Tuesday, January 16, 2018

Equine H3N8: Looking At A long-shot In The Pandemic Sweepstakes

Viruses 2018, 10(1), 31; doi:10.3390/v10010031


When it comes to influenza, conventional wisdom can often to blind us to an ever-changing fluscape.  Many things we thought we knew five, or ten years ago, we now find have either changed . . . or were never true to begin with.
Consider that just 15 years ago bats, cattle, and dogs and cats were not generally considered susceptible to influenza viruses.
Since then we've learned that:
I could go on, with reports on other improbable flu hosts, including camels, donkeys, seals and sea lions, minks, and skunks . . . .  but the point is, when it comes to influenza . . . there are more places to look than just in humans, birds, and pigs.

While long-shots in the influenza pandemic derby, canine and equine flu are of particular interest because the H3N8 and H3N2 subtypes they carry are similar to pandemic strains of the past (see chart below).

There is a lot of debate over these pre-1900 influenza pandemics, with conflicting views over whether the 1890-93 `Russian flu’ was due to the H2N2, H3N2, or H3N8 virus, but with most attributing the 1900 outbreak to H3N8 (see Transmissibility and geographic spread of the 1889 influenza pandemic). 

In the past couple of years we've looked repeatedly at the evolution, and potential threat, of canine influenza (see J. Virology: Zoonotic Risk, Pathogenesis, and Transmission of Canine H3N2 and J. Infect. Dis.: Molecular, Antigenic & Pathological Features of Canine H3N2 Influenza) - particularly since the Asian H3N2 canine flu has arrived in North America.

Equine H3N8 influenza - because it has remained relatively stable for 50 years (aside from jumping to dogs in 2004) - gets less attention, although we have ventured there occasionally (see J.Virol.: Experimental Infectivity Of H3N8 In Swine).
While we don't know the source of any of the older pandemics (or regional epidemics) going back several centuries, historical accounts have occasionally linked them to concurrent outbreaks in domesticated animals.

In 2010 the NIH tag team flu experts David Morens and Jeffrey K. Taubenberger penned a fascinating account of the 1872 equine epizootic - an epidemic in horses that spread from Canada to Mexico in a matter of months - and brought transportation to a standstill in this country (see A New Look At The Panzootic Of 1872)

This report provides a tantalizing review of anecdotal reports of a concurrent epizootic affecting poultry, and even causing human illness across the nation.
They wrote:

An explosive fatal epizootic in poultry, prairie chickens, turkeys, ducks, and geese occurred over much of the populated United States between November 15 and December 15, 1872. The epizootic progressed in temporal-geographic association with a well-reported panzootic of equine influenza, which had begun in or around Markham, Ontario, during the last few days of September 1872,1–4 at a time when human influenza had not been recently prevalent.

The equine epizootic spread rapidly into the United States along railroad lines, with separate simultaneous introductions into Michigan and upper New York State. It quickly spread over the entire United States to the Caribbean and Central America (Figure 1). Horses, mules, and menagerie/circus zebras were involved, with “spill over” infections into dogs and cats.4

Numerous individual human cases and localized outbreaks throughout the United States, often associated with exposures to ill horses, were reported. The human disease, generally mild and uncomplicated, was popularly referred to as the “epizooty”, or “zooty”.4
Whether this was an avian flu that jumped to horses, or an equine flu that spilled over into poultry - or two separate events - may never be known.  But Taubenberger and Morens wrote in their conclusion:
Another microbial agent could have caused the avian outbreak; however, its strong temporal and geographic association with the equine panzootic, and its clinical and epidemiologic features, are most consistent with highly pathogenic avian influenza. The avian epizootic could thus have been an early instance of highly pathogenic avian influenza.
All of which serves as prelude to a new study, published in Viruses, which looks at an oddball - isolated -  case of equine H3N8 in a horse from Montana.  The virus, surprisingly, carried both North American and Malaysian Equine H3N2 gene segments, and showed the ability to infect and replicate in a variety of non-equine cell lines.

A link, and a few excerpts, from a much longer (and fascinating) report:

Phylogenetic Analysis and Characterization of a Sporadic Isolate of Equine Influenza A H3N8 from an Unvaccinated Horse in 2015

Chithra C. Sreenivasan 1, Sunayana S. Jandhyala 1, Sisi Luo 1, Ben M. Hause 2, Milton Thomas 3, David E. B. Knudsen 3, Pamela Leslie-Steen 3, Travis Clement 3, Stephanie E. Reedy 4, Thomas M. Chambers 4, Jane Christopher-Hennings 3, Eric Nelson 3, Dan Wang 1,5, Radhey S. Kaushik 1,3 and Feng Li 1,3,5,*
Received: 26 December 2017 / Accepted: 9 January 2018 / Published: 11 January 2018

Equine influenza, caused by the H3N8 subtype, is a highly contagious respiratory disease affecting equid populations worldwide and has led to serious epidemics and transboundary pandemics. This study describes the phylogenetic characterization and replication kinetics of recently-isolated H3N8 virus from a nasal swab obtained from a sporadic case of natural infection in an unvaccinated horse from Montana, USA.

The nasal swab tested positive for equine influenza by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR). Further, the whole genome sequencing of the virus confirmed that it was the H3N8 subtype and was designated as A/equine/Montana/9564-1/2015 (H3N8). A BLASTn search revealed that the polymerase basic protein 1 (PB1), polymerase acidic (PA), hemagglutinin (HA), nucleoprotein (NP), and matrix (M) segments of this H3N8 isolate shared the highest percentage identity to A/equine/Tennessee/29A/2014 (H3N8) and the polymerase basic protein 2 (PB2), neuraminidase (NA), and non-structural protein (NS) segments to A/equine/Malaysia/M201/2015 (H3N8).

Phylogenetic characterization of individual gene segments, using currently available H3N8 viral genomes, of both equine and canine origin, further established that A/equine/Montana/9564-1/2015 belonged to the Florida Clade 1 viruses.
Interestingly, replication kinetics of this H3N8 virus, using airway derived primary cells from multiple species, such as equine, swine, bovine, and human lung epithelial cells, demonstrated appreciable titers, when compared to Madin–Darby canine kidney epithelial cells. These findings indicate the broad host spectrum of this virus isolate and suggest the potential for cross-species transmissibility.

Overall, this study provided us insights about the evolutionary relationship and in vitro cross-species infectivity of A/equine /Montana/9564-1/2015 (H3N8) virus. A comprehensive genome-scale analysis of new isolates is essential to understand the molecular evolution and phylodynamics of EIV, which in turn would help in the strategic selection of vaccine strains, effective surveillance, and control.
Antigenic and genetic variations caused by evolutionary processes play a critical role in determining the dynamics of host range and tropism of influenza viruses. Further in vivo studies are needed to evaluate the cross-species transmissibility of EIV H3N8 and its ability to cause infections and respiratory diseases in other mammalian hosts, including humans.
         (Continue . . . .)

If you are betting on the source of the next influenza pandemic - human, avian, or swine hosts (or a combination) - are by far the most likely springboards.  At least based on the past 100 years of observation.

But influenza is notoriously unpredictable, and we have to be prepared for the fact that every once in awhile, a long shot may come in.

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