H5N1 (influenza A) is one of the most dangerous viruses around; fortunately it has a great deal of trouble infecting people. Thus, news of scientists configuring an H5N1 that can attach to respiratory tract cells, and then encouraging it to mutate into a form that spreads directly from mammal to mammal – in this case, ferrets, the research animal of choice for influenza scientists – was met with alarm by scientists at this year’s European Scientific Working Group on Influenza (ESWI) conference in Malta.
What Ron A.M. Fouchier and colleagues at the Erasmus Medical Center in the Netherlands said they did was simply to put their new respiratory-tract attaching mutant into the nose of one ferret after the other, for it to become increasingly infective. The rapidity with which it spread also suggests the mutant H5N1 can become airborne – but even if that’s not the case, the evolution of an H5N1 virus, capable of person-to- person transmission, is so worrying to influenza experts that the National Science Advisory Board for Biosecurity (NSABB) quickly began conducting a review of Fouchier’s findings. The manuscript describing the experiment in detail has been embargoed until the NSABB is finished with the review.
Albert Osterhaus, also at the Erasmus Medical Center and the ESWI chairman, says that if this transition can happens in the lab, it’s probably happening in nature. “The mutations are out there, they just haven’t come together yet,” he cautions. However, Paul Offit from the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania wonders why, if such mutations are naturally occurring, “we haven’t as yet had an H5N1pandemic.”
Getting the bird flu virus airborne and easily infective in ferrets not so easy, say CDC scientists
A partially-viable airborne version of a ferret-to-ferret infecting H5N1 has recently been reported by Ruben O. Donis and his team at the Centers for Disease Control and Prevention in Atlanta, Georgia. However, it took a great deal more manipulation than the Fouchier transition. Knowing that the acquisition of α2-6 sialoside receptor specificity by α2-3 specific highly pathogenic avian influenza (HPAI) viruses is a prerequisite for efficient transmission in humans, the CDC team selected for α2-6 sialosides binding among HPAIs in vitro and identified four promising variant viruses. Then they combined one of the variants with two mutations from previous pandemic H5N1 viruses to create a novel virus that could be transmitted by direct contact in ferrets. Once this was accomplished, the scientists used the mutant hemagglutinin, a human N2 neuraminidase, and genes from H5N1 to configure a reassortant virus which could be partially transmitted on respiratory droplets. So many complex changes were needed to get this virus airborne, these scientists consider it unlikely that the avian H5N1 influenza virus will ever become as easily transmissible to people as seasonal influenza.
Pandemic influenza viruses more deadly than the seasonal strains
Since it was first reported in 1997, outbreaks of H5N1 have devastated birds, both wild and domestic, but have only infected about 573 humans (336 of whom have died). However, there has been continuing concern among experts since that H5N1 might either mutate on its own, or combine gene segments with human influenza viruses and evolve into a new virus that’s both highly lethal and easily transmitted from person to person. It wouldn’t be a first for an influenza virus – that’s exactly what happened right before the pandemics of 1918, 1957, and 1968. Kumnuan Ungchusak and colleagues, from Mahidol University in Bangkok Thailand, as well as the Centers for Disease Control and Prevention in Atlanta, Georgia point out that “…the currently circulating influenza A (H5N1) viruses have in fact evolved to more virulent forms since 1997 with a higher mortality among human cases, different antigenic properties, a different internal gene constellation and expanded host range.”
Avian influenza common in wild birds, but poultry carry the most deadly strains
H5N1 has been isolated from at least 105 wild bird species of 26 different families as well as pigs, horses, felids, and marine mammals. But wildfowl and shore birds provide the viral reservoir in nature, says Fouchier. Most birds carry a relatively benign phenotype of the virus but the switch from a low pathogenic avian influenza virus to the high pathogenicity phenotype is achieved by introduction of basic amino acid residues into the HA0 cleavage site, which enables the virus to replicate outside the respiratory and intestinal tracts. “The HPAI strains have come primarily from commercially raised poultry,” he adds.
The host-cells of choice for bird flu viruses are in the intestinal tract lining if, for no other reason, than their progeny are efficiently released in feces. Water provides an ideal environment for dissemination – influenza viruses remain infectious in lakes for up to 4 days at 22 C, and more than 30 days at 0 degrees C. This explains why water birds, including ducks, especially dabbling ducks like mallards (Anas platyrhynchos) which feed mostly in surface waters, are so frequently colonized by influenza viruses. Moreover, these influenza viruses don’t seem to sicken ducks. Mallards, for example, show no clinical signs after experimental infection with H5N1 and only mount a low-level transient humoral immune response. However, ducks appear to be the exception, and some experts argue that most infected wild birds become too sick to migrate and are, therefore, unlikely to play an active role in the geographic spread of disease.