Avian Flu Diary: Nature Comms: Pathogenicity and Transmissibility of Bovine H5N1 Influenza Virus

Flu Virus binding to Receptor Cells – Credit CDC

#18,172

We've a small glimpse today at a new paper - published in Nature Comms - from researchers at the University of Wisconsin that finds that the bovine H5N1 strain circulating in American dairy cattle may be slightly better suited for transmission to humans than previously thought.

Avian adapted flu viruses, like the H5N1 virus, bind preferentially to the α2,3-linked receptor cells found primarily in the gastrointestinal tract of birds.

Human adapted influenza viruses have an RBS - Receptor Binding Site (the area of its genetic sequence that allows it to attach to, and infect, host cells) that `fit’ the receptor cells commonly found in the human upper respiratory tract; the α2,6-linked receptor cell.

So far, H5N1 has shown little or no affinity for mammalian (α2,6-linked) receptor cells. Humans, however, are not completely devoid of the avian-type receptors, which may account for the occasional human infection.

Today's report indicates that the bovine H5N1 is becoming somewhat better at binding to α2,6-linked receptor cells, which would be a prerequisite for the virus to become a bigger public health threat. Airborne transmission between ferrets, however, remains marginal.

The study is behind a paywall, and the details provided by the abstract (below), and accompanying press release, are fairly generic. I expect we'll learn more in the days ahead.

Pathogenicity and transmissibility of bovine H5N1 influenza virus

Amie J. Eisfeld, Asim Biswas, Lizheng Guan, Chunyang Gu, Tadashi Maemura, Sanja Trifkovic, Tong Wang, Lavanya Babujee, Randall Dahn, Peter J. Halfmann, Tera Barnhardt, Gabriele Neumann, Yasuo Suzuki, Alexis Thompson, Amy K. Swinford, Kiril M. Dimitrov, Keith Poulsen & Yoshihiro Kawaoka

Nature (2024)Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract

Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. In the Spring of 2024, an unprecedented outbreak of HPAI H5N1 in bovine herds occurred in the US, with virus spread within and between herds, infections in poultry and cats, and spillover into humans, collectively indicating an increased public health risk1-4.

Here, we characterized an HPAI H5N1 virus isolated from infected cow milk in mice and ferrets. Like other HPAI H5N1 viruses, the bovine H5N1 virus spread systemically, including to the mammary glands of both species; however, this tropism was also observed for an older HPAI H5N1 virus isolate.

Importantly, bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals.

From the University of Wisconsin-Madison newsroom:

Raw milk is risky, but airborne transmission of H5N1 from cow’s milk is inefficient in mammals.
July 8, 2024

By Will Cushman For news media

While H5N1 avian influenza virus taken from infected cow’s milk makes mice and ferrets sick when dripped into their noses, airborne transmission of the virus between ferrets — a common model for human transmission — appears to be limited.

These and other new findings about the strain of H5N1 circulating among North American dairy cattle this year come from a set of laboratory experiments led by University of Wisconsin–Madison researchers, reported today in the journal Nature. Together, they suggest that exposure to raw milk infected with the currently circulating virus poses a real risk of infecting humans, but that the virus may not spread very far or quickly to others.

“This relatively low risk is good news, since it means the virus is unlikely to easily infect others who aren’t exposed to raw infected milk,” says Yoshihiro Kawaoka, a UW–Madison professor of pathobiological sciences who led the study alongside Keith Poulsen, director of the Wisconsin Veterinary Diagnostic Laboratory, and with collaborators at Texas A&M University, Japan’s University of Shizuoka and elsewhere.

Kawaoka cautioned, however, that the findings represent the behavior of the virus in mice and ferrets and may not account for the infection and evolution process in humans.

In their experiments, the UW–Madison team found that mice can become ill with influenza after drinking even relatively small quantities of raw milk taken from an infected cow in New Mexico.

Kawaoka and his colleagues also tested the bovine H5N1 virus’s ability to spread through the air by placing ferrets infected with the virus near but out of physical contact with uninfected ferrets. Ferrets are a common model for understanding how influenza viruses might spread among humans because the small mammals exhibit respiratory symptoms similar to humans who are sick with the flu, including congestion, sneezing and fever. Efficient airborne transmission would signal a serious escalation iUniversity of Wisconsin n the virus’s potential to spark a human pandemic.

None of the four exposed ferrets became ill, and no virus was recovered from them throughout the course of the study. However upon further testing, the researchers found that one exposed ferret had produced antibodies to the H5N1 virus.

“That suggests that the exposed ferret was infected, indicating some level of airborne transmissibility but not a substantial level,” Kawaoka says.

Separately, the team mixed the bovine H5N1 virus with receptors — molecules the virus binds to in order to enter cells — that are typically recognized by avian or human influenza viruses. They found that bovine H5N1 bound to both types of molecules, representing one more line of evidence of its adaptability to human hosts.

While that adaptability has so far resulted in a limited number of human H5N1 cases, previous influenza viruses that caused human pandemics in 1957 and 1968 did so after developing the ability to bind to receptors bound by human influenza viruses.

Finally, the UW–Madison team found that the virus spread to the mammary glands and muscles of mice infected with H5N1 virus and that the virus spread from mothers to their pups, likely via infected milk.

These findings underscore the potential risks of consuming unpasteurized milk and possibly undercooked beef derived from infected cattle if the virus spreads widely among beef cattle, according to Kawaoka.

“The H5N1 virus currently circulating in cattle has limited capacity to transmit in mammals,” he says. “But we need to monitor and contain this virus to prevent its evolution to one that transmits well in humans.”

We've seen previous studies on the evolution of the receptor binding of H5N1, including 2 weeks ago in Preprint: A Single Mutation in Dairy Cow-Associated H5N1 Viruses Increases Receptor Binding Breadth) which described the shifting, and growing, range of avian receptor cells it can bind to.