St. Jude Children’s Research Hospital scientists and China Agricultural
University identify the changes in H9N2 flu virus in chickens that could
signal emergence of viruses with potential to trigger a pandemic.
An international research team has shown how changes in a flu virus
that has plagued Chinese poultry farms for decades helped create the
novel avian H7N9 influenza A virus that has sickened more than 375
people since 2013. The research appears in the current online early
edition of the scientific journal Proceedings of the National Academy of Sciences.
The results underscore the need for continued surveillance of flu
viruses circulating on poultry farms and identified changes in the H9N2
virus that could serve as an early warning sign of emerging flu viruses
with the potential to trigger a pandemic and global health emergency.
The work focused on the H9N2 chicken virus, which causes egg production
to drop and leaves chickens vulnerable to deadly co-infections.
Scientists at St. Jude Children’s Research Hospital and the China
Agricultural University, Beijing, led the study.
Researchers used whole genome sequencing to track the evolution of
the H9N2 chicken virus between 1994 and 2013. The analysis involved
thousands of viral sequences and showed that the genetic diversity of
H9N2 viruses fell sharply in 2009. From 2010 through 2013 an H9N2 virus
emerged as the predominant subtype thanks to its genetic makeup that
allowed it to flourish despite widespread vaccination of chickens
against H9N2 viruses.
Evidence in this study suggests the eruptions set the stage for the
emergence of the H7N9 avian virus that has caused two outbreaks in
humans since 2013, with 115 confirmed deaths. The H9N2 infected chickens
likely served as the mixing vessel where H9N2 and other avian flu
viruses from migratory birds and domestic ducks swapped genes,
researchers noted. The resulting H7N9 virus included six genes from the
H9N2.
"Sequencing the viral genome allowed us to track how H9N2 evolved
across time and geography to contribute to the H7N9 virus that emerged
as a threat to human health in 2013," said Robert Webster, Ph.D., a
member of the St. Jude Department of Infectious Diseases. He and Jinhua
Liu, Ph.D., of the College of Veterinary Medicine at the China
Agricultural University, are co-corresponding authors.
"The insights gained from this collaboration suggest that tracking
genetic diversity of H9N2 on poultry farms could provide an early
warning of emerging viruses with the potential to spark a pandemic,"
Webster said.
The analysis also provided insight into the creation of the H9N2
virus that emerged as the predominant subtype in 2010. Factors included
widespread use of poultry vaccines and the natural tendency of flu to
mutate, mix and swap genes.
Beginning in 1998, vaccinating poultry against H9N2 prevented flu
outbreak for more than a decade. Vaccines work by recognizing and
attaching to the spike-shaped hemagglutinin (HA) protein on the surface
of the flu virus. That blocks the virus from infecting healthy cells.
Changes in the HA gene that change the shape of the HA protein can
reduce vaccine effectiveness and result in disease outbreaks. HA
mutations occur naturally over time. Vaccines increase pressure for HA
mutations that help the virus escape vaccine detection and cause
infection.
Researchers at the China Agricultural University checked H9N2 vaccine
effectiveness against the predominant H9N2 virus from 2010-11. Working
in vaccinated and unvaccinated chickens, investigators found the vaccine
neither protected vaccinated chickens from infection nor prevented
spread of the virus in vaccinated chickens. Those failures suggest that
due to HA mutations vaccines were less able to recognize the virus.
The tendency of flu viruses to swap genes also contributed to the
enhanced ability of the predominant H9N2 subtype to spread. Researchers
found that prior to the virus’ emergence as the predominant H9N2 the
virus had swapped genes with quail and duck influenza viruses.
The combination fueled the recent outbreaks of H9N2 on chicken farms
by helping the virus escape vaccine detection and spread rapidly in
vaccinated and unvaccinated poultry, said co-first author Juan Pu,
Ph.D., a St. Jude visiting scientist from the China Agricultural
University. The other first authors are Shuoguo Wang, Ph.D., of the St.
Jude Department of Computational Biology, and Yanbo Yin, Ph.D., of
Qingdao Agricultural University, Qingdao, China.
"The emergence of this dominant H9N2 virus was the first step in the
genesis of the H7N9 viruses because it greatly increased the likelihood
of reassortment between H9N2 and other flu subtypes," Liu said.
Reassortment refers to the tendency of flu viruses to swap genes.
The other authors are Robert Carter, Yuannian Jiao, Susu Duan, Hui
Zhang and Gang Wu, all of St. Jude; Gordon Lemmon, formerly of St. Jude;
Guozhong Zhang, Jinliang Wang, Guanlong Xu, Honglei Sun, Min Wang, Chu
Wen, Yandi Wei, Qian Wang, Qian Du, Meng Sun, Jinnan Bao, Yipeng Sun and
Jixun Zhao, all of the China Agricultural University; Dongdong Wang,
Qingdao Agricultural University; and Baoli Zhu, Chinese Academy of
Sciences.
The research was funded in part by grants from the National Natural
Science Foundation of China; the National Basic Research Program; the
China Scholarship Foundation; Key Technologies Research and Development
Program of China; the China Agriculture Research System; a contract
(N266200700005C) from the National Institute of Allergy and Infectious
Diseases, part of the National Institutes of Health; and ALSAC.