequences16. However, this result made limited influence
> on our model, which compromised most of available evidences.

we have 2 different MPs. (Shanghai/Anhui and Taiwan/Nanjing)
One was obviously subsequently introduced into H7N9 from H9N2.


Since an introduction of new wildbird (mallard) genes into poultry
is a rare event, a double introduction of two different genes
should be O(2) rarer.
However HA,NA, and other genes frequently do reassort in mallards,
so likely the H7+N9 were present together, when the basic reassortment happened.

Reassortments wildbird+wildbird-->wildbird are common
Reassortments poultry+poultry-->poultry are also common.
But wildbird-genes --> poultry (or vice versa) are rare

_________________
no patents on genes, publish the GISAID sequences !

[DaCaiNiao]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

Hi, this is Yu Xue, who is responsible for this paper. OK, I originally thought that no one will take a look on this paper, however, since gsgs kindly presented his/her comments on this paper, I just registered an account and have sth to speak.

I'm no native English speaker either, but this paper looks to me
like a bad translation from Chinese.

YX: No, no, we did not "translate" the manuscript from Chinese. The truth is: My friend, Dr. Jiankui He submitted a paper to Arxiv (http://arxiv.org/abs/1304.1985) on the origin of H7N9 on 7 Apr 2013. His phylogenetic analysis supported NA is from korea wild bird, but they stated that NA is from Czech mallard. At that time, you know, in China everyone were talking about H7N9, but no one knew where the **** virus was originated. My mother gave me a phone and ask me the H7N9, and then we tried to find the answer by ourselves. OK, we finalized the job on 16 Apr, with only 9 days, for all calculations, analyses and manuscript written. Yes, the paper can be significantly improved if I have 30 days for writing. I wrote it for only two days. Thus, the language is far from OK, but I believe my points were clearly presented.

-----------------------------------------------
> Thus, a more rigorous surveillance will be helpful for further
> preventing the pandemic outbreak.

yes, but don't count on that. Surveillance alone is not sufficient

YX: Sure. Maybe you know, not only virologists paid attention on this outbreak, even non-professional public such as me is also kept an eye on it. Well, for a bioinformatist who never worked on virus, understanding the importance of surveillance is not an easy affair. We are waiting for understanding more sufficient things from experts.

> In addition, the phylogenetic analysis is not helpful for calibrating
> a more precisely reassortant model,
> because the time scale is too short that the reassortment started
> around November 2012 (the data that A/brambling/Beijing/16/
> 2012 was sequenced) and ended in February 2013.

how long does a reassortment take ? Just one replication cycle, ~8 hours.

YX: The reassortment events can be taken place for a lot of times during the period, however, the effective reassortment that HPAI genes were reassorted will not be so frequent. Can you guarantee that one replication cycle will generate such a virus?

> (Fig. 7): 1) The reassortment of six internal genes
> might occur in the Yangtze river delta, start before 11/2012 and still
> not finalize after the date, because A/brambling/Beijing/16/2012 was
> sequenced in November 2012 (From its annotation information);


>2) HA of H7N3 subtype was reassorted with six genes of H9N2 subtype
> in Zhejiang Province after November 2012, because H7N9 subtype
> HA was not reassorted from A/brambling/Beijing/16/2012;

the brambling had just a related virus, it needn't be (and unlikely is) the direct
ancester of H7N9 in any segment

YX: Plz let the data speaking, if you can an additional intermediate.

> 3) The reassortment of NA from H7N9 virus in Korean wild bird occurred
> in Shanghai before 19/02/2013, the date when the first Shanghai
> patient was infected.

sure.

YX: Aha, it's the only sure in your comments. Thanks.

> Our results can?t fully exclude the probability
> of other models, if new data was reported. For example, Liu et al.
> argued that NS might have at least two origins based on newly
> released sequences16. However, this result made limited influence
> on our model, which compromised most of available evidences.

we have 2 different MPs. (Shanghai/Anhui and Taiwan/Nanjing)
One was obviously subsequently introduced into H7N9 from H9N2.

YX: Yes, yes. Someone else told me that one of the six internal genes can be originated from different sources. So it's quite complicated for the virus origin.


Since an introduction of new wildbird (mallard) genes into poultry
is a rare event, a double introduction of two different genes
should be O(2) rarer.
However HA,NA, and other genes frequently do reassort in mallards,
so likely the H7+N9 were present together, when the basic reassortment happened.

Reassortments wildbird+wildbird-->wildbird are common
Reassortments poultry+poultry-->poultry are also common.
But wildbird-genes --> poultry (or vice versa) are rare

YX: Sorry, I do not fully understand your point. The H7+N9 present together is not sound, because you can not find a strain together with both H7 and N9 from one source. The H7, six internal genes, and NA are from at least three sources. The H7 and six internal genes will be firstly reassorted because the strain-containing bramblings and poultries existed in Yangtze river delta for many years. However, the NA is from the korea wild bird and will be reassorted as the last step. Also, you can not find more additional strains in Yangtze river delta also with korea NA.

_________________
no patents on genes, publish the GISAID sequences !

YX: Sorry, bioinformatists DO not produce data, but play with the data.

[sharon sanders]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

Welcome to FluTrackers Dr. Xue.

[DaCaiNiao]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

Welcome to FluTrackers Dr. Xue.

Thanks, Sharon. We are not experts on virology, and never touched virus. We will not continue to work on influenza, but hope virologists can raise some effective approaches to stop the outbreak. Maybe you know, the H7N9 re-occurred in China recently. It's weird that the influenza can spread in such hot summer. If the large-scale outbreak occurs in the autumn, how to stop it? My whole family lived in Anhui of the Yangtze river delta. It's difficult for me not to pay attention on it.

[sharon sanders]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

Thanks, Sharon. We are not experts on virology, and never touched virus. We will not continue to work on influenza, but hope virologists can raise some effective approaches to stop the outbreak. Maybe you know, the H7N9 re-occurred in China recently. It's weird that the influenza can spread in such hot summer. If the large-scale outbreak occurs in the autumn, how to stop it? My whole family lived in Anhui of the Yangtze river delta. It's difficult for me not to pay attention on it.

Yes, we are aware of the known H7N9 cases, including the 2 cases this Summer. We have maintained a case list here that is used by health departments all over the world:

http://www.flutrackers.com/forum/showpost.php?p=489904&postcount=1

If a large-scale outbreak occurs this Autumn, there will be no way to stop it. Influenza can not be stopped. Usually people are contagious in the first stage of the illness and they can infect others before the symptoms become severe enough that they must stay in bed. Anti-virals must be given very early in the disease stage to be effective. This is not always possible.

If you want to protect yourself, and everyone that you know consider the following:

1) Make everyone you know is aware of H7N9,

2) Talk to your medical practitioner about the pneumonia vaccine,

3) Wash hands frequently,

4) Try to wear a mask in crowds and when taking care of sick relatives,

5) Try to stand 6 feet away from people when out in public,

6) Do not eat sick animals. Cook all meat to the "well done" stage. Make sure the blood in the animals is not red anymore before eating,

7) Wash hands and all cooking surfaces frequently throughout the cooking process,

8) If the government ever determines the animal reservoir for H7N9 - stay away from that animal and don't eat it,

9) Stop smoking, contact your medical practitioner immediately about any fever + cough, or fever + diarrhea, any high fever, any difficulty breathing, any bleeding,

10) Make sure all of your family members are regularly taking their medicines - especially if they are over 50,

11) Regularly clean door knobs and other surfaces at work,

12) Tell sick people to stay at home until they are better,

13) Keep your children at home if they are sick and/or the local area is experiencing an H7N9 epidemic,

14) Stay in contact with your medical practitioner and don't believe all the rumours on the internet. Use at least 2 sources for your health news.

[Giuseppe]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

After the precious advice list by Sharon, I can only add that one of the last resort measures to reduce infection opportunity is to increase distance between humans and farmed birds (other than those in live birds markets).

Without distancing infected animals from humans, there will be little hope to avoid further sporadic cases, small clusters and finally community outbreaks caused by this novel avian influenza virus.

Undestanding this critical joint is the better insurance toward an less Dangerous passage into wet and cold season. GM

(Of course, better testing procedures and kits should be urgently dispatched in industrial poultry farms in order to detect, isolate and destroy active H7N9 virus epizootics there.)

[gsgs]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

hi Yu Xue, thanks for showing up. It's always good to get the authors
discuss their papers !
I didn't realize it was written Apr.16. I remember, that in early April I also thought
the reassortment happened 1-2 years ago, because of the Shanghai/1 genome.
But that sequence was not confirmed,repeated - it's a singleton meanwhile,
all the many other sequences rather point to an initial reassortment in early 2013.

The database has big holes, most sequences that occur in nature are not in the database.
I.e. HA switches frequently in wild birds and they fly Europe <--> Asia
So it's no surprise that the best matches for H7 and N9 are different
in the database, but still in nature I think it was in one wild bird
that mixed into poultry H9N2.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003443

HA antigenic variation , IAV subtype diversity

[Giuseppe]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

The occurrence of sporadic human cases of avian influenza virus H7 during hot season should not seen as unusual.

I have just read of a HPAI epizootic here in Italy (h/t Tetano, http://www.ilsole24ore.com/art/notiz...?uuid=AbIYhHNI ), about a poultry farm infected by an H7 subytpe in Northern Italy.

These outbreaks are not unusual here and I think that also for sub-tropical China prevalence of these viruses among poultry have to be similar. The missing link is a more transparent and sensitive veterinary laboratory network system. Perhaps?

[gsgs]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

I assume you don't have these live poultry markets in Italy

[Giuseppe]

Re: Nature Sci Rep. Towards a better understanding of the novel avian-origin H7N9 influenza A virus in China

I assume you don't have these live poultry markets in Italy

Not live poultry market. But enormous industrial combined poultry farms.

Backyard poultry are also common in rural areas.

Past H5/H7 mild human cases were reported in Italy, as you know.