Abstract
Since 2003, H5N1 influenza viruses have caused over 400 known cases of human infection with a mortality rate greater than 60%. Most of these cases resulted from direct contact with virus-contaminated poultry or poultry products. Although only limited human-to-human transmission has been reported to date, it is feared that efficient human-to-human transmission of H5N1 viruses has the potential to cause a pandemic of disastrous proportions. The genetic basis for H5N1 viral transmission among humans is largely unknown. In this study, we used guinea pigs as a mammalian model to study the transmission of six different H5N1 avian influenza viruses. We found that two viruses, A/duck/Guangxi/35/2001 (DKGX/35) and A/bar-headed goose/Qinghai/3/2005(BHGQH/05), were transmitted from inoculated animals to naïve contact animals. Our mutagenesis analysis revealed that the amino acid asparagine (Asn) at position 701 in the PB2 protein was a prerequisite for DKGX/35 transmission in guinea pigs. In addition, an amino acid change in the hemagglutinin (HA) protein (Thr160Ala), resulting in the loss of glycosylation at 158–160, was responsible for HA binding to sialylated glycans and was critical for H5N1 virus transmission in guinea pigs. These amino acids changes in PB2 and HA could serve as important molecular markers for assessing the pandemic potential of H5N1 field isolates.
Highlights
The H5N1 avian influenza viruses (AIVs) have attracted extensive attention for their deadly impact on both animals and humans
We demonstrate that the amino acid residue at 701 of PB2 is a prerequisite for transmission of H5N1 viruses in a mammalian guinea pig model
We found that the absence of glycosylation at residues 158–160 of the HA gene is pivotal for the H5N1 virus to bind to human-like receptors and to transmit in a mammal host
Summary
The H5N1 avian influenza viruses (AIVs) have attracted extensive attention for their deadly impact on both animals and humans. The number of people who have been subclinically infected with H5N1 viruses is very limited [1], and H5N1 AIVs have a 60% fatality rate in humans (World Health Organization [WHO]; http://www.who.int). In 1997, a reassortant H5N1 AIV that carried the HA gene from an A/goose/ Guangdong/1/96-like virus caused an outbreak of disease in poultry in Hong Kong and crossed over into humans, resulting in 18 cases of infection with six deaths [4,5]. H5N1 AIVs have caused disease in more than 60 countries (Office International des Epizooties [OIE]; http:// www.oie.int), with cases of human infection being reported in 15 countries Despite substantial efforts to control these outbreaks, H5N1 AIVs have continued to evolve and spread, perpetuating the fear of an influenza pandemic if these viruses acquire the ability to transmit efficiently among humans. Understanding the genetic determinants that control H5N1 AIV transmission in mammalian hosts will help protect public health
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