mBio: Characterizing A Novel Influenza C Virus In Bovines & Swine

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In virology, perhaps as much as any field of scientific endeavor, the half-life of `facts’  continues to decline.  Fresh discoveries, propelled by new technologies and concerns over the threats posed by emerging viruses, have conspired to obsolete many textbooks (and blog articles) almost as soon as they are published.

 

Case in point:  A year ago, little thought was given to influenza C viruses. 

 

A visit to the CDC’s Flu Basics `Types Of Influenza Viruses’ page barely finds mention of  influenza C.

 

There are three types of influenza viruses: A, B and C. Human influenza A and B viruses cause seasonal epidemics of disease almost every winter in the United States. The emergence of a new and very different influenza virus to infect people can cause an influenza pandemic. Influenza type C infections cause a mild respiratory illness and are not thought to cause epidemics.

 

Since most of us are exposed as children, influenza C is regarded as posing a minimal health threat. This lack of respect for influenza C is due mainly to its lack of genetic diversity and slow rate of evolution. 

 

Essentially, it was believed if you’d seen one subtype of Influenza C, you’ve pretty much seen them all. 

 

But last year, a group of researchers published (PLoS Pathogens) their finding and Isolation of a Novel Swine Influenza Virus from Oklahoma in 2011 Which Is Distantly Related to Human Influenza C Viruses, which threatened to rewrite the textbooks on Influenza C.  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). Phylogenetic analysis of the predicted viral proteins found that the divergence between C/OK and human influenza C viruses was similar to that observed between influenza A and B viruses. No cross reactivity was observed between C/OK and human influenza C viruses using hemagglutination inhibition (HI) assays.

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.

 

Fast forward a year, and these same researchers are back, this time in the open access journal mBio, with an update on this new influenza C subtype, which they now have found circulates in both cattle and swine.

 

Characterization of a Novel Influenza Virus in Cattle and Swine: Proposal for a New Genus in the Orthomyxoviridae Family

Ben M. Hause^a, Emily A. Collin^a,b, Runxia Liu^b,c, Bing Huang^b,c,d, Zizhang Sheng^e, Wuxun Lu^b,c, Dan Wang^b,c, Eric A. Nelson^b,c, Feng Li^b,c

ABSTRACT

We have recently reported the isolation of a novel virus, provisionally designated C/swine/Oklahoma/1334/2011 (C/OK), with 50% overall homology to human influenza C viruses (ICV), from a pig in Oklahoma. Deep RNA sequencing of C/OK virus found a matrix 1 (M1) protein expression strategy that differed from that of ICV. The novelty of C/OK virus prompted us to investigate whether C/OK virus could exist in a nonswine species.

Significantly, we found that C/OK virus was widespread in U.S. bovine herds, as demonstrated by reverse transcription (RT)-PCR and serological assays. Genome sequencing of three bovine viruses isolated from two herds in different states further confirmed these findings. To determine whether swine/bovine C/OK viruses can undergo reassortment with human ICV, and to clarify the taxonomic status of C/OK, in vitro reassortment and serological typing by agar gel immunodiffusion (AGID) were conducted. In vitro reassortment using two human ICV and two swine and bovine C/OK viruses demonstrated that human ICV and C/OK viruses were unable to reassort and produce viable progeny. Antigenically, no cross-recognition of detergent split virions was observed in AGID between human and nonhuman viruses by using polyclonal antibodies that were reactive to cognate antigens.

Taken together, these results demonstrate that C/OK virus is genetically and antigenically distinct from ICV. The classification of the new virus in a separate genus of the Orthomyxoviridae family is proposed. The finding of C/OK virus in swine and bovine indicates that this new virus may spread and establish infection in other mammals, including humans.

IMPORTANCE Influenza C viruses (ICV) are common human pathogens, infecting most people during childhood and adolescence, and typically cause mild respiratory symptoms. While ICV have been isolated from both pigs and dogs, humans are thought to be the natural viral reservoir. Previously, we characterized an ICV-like virus isolated from pigs exhibiting symptoms of influenza virus-like illness. Here, we show molecular and serological data demonstrating widespread circulation of similar viruses in bovines.

Deep RNA sequencing, phylogenetic analysis, and in vitro reassortment experiments demonstrate that animal ICV-like viruses are genetically distinct from human ICV. Antigenically, we show that ICV-like viruses are not recognized by ICV antibodies. En masse, these results suggest that bovine influenza virus warrants classification as a new genus of influenza virus. The finding of this novel virus that can infect multiple mammalian species warrants further research into its role in human health.

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Although first isolated in swine, seroprevalence studies only showed about 10% of pigs sampled had antibodies to this influenza C virus, prompting researchers to look for another host species. Subsequent testing of cattle across multiple states found high antibody titers to C/OK viruses, suggesting they are the likely primary reservoir host for this subtype.

 

It seems that hardly a month goes by when we don’t learn of a new virus or pathogen, such as we saw last year in PLoS Pathogens: New World Bats Harbor Diverse Flu Strains.  Until 2012, bats were never thought of as a host for influenza viruses, but now we know different.

 

Last September, in mBio: A Strategy To Estimate The Number Of Undiscovered Viruses, we looked at an attempt by researchers at Columbia University's Mailman School of Public Health, EcoHealth Alliance, the NIH, and universities and research centers around the world to estimate the number of viruses in the wild, awaiting discovery.

 

The good news is, the estimated number of viruses out there is finite, the bad news is, we are probably talking 6 figures.

 

As far at the potential human health impact from this recently discovered C/OK virus is concerned, the jury is still out.  The authors write:

 

It is unknown if C/OK virus has an impact on human health. The ability to infect and transmit in ferrets, a model for human influenza virus pathogenesis studies, suggests this pathogen has the potential to cause disease in humans. Limited serology on a subset of human serum samples showing a 1.3% positive rate also supports this hypothesis. The prevalence of C/OK virus in cattle and presumptive spillover to swine, both of which live in close proximity to humans, further highlights its potential threats to human health, which merit further studies.

 

 

Regardless of the future impact of this particular discovery, one thing is certain.  We are unlikely to run out of new things to talk about in virology anytime in our lifetimes.

 

It is truly a vast, and largely undiscovered, scientific frontier.

PLoS Pathogens: A New Influenza C Virus Detected In Swine

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When we talk about influenza viruses, Influenza A and Influenza B pretty much capture all of the headlines.  Less well known are the Influenza C viruses - which while less common - circulate both in humans and in swine.

 

For those looking for a detailed virology lesson, Vincent Racaniello wrote about the three types of influenza viruses in 2009 on his Virology Blog in a piece called The A, B, and C of influenza virus.

 

Although most adults have encountered the influenza C virus at least once in their life, it tends to produce only mild upper respiratory tract infections. The CDC  describes influenza B & C viruses this way.

 

Influenza Type B

Influenza B viruses are usually found only in humans. Unlike influenza A viruses, these viruses are not classified according to subtype. Influenza B viruses can cause morbidity and mortality among humans, but in general are associated with less severe epidemics than influenza A viruses. Although influenza type B viruses can cause human epidemics, they have not caused pandemics.

Influenza Type C

Influenza type C viruses cause mild illness in humans and do not cause epidemics or pandemics. These viruses are not classified according to subtype.

 

Our knowledge of influenza C is somewhat limited, but last December, Lisa Schnirring at CIDRAP NEWS wrote this report on a study of Influenza C viruses.

 

Study finds influenza C in kids hospitalized with pneumonia

Lisa Schnirring Staff Writer

Dec 7, 2012 (CIDRAP News) – Influenza C generally isn't thought to be a cause clinically significant disease, but a study in Italian children who were seen in the emergency department for pneumonia found the virus in five children, with a disease severity that resembled influenza A.

 

The study evaluated data from four flu seasons from 2008-09 to 2011-12 at a pediatric clinic in Milan and appeared today in an early online edition of Influenza and Other Respiratory Viruses.

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Influenza B and C are considered unlikely to have much in the way of pandemic potential because they lack the multiple sub-types found with influenza A viruses (17 hemagglutinin and 9 neuraminidase subtypes) that allow for viral reassortment.

 

Two Influenza A viruses can swap genetic segments to produce new hybrid (reassortant) viruses.

 

But of course, one should never say `never’. . . .

 

From PloS Pathogens  today we get the first study to suggest that influenza C viruses might have the ability to reassort and evolve at a rate that could pose a greater threat than previously believed.

 

The study is called:

 

Isolation of a Novel Swine Influenza Virus from Oklahoma in 2011 Which Is Distantly Related to Human Influenza C Viruses

Ben M. Hause , Mariette Ducatez, Emily A. Collin, Zhiguang Ran, Runxia Liu, Zizhang Sheng, Anibal Armien, Bryan Kaplan, Suvobrata Chakravarty, Adam D. Hoppe, Richard J. Webby, Randy R. Simonson, Feng Li

EXCERPTS (slightly reparagraphed)

Abstract

Of the Orthomyxoviridae family of viruses, only influenza A viruses are thought to exist as multiple subtypes and has non-human maintenance hosts.

 

In April 2011, nasal swabs were collected for virus isolation from pigs exhibiting influenza-like illness. Subsequent electron microscopic, biochemical, and genetic studies identified an orthomyxovirus with seven RNA segments exhibiting approximately 50% overall amino acid identity to human influenza C virus.

 

Based on its genetic organizational similarities to influenza C viruses this virus has been provisionally designated C/Oklahoma/1334/2011 (C/OK). Phylogenetic analysis of the predicted viral proteins found that the divergence between C/OK and human influenza C viruses was similar to that observed between influenza A and B viruses.

 

No cross reactivity was observed between C/OK and human influenza C viruses using hemagglutination inhibition (HI) assays.

 

Additionally, screening of pig and human serum samples found that 9.5% and 1.3%, respectively, of individuals had measurable HI antibody titers to C/OK virus. C/OK virus was able to infect both ferrets and pigs and transmit to naive animals by direct contact.

 

Cell culture studies showed that C/OK virus displayed a broader cellular tropism than a human influenza C virus. The observed difference in cellular tropism was further supported by structural analysis showing that hemagglutinin esterase (HE) proteins between two viruses have conserved enzymatic but divergent receptor-binding sites.

 

These results suggest that C/OK virus represents 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.

Author Summary

Influenza C viruses infect most humans during childhood. Unlike influenza A viruses, influenza C viruses exhibit little genetic variability and evolve at a comparably slower rate. Influenza A viruses exist as multiple subtypes and cause disease in numerous mammals.

 

In contrast, influenza C viruses are comprised of a single subtype in its primary human host. Here we characterize a novel swine influenza virus, C/swine/Oklahoma/1334/2011 (C/OK), having only modest genetic similarity to human influenza C viruses. No cross-reaction was observed between C/OK and human influenza C viruses.

 

Antibodies that cross react with C/OK were identified in a significant number of swine but not human sera samples, suggesting that C/OK circulates in pigs. Additionally, we show that C/OK is capable of infecting and transmitting by direct contact in both pigs and ferrets.

 

These results suggest that C/OK represents a new subtype of influenza C viruses. This is significant, as co-circulation of multiple subtypes of influenza allows for rapid viral evolution through antigenic shift, a property previously only shown for influenza A viruses.

 

The ability of C/OK 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.

 

This is a fascinating paper, well worth exploring in its entirety. 

 

How much of a threat influenza C viruses really pose is something that needs to be established, but once again we are reminded that our understanding of the world of influenza viruses – while continually expanding – remains far from complete.