Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.
Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus-comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus-that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian-human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures.
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
Masaki
M
Imai
Tokiko
T
Watanabe
Masato
M
Hatta
Subash C
SC
Das
Makoto
M
Ozawa
Kyoko
K
Shinya
Gongxun
G
Zhong
Anthony
A
Hanson
Hiroaki
H
Katsura
Shinji
S
Watanabe
Chengjun
C
Li
Eiryo
E
Kawakami
Shinya
S
Yamada
Maki
M
Kiso
Yasuo
Y
Suzuki
Eileen A
EA
Maher
Gabriele
G
Neumann
Yoshihiro
Y
Kawaoka
D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D023482:Bioterrorism / Q000517:prevention & control; D001717:Birds / Q000821:virology; D001826:Body Fluids / Q000821:virology; D002460:Cell Line; D004285:Dogs; D019143:Evolution, Molecular; D005260:Female; D005289:Ferrets / Q000821:virology*; D057809:HEK293 Cells; D006367:HeLa Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000635:transmission / Q000821:virology; D007251:Influenza, Human / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D017720:Molecular Epidemiology / Q000379:methods; D009976:Orthomyxoviridae Infections / Q000635:transmission* / Q000821:virology*; D058873:Pandemics; D011159:Population Surveillance / Q000379:methods; D055550:Protein Stability; D016865:Reassortant Viruses / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism; D012137:Respiratory System / Q000033:anatomy & histology / Q000821:virology*; D012637:Security Measures; D015047:Zoonoses / Q000635:transmission / Q000821:virology
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus