Sunday, April 03, 2016

JVI: Pathogenesis Of Influenza D in Cattle

Credit NIAID


Two years ago a group of researchers reported their findings on a novel influenza virus detected in swine from Oklahoma.  Their study – published PLoS Pathogens –  Isolation of a Novel Swine Influenza Virus from Oklahoma in 2011 Which Is Distantly Related to Human Influenza C Viruses immediately caused a stir in the flu research community.

The authors wrote:
Based on its genetic organizational similarities to influenza C viruses this virus has been provisionally designated C/Oklahoma/1334/2011 (C/OK). 
Additionally, the authors found that this new (provisional) influenza C virus could infect, and transmit, in both ferrets and pigs.  The authors described this new discovery as:
. . .  a new subtype of influenza C viruses that currently circulates in pigs that has not been recognized previously. The presence of multiple subtypes of co-circulating influenza C viruses raises the possibility of reassortment and antigenic shift as mechanisms of influenza C virus evolution.

Six months later, in mBio: Characterizing A Novel Influenza C Virus In Bovines & Swine we looked at a second paper by these same researchers, which added cattle to the list of hosts found to carry this novel virus.  While still calling it an Influenza C, they wrote:

Detailed genetic, biological, and antigenic characterization suggests that C/OK viruses in cattle and swine are distinct from human ICV and likely represent a new genus in the Orthomyxoviridae family, with C/OK virus as the type species of influenza D virus.
Additionally, widespread and high antibody titers to C/OK virus and relative ease of virus isolation in cattle indicate that bovines may represent the reservoir to this novel influenza virus. The finding of C/OK virus in both swine and bovine indicates that this new virus may spread and establish infection in other mammals, including humans.

Since then, researchers have found evidence of a much wider spread of this virus (now provisionally called Influenza D)  than just in the American Midwest (see Influenza D Virus in Cattle, France, 2011–2014  and Detection of Influenza D Virus among Swine and Cattle, Italy).

Despite this flurry of scientific research, relatively little is known about the spread, pathogenesis, and zoonotic potential of Influenza D viruses.  

Late last week another paper appeared - this time in the Journal of Virology - that attempts to shed additional light on the matter:

Pathogenesis of Influenza D virus in Cattle
Cattle have been proposed as the natural reservoir of a novel member of the Orthomyxoviridae virus family which has been tentatively classified as influenza D virus (IDV). Although isolated from sick animals it is unclear IDV causes any clinical disease in cattle. 

To address this aspect of Koch's postulates, three dairy calves (treatment animals) held in individual pens were inoculated intranasally with D/bovine/Mississippi/C00046N/2014. At 1 day post inoculation a seronegative calf (contact animal) was added to each of the treatment animal pens. The cattle in both treatment and contact groups seroconverted and virus was detected in their respiratory tracts.
Histologically there was a significant increase in neutrophil tracking in tracheal epithelia of the treatment calves as compared to control animals. While infected and contact animals demonstrated various symptoms of respiratory infection, these were mild and calves in the treatment group did not differ from controls in terms of heart rate, respiratory rate or rectal temperature. 

To mimic zoonotic transmission, two ferrets were exposed to a plastic toy fomite soaked with infected nasal discharge from the treatment calves. These ferrets did not shed the virus or seroconvert. 

In summary, this study demonstrates that IDV causes a mild respiratory disease upon experimental infection of cattle and can be transmitted effectively among cattle by in-pen contact, but not from cattle to ferrets through fomite exposure. These findings support the hypothesis that cattle are a natural reservoir for this virus. 

In previous studies, ferrets - after being intranasally inoculated with influenza D - seroconverted and were able to infect other ferrets.  This, along with the observed spread in both cattle and pigs, raised red flags, with the authors writing:

The ability of C/OK (now Influenza D - Ed.) to infect ferrets along with the absence of antibodies to C/OK in humans, suggests that such viruses may become a potential threat to human health.

The lack of ferret infection (in limited testing) via a fomite route may attenuate those concerns slightly, but much more study is needed to determine the potential zoonotic threat from influenza D.

Every year our understanding of the diversity and host range of novel influenza viruses increases. Most of these viruses are likely to remain little more than obscure, scientific curiosities, posing little or no threat to public health.

But our track record of knowning which viruses we should worry about, and which ones we can safely ignore, hasn't always been spot on.
After all, that is exactly how we would have described the Zika virus only a few short months ago.

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