# 4903
One of the (many) unanswered questions about H5N1 avian flu is why it doesn’t more easily infect humans and why is human-to-human transmission so rare?
We think we know part of the reason:
Avian adapted influenza viruses bind preferentially to Alpha 2,3 receptor cells, which are commonly found in the digestive tract of birds. This explains why most avian flu viruses are gastrointestinal infections in birds.
Human adapted viruses have an affinity for the alpha 2,6 receptor cell, which populate the upper airway and lungs. This is why influenza is a respiratory virus in humans.
But of course, we’ve got at least 500 exceptions to the rule. H5N1 does, on rare occasion, find a home in a human host.
Some scientists believe these rare human infection occur due to the presence of α2-3 receptor cells deep in the lungs and in the human gut, areas where the virus can reach, albeit with difficulty.
But of course, until proven, that remains a less than satisfactory answer.
Adding to our list of unanswered questions, is exactly how influenza viruses are transmitted from one host to the next. The easy answer is via coughs and sneezes, but we are actually looking for something more specific than that.
The three commonly cited routes are large-droplets, aerosols, and direct contact with secretions and fomites. Most scientists concede that all three probably play a role in transmission, but how much each method contributes is less certain.
Coughing and sneezing produces virus laden large-droplets that remain airborne for a very short period of time, and then settle to the ground (or other surfaces).
The `range’ of these droplets is assumed to be 6 to 10 feet, and traditionally this has been considered the primary route of transmission.
Photo Credit PHIL (Public Health Image Library)
But coughs and sneezes also produce fine aerosolized particles, that can remain airborne for extended periods.
Tellier, in Review of Aerosol Transmission of Influenza A Virus, makes the case for the aerosol transmission of influenza as being an important mode of transmission.
Aerosolized particles, in addition to remaining airborne longer, are also more likely to be drawn deeper into a human’s respiratory system.
This would – theoretically, at least – give an avian virus with an affinity for the α2-3 receptor cells found deep in the lungs a better shot at binding and taking hold.
The third mode of transmission, is the transfer of virus particles or secretions from fomites (inanimate objects) or an infected host to a new host’s oral, conjunctival and nasal mucus membranes.
All of which is prelude to a study, published today in the Virology Journal titled:
John A Lednicky , Sara B Hamilton , Richard S Tuttle , William A Sosna , Deirdre E Daniels and David E Swayne
Virology Journal 2010, 7:231doi:10.1186/1743-422X-7-231
Background
There is limited knowledge about the potential routes for H5N1 influenza virus transmission to and between humans, and it is not clear whether humans can be infected through inhalation of aerosolized H5N1 virus particles. Ferrets are often used as a animal model for humans in influenza pathogenicity and transmissibility studies.
In this manuscript, a nose-only bioaerosol inhalation exposure system that was recently developed and validated was used in an inhalation exposure study of aerosolized A/Vietnam/1203/2004 (H5N1) virus in ferrets. The clinical spectrum of influenza resulting from exposure to A/Vietnam/1203/2004 (H5N1) through intranasal verses inhalation routes was analyzed.
Results
Ferrets were successfully infected through intranasal instillation or through inhalation of small particle aerosols with four different doses of Influenza virus A/Vietnam/1203/2004 (H5N1).
The animals developed severe influenza encephalomyelitis following intranasal or inhalation exposure to 10E1, 10E2, 10E3, or 10E4 infectious virus particles per ferret.
Conclusions
Aerosolized Influenza virus A/Vietnam/1203/2004 (H5N1) is highly infectious and lethal in ferrets. Clinical signs appeared earlier in animals infected through inhalation of aerosolized virus compared to those infected through intranasal instillation.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
Of course, this doesn’t really answer the question as to why H5N1 doesn’t more readily infect humans. In fact, it raises questions, since ferrets appear to be quite susceptible to aerosolized H5N1.
That aside, there are some very interesting findings in this study.
The researchers first simulated large-droplet infection of test ferrets with direct intranasal inoculation of three different H5N1 viruses (A/Mongolia/244/2005, A/Iraq/207-NAMRU3/2006, and A/Vietnam/1203/2004).
Although all three strains induced influenza infection in the ferrets, one; A/Vietnam/1203/2004 (VN/04) caused neurological symptoms and was seen as particularly virulent.
This strain was selected for aerosol testing using a nose-only bioaerosol inhalation exposure system (NBIES).
While they caution that the number of test subjects was small, and large conclusions shouldn’t be drawn, the authors note that infection through inhalation of aerosols resulted in more abrupt clinical signs and a greater probability of developing neurological disease than through intranasal inoculation.
They write:
Some general conclusions inferred from our histology/ immunohistochemistry and virology work are that:
(a) histologic changes may not be present even with high virus titer in particular tissues, and
(b) that brain lesions are possible without lung lesions in H5N1 infections suggesting direct extension of the virus from posterior nasal cavity through olfactory nerves into the brain, in agreement with a previous report
They also write:
Furthermore, sneezing, which primarily results in the formation of droplets, was rarely observed in the infected animals. Thus, droplet transmission may be lower than that encountered with seasonal influenza viruses. It remains unclear why ferret to ferret transmission is inefficient with this virus; perhaps the virus is not present in significant quantities in aerosols that might accompany sneezes or coughs.
After reviewing some of the theories regarding why H5N1 has yet to transmit efficiently in humans, the authors write:
Taken together, tropism for cells of the LRT tract, and the rarity of sneezing/coughing in ferrets, result in poor transmissibility of the virus. This study predicts that person-to-person transmission will readily occur if H5N1 acquires the ability to replicate in the URT and is readily aerosolized or expelled in droplets.
Something, we obviously hope, will never happen.
The entire article is open access, interesting, and worth reading in its entirety. I’ve only provided a brief overview in order to hopefully whet your appetite.
