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Researchers Report, Characterize First Known H6N1 Flu Virus to Infect Human

NEW YORK (GenomeWeb News) – Researchers from the Centres for Disease Control in Taiwan have isolated and genetically characterized a type of bird flu virus from a 20-year-old woman that had not been seen before in humans, as they reported in Lancet Respiratory Medicine yesterday.

Genetic and phylogenetic analysis of the influenza virus from the patient indicated that it belonged to an H6N1 subtype that typically infects poultry, and that it had a particular substitution in the hemagglutinin protein that might make it easier for the virus to enter human cells.

"A genetic analysis of the H6N1 virus identified in a 20-year-old woman shows a virus that has evolved the ability to target a receptor called SAα-2,6 found in the human upper respiratory tract, potentially enabling adaptation of the virus to human cells," said Ho-Sheng Wu from the Centres for Disease Control in Taiwan in a statement.

According to the researchers, H6N1 flu has not been previously described in humans. A 1991 Archives of Virology study they referenced found that two of 11 volunteers inoculated with an H6N1 virus shed the virus a few days later but they did not produce an antibody response, suggesting that the virus was not well adapted for infecting people. Instead, H6N1 typically infects birds — it has been circulating in Taiwanese chickens since 1972 — and has a low rate of pathogenicity in avian species.

Its appearance in infecting a woman underscores the "unpredictability of influenza viruses in human populations," Wu and colleagues wrote. They added that their finding highlights the need for better viral surveillance and pandemic preparation.

The index patient, a 20-year-old woman from Taiwan — who worked in a delicatessen but was not exposed to live animals — fell ill in May. Throat swabs taken from her during two different hospital visits were analyzed using a real-time RT-PCR assay that confirmed a previous immunofluorescence assay finding of influenza A. She was treated with oseltamivir, her symptoms receded, and she was discharged.

Samples from the patient were tested for a host of other respiratory viruses — including adenovirus, respiratory syncytial virus, rhinovirus, and a number of coronaviruses — using multiplex real-time RT-PCR/PCR reactions. All were negative.

The researchers also investigated the index patient's close contacts and environment for traces of the virus, but were unable to find any. Six of her 36 close contacts had flu-like symptoms, but researchers couldn't confirm that they had been infected. A neighbor kept ducks, chickens, and geese, but the birds were negative for virus. Other flu cases in the region also tested negative for H6N1.

Based on full-length viral sequences, the researchers determined that the virus isolated from the patient — dubbed TW02/13 — had high homology with an H6N1 strain found in chickens in Taiwan in 2013. However, one gene, PB1, had high homology with an older H6N1 chicken virus that circulated in Taiwan.

Through a neighbor-joining approach, Wu and colleagues constructed a phylogenetic tree comprised of H6N1 sequences isolated in Taiwan and housed in the US National Center for Biotechnology Information database. Based on that, they found that the eight gene segments of TW02/13 belong to a viral lineage that has been circulating in Taiwanese chickens since 1997. Further, they noted that that lineage is distinct from ones circulating in Hong Kong and other nearby regions.

However, the phylogenetic analysis also indicated that TW02/13 is made up of bits and bobs of other viruses in that lineage. For instance, the neuraminidase, PB2, NS, and other segments of TW02/13 traced back to a virus called A342/05, while the PB1 gene appeared to be related to the virus PF3/02. Meanwhile, the hemagglutinin gene harked back to a separate virus, called 0204/05.

"The incongruent relation between various segments of these phylogenetic topologies suggested that TW02/13 was generated from complex interclade reassortments," Wu and colleagues said.

Interestingly, the TW02/13 hemagglutinin protein bears a G228S substitution. This change, the researchers said, has been linked to making the protein a better match to the human α2,6-sialic acid receptor, which could allow the virus to replicate and be passed among people. Wu and colleagues further reported that this human-adapted substitution appeared to be becoming "endemic and predominant" in Taiwan's poultry.

The researchers also noted a deletion in that stalk portion of the neuraminidase protein, a change that is of unknown significance, but which has been linked to adaptation and virulence of aquatic viruses in chickens. They suggested that this change should be monitored

Overall, the researchers said that there should be better influenza surveillance and preparedness, a sentiment that was echoed in an accompanying commentary from Marion Koopmans at the National Institute for Public Health and the Environment in the Netherlands.

"[T]he question again is what would it take for these viruses to evolve into a pandemic strain? And an overriding question is if it is time to review our approaches to influenza surveillance at the human–animal interface," Koopmans wrote, noting that influenza pandemics from the past century have emerged from animal strains. "We surely can do better than to have human beings as sentinels."

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