Monday, July 22, 2019

PLoS One: Continuous Evolution of Influenza A Viruses of Swine from 2013 to 2015 in Guangdong, China


While the primary influenza viruses that circulate in pigs are swine-origin H1N1, H1N2, and H3N2 - pigs are also susceptible to wide variety of human, avian, and even canine flu viruses - which can sometimes co-circulate in swine herds and lead to viral reassortment.
Influenza reassortment can occur whenever a host (human, avian, porcine, etc.) is co-infected with two flu viruses. Under the right conditions they can swap gene segments and produce a hybrid virus, but only rarely are these reassortants biologically `fit' enough to thrive.
Reassortment is the primary force behind the creation of novel or pandemic flu viruses (see NIAID Video: How Influenza Pandemics Occur), and swine appear particularly well suited to serve as `flu factories'. 
While reassortment can happen anywhere, and anytime (2009's H1N1 swine-origin pandemic began in North America), China's ample diversity of circulating avian, swine, human, and canine flu viruses makes it well equipped to produce novel reassortant viruses.
Long time readers will recall that a little over three years ago, Chen Hualan - director of China's National Avian Influenza Reference Laboratory - pegged the EA (Eurasian Avian-like) H1N1 swine virus (EAH1N1) as having perhaps the greatest pandemic potential of any of the novel viruses in circulation.
Avian-like H1N1 swine flu may "pose highest pandemic threat": study

WASHINGTON, Dec. 28 (Xinhua) -- The Eurasian avian-like H1N1 (EAH1N1) swine flu viruses, which have circulated in pigs since 1979, have obtained the ability to infect humans and may "pose the highest pandemic threat" among the flu viruses currently circulating in animals, Chinese researchers said Monday.
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Her comments came after the publication of her paper (see PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza) by Hualan et al. that described the Prevalence, genetics, and transmissibility in ferrets of Eurasian avian-like H1N1 swine influenza viruses.

Since then we've seen even more diversity of flu viruses circulating in Chinese pigs. A few recent blogs include:
Emerg. Microbes & Inf.: Characterization of Swine-origin H1N1 Canine Influenza Viruses
J.O.I. : A Human Infection with a Novel Reassortant H3N2 Swine Virus in China

Emerg. Infect. & Microbes: Novel Triple-Reassortant influenza Viruses In Pigs, Guangxi, China
Emerg. Microbes & Inf.: Pathogenicity & Transmission Of A Swine Influenza A(H6N6) Virus - China

To this growing list we can add a new, highly detailed, research article published this past week in PloS One, detailing swine influenza surveillance and viral evolution in Guangdong Province between 2013 and 2015.
While highly useful in showing the acceleration of influenza evolution in China's pigs following the 2009 H1N1 pandemic, the data presented in today's study was gathered between 4 and 6 years ago, and so it may not reflect what is currently happening in China.
First some excerpts from a much longer report, which you'll probably want to read in its entirety.  When you return, I'll have a bit more.

Research Article 
Continuous evolution of influenza A viruses of swine from 2013 to 2015 in Guangdong, China

Zhenpeng Cao ,Weijie Zeng , Xiangqi Hao, Junming Huang, Mengkai Cai, Pei Zhou , Guihong Zhang


Southern China is considered an important source of influenza virus pandemics because of the large, diverse viral reservoirs in poultry and swine. To examine the trend in influenza A virus of swine (IAV-S), an active surveillance program has been conducted from 2013 to 2015 in Guangdong, China. 

The phylogenetic analyses showed that the external genes of the isolates were assigned to the Eurasian avian-like swine (EA) H1N1 and/or human-like H3N2 lineages with multiple substitutions, indicating a notable genetic shift. 

Moreover, the internal genes derived from different origins (PB2, PB1, PA, NP: pdm/09 (pandemic influenza virus 2009)-origin, M: pdm/09- or EA-origin, NS: North American Triple Reassortant (TR)-origin have become the dominant backbone of IAV-S in southern China. According to the origins of the eight gene segments, the isolates can be categorized into five genotypes. 

The results of mice experiment showed that the YJ4 (genotype 1) and DG2 (genotype 4) are the most pathogenic to mice, and the viruses are observed in kidneys and brains, indicating the systemic infection. 

The alterations of the IAV-S gene composition supported the continued implementation of the intensive surveillance of IAV-S and the greater attention focused on potential shifts toward transmission to humans.

After the pandemic, the 2009 pandemic virus was repeatedly transmitted to pigs in many countries [1517] and reassorted with endemic viruses [18, 19], which increased the genetic diversity of IAV-S circulating in pig herds. Phylogenetic and genetic analyses revealed that pdm/09-origin internal genes became established and evolved variants [20]. 

To research the trend in IAV-S in pig herds, an active surveillance program has been conducted in pigs from 2013 to 2015 in Guangdong, China. The origin, gene diversity and genetic markers of the isolates in this program were estimated through phylogenetic and molecular analysis. 

Mouse is one of the most mature mammal models for influenza virus infection, which has been used for evaluating the virulence of avian- and mammal-origin influenza viruses [21]. The pathogenicity of the strains to mice has been assessed in this study.

Due to unique geographical and environmental factors, southern China is considered an important reservoir of influenza virus. In the first decade of the 21st century, Multiple lineages of IAVs-S have emerged and become established in pigs in southern China: classical swine H1N1 (CS), European avian-like H1N1 (EA) and triple-reassortant H1N2 viruses (TRIG).
In 2001, the first case of infection with the EA-origin virus in pigs in Asia was reported in Hong Kong, and EA-origin viruses have since formed a stable phyletic clade in China [36]. In addition, TR-origin viruses have been regularly isolated from pigs in China since 2002 [37].
Since the pdm/09-origin virus outbreaks in humans, this virus has been repeatedly transmitted in pig herds [3840]. Reassortant variants with pdm/09-origin gene segments and endemic genes were subsequently found in Asia [4143]. The swine-origin H1N1 viruses were found reassorting with the H3N2 canine influenza viruses circulate endemically in Asian dogs [44].
Furthermore, the novel triple EA H1N1 and Human Like H3N2 reassortants, containing the CS H1N1 NS genes and the remaining five or four genes originating from H1N1/2009 pandemic, may have become established in pig herds in Southern China [40, 45].
Notably, the reassortant EA H1N1 viruses with EA-origin M gene, pdm/09-origin internal genes and CS-origin NS gene have been reported in human infections in Hunan, China [46].
In this study, phylogenetic analyses assigned the external genes of the novel isolates to the EA-origin H1N1 and/or human-origin H3N2, and the isolates were categorized into H1N1, H1N2 and H3N2

The regular isolation of H1N1 and H1N2 viruses demonstrates their continuing presence in pig herds, which means that the EA-origin variants reassorted with pdm/09-origin internal genes have become the major swine influenza lineage prevailing in southern China [41]. 

In addition, one H3N2 reassortant virus containing the pdm/09-origin internal genes was isolated in this study, indicating that the genotype of internal genes has reassorted with other endemic influenza viruses, indicating the pdm/09-origin internal genes affected the prevalence of H3N2 viruses in pig herds.
The mice experiment demonstrated that the novel reassortant viruses showed different pathogenicity, indicating a risk for the new potential pandemic. The alterations of IAV-S gene composition combined with the complex epidemic situation underlines the importance of continued swine surveillance in China to maintain public health.
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Since the influenza subtypes that commonly circulate in swine (H1, H2 & H3) are also the same HA subtypes as have caused all of the human pandemics going back 130 years (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), the continued evolution of influenza A viruses in pigs is a legitimate public health concern. 
It is possible, however, that the year-long African Swine Fever outbreak in China - which has reportedly led to the loss of tens of millions of pigs -  has (at least temporarily), reduced the risks of seeing a pandemic flu virus emerge from Chinese pig.
But the Chinese government has a history of  holding `bad news' very close to the vest, and routinely treats infectious disease outbreaks as `national security' issues, making it difficult to get any real-time data on what is going on there.

Admittedly, we are always looking at surveillance data in a rear view mirror, but the older the data, the stronger the caveat that `some pandemics may be closer than they appear'.