Friday, April 07, 2017

Sci Rpts: Avian & Human Influenza Compatible Receptor Cells In Little Brown Bats

Credit Wikipedia


Bats are the most abundant and geographically dispersed vertebrates on earth. While an important part of our shared ecosystem, their ability to carry and vector dangerous diseases - like rabies & Nipah, coronaviruses like SARS and MERS, and hemorrhagic fever viruses like Ebola  - is increasingly viewed as a potential public health threat.
In 2012 another pathogen - influenza A - was detected in bats for the very first time (see A New Flu Comes Up To Bat), when a novel H17 flu subtype was detected in little yellow-shouldered bats (Sturnira lilium) captured at two locations in Guatemala.

While preliminary research suggested that this H17 virus was genetically compatible with human influenza viruses, it did not yet have the ability to infect humans.  The CDC wrote
As a result, it is possible that these bat viruses could eventually gain the ability to cause infections in humans. However, CDC experts have been unable to grow the bat influenza virus in test tubes, suggesting that the virus is currently not well suited to causing human illness. For the bat influenza virus to infect humans, it would need to obtain some genetic properties of human influenza viruses

Eighteen months later, in PLoS Pathogens: New World Bats Harbor Diverse Flu Strains,  we saw yet another new HA subtype - H18 - identified in bats.  H18N11, to be precise, collected from bats in Peru.

Among their findings:
  • A high seroprevalence of influenza antibodies in bats they tested, suggesting `widespread circulation of influenza A viruses among New World bats’. 
  • The author’s also found, that unlike human influenza viruses,  `The crystal structures of the hemagglutinin and neuraminidase proteins indicate that sialic acid is not a receptor for virus attachment nor a substrate for release, suggesting a novel mechanism of influenza A virus attachment and activation of membrane fusion for entry into host cells.’
The discovery that sialic acid - the cellular attachment point for most flu viruses - wasn't part of H18's receptor cell binding process was considered a bit of good news, as it made it less likely to become a human health risk.

A finding further bolstered the following year in Nature Comms: A Chimeric Bat Flu Study, that found the H17N10 bat flu discovered in 2012 had similarly large genetic barriers to overcome in order to jump to humans. 

Things grew a little less reassuring in 2015 when PLoS One published Serological Evidence of Influenza A Viruses in Frugivorous Bats from Africa, which detected serological evidence of prior H9 influenza infection in roughly 30% of bats examined in Ghana.

The author's wrote:

Preliminary results indicate serological evidence against avian influenza subtype H9 in about 30% of the animals screened, with low-level cross-reactivity to phylogenetically closely related subtypes H8 and H12. To our knowledge, this is the first report of serological evidence of influenza A viruses other than H17 and H18 in bats. As avian influenza subtype H9 is associated with human infections, the implications of our findings from a public health context remain to be investigated.

While the non-sialic receptor binding quality of H18N11 might preclude it jumping easily to humans, the obvious question became - are bats susceptible to other subtypes of human, swine, and avian flu?  

For an influenza virus to infect a host, the virus must bind (attach) itself to the surface of a cell (see graphic below).

Avian flu viruses bind preferentially to the a2,3-linked sialic acid receptor cells found in the gastrointestinal tract of birds, while human and other mammalian-adapted flu viruses bind to a2,6-linked sialic acid receptor cells found in the respiratory system. 

Some hosts - like pigs - have an abundance of both types of receptor cells, and are therefore susceptible to - and viewed as potential `mixing vessels' for - different types of influenza, which can facilitate the creation of new reassortant subtypes.

Today we have an open access report that finds that both types of receptor cells are present in the respiratory tract of North American little brown bats (LBBs), making them potential hosts for human, swine, and avian flu strains.

Avian and human influenza virus compatible sialic acid receptors in little brown bats

Shubhada K. Chothe, Gitanjali Bhushan, Ruth H. Nissly, Yin-Ting Yeh,Justin Brown,Gregory Turner, Jenny Fisher, Brent J. Sewall, DeeAnn M. Reeder,Mauricio Terrones,Bhushan M. Jayarao &Suresh V. Kuchipudi

Scientific Reports 7, Article number: 660 (2017) doi:10.1038/s41598-017-00793-6
Published online: 6 April 2017


Influenza A viruses (IAVs) continue to threaten animal and human health globally. Bats are asymptomatic reservoirs for many zoonotic viruses. Recent reports of two novel IAVs in fruit bats and serological evidence of avian influenza virus (AIV) H9 infection in frugivorous bats raise questions about the role of bats in IAV epidemiology. 

IAVs bind to sialic acid (SA) receptors on host cells, and it is widely believed that hosts expressing both SA α2,3-Gal and SA α2,6-Gal receptors could facilitate genetic reassortment of avian and human IAVs. 

We found abundant co-expression of both avian (SA α2,3-Gal) and human (SA α2,6-Gal) type SA receptors in little brown bats (LBBs) that were compatible with avian and human IAV binding. This first ever study of IAV receptors in a bat species suggest that LBBs, a widely-distributed bat species in North America, could potentially be co-infected with avian and human IAVs, facilitating the emergence of zoonotic strains.



As the novel bat influenza viruses are different from other IAVs, it was proposed that these viruses would therefore require significant changes before they can infect and spread among humans11. However, a recent study rescued these viruses using reverse genetics in cell culture and found that the novel bat influenza viruses can infect a range of mammalian cells including canine cells29.

All the existing data suggests that bats could be susceptible to many different IAV subtypes and even support co-infection of avian and human IAVs. It is believed that the novel bat influenza viruses found in fruit bats are probably the ancient influenza viruses from which the modern world IAVs have been derived over time30. Evidence of high seroprevalence of avian influenza in frugivorous bats together with the evidence of abundant SA receptors in LBBs found in this study, raises a strong possibility that bats could be a major influenza virus reservoir.

Despite many rigorous scientific pursuits, we have been unable to understand the mechanism by which new pandemic influenza viruses emerge.

Consequently, we do not yet have sufficient scientific understanding needed to accurately predict which IAV strains may cause the next pandemic. The extensive diversity of bat species globally and the limited understanding of the role of bats in IAV biology raises an urgent need for comprehensive epidemiological surveillance of IAVs across different bat species.

While chickens and pigs remain the most likely hosts for generating the next novel flu virus, the list of potential `mixing vessels'  continues to expand.
In addition to the recent inclusion of bats into the world of influenza, we've also seen H5N1 in Egyptian Donkeys, H3N8 in camels and in harbor seals, a novel Influenza D virus emerge in cattle, and studies suggesting that dogs and cats may also play a role in influenza's evolution. 

When Steven Soderbergh made his pandemic thriller `Contagion’ a few years ago, technical advisor Professor Ian Lipkin created fictional MEV-1 virus based on a mutated Nipah virus (see The Scientific Plausibility of `Contagion’) because of the potential of someday seeing a bat-borne pandemic virus.

A scenario that the scientific discoveries of the last six years have only made more plausible.

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