Wednesday, January 25, 2023

ASM J.: HPAI H5N1 Virus Infections in Wild Red Foxes (Vulpes vulpes) Show Neurotropism and Adaptive Virus Mutations


The rise of HPAI H5N1 clade - ECDC/EFSA Avian influenza overview


Recent reports of sporadic mammalian infection with clade HPAI H5N1 (see here, here, and here), apparent mammal-to-mammal transmission of virus in farmed mink, and large die offs of marine mammals infected with the virus, have raised concerns over the pandemic potential of this zoonotic avian virus. 

Late yesterday  Kai Kupferschmidt published an excellent overview of the situation in Science, with comments from several well known researchers, including virologist Tom Peacockveterinary pathologist Thijs Kuiken, and influenza researcher Richard Webby.

Highly recommended. 

Spread among captive mink could give the H5N1 strain opportunities to evolve and adapt to mammals

24 JAN 2023
5:00 PM

Although we've stood on this precipice before only to see the H5N1 threat recede, there are no guarantees we'll get lucky again. Clade of HPAI H5N1 has spread faster and farther than any previous avian flu strain, is rapidly mutating (see Rapid Evolution of A(H5N1) Influenza Viruses), and shows more `affinity' for infecting mammals.

This increased susceptibility of mammalian hosts of HPAI H5N1 is an obvious concern - particularly given the reports of severe illness and neurological manifestations - and the fact that 3 of the 7 known human infections with this clade have been severe (1 fatal).

In May of 2021, in Netherlands: Two Foxes Test Positive For (non-Zoonotic) Avian H5N1, we looked at an unusual report from Wageningen Bioveterinary Research (WBVR) where they reported finding two foxes in the province of Groningen that had been infected with avian H5N1.

Last summer we looked at a preprint from Wageningen Bioveterinary Research (WBVR) , published in BioRxiv, that found evidence that the H5N1 virus was actively adapting to its new-found mammalian hosts by generating PB2-627K mutations which promote increased viral replication at lower temperatures.

Since then, we've seen numerous new reports of mammalian infection with H5N1, the aforementioned mink farm outbreak, and have now seen severe human infection with this emerging virus. Yesterday, the preprint from last summer was published the ASM journal Microbiology Spectrum. 

Given the events of the past few months, this study is well worth a second look.  Follow the link to read the report in its entirety.  I'll have a brief comment after the break. 

Highly Pathogenic Avian Influenza H5N1 Virus Infections in Wild Red Foxes (Vulpes vulpes) Show Neurotropism and Adaptive Virus Mutations

Authors: Luca Bordes, Sandra Vreman, Rene Heutink, Marit Roose, Sandra Venema, Sylvia B. E. Pritz-Verschuren, Jolianne M. Rijks, José L. Gonzales , Evelien A. Germeraad, Marc Engelsma, Nancy Beerens 1 nancy.beerens@wur.nlAUTHORS INFO & AFFILIATIONS



During the 2020 to 2022 epizootic of highly pathogenic avian influenza virus (HPAI), several infections of mammalian species were reported in Europe. In the Netherlands, HPAI H5N1 virus infections were detected in three wild red foxes (Vulpes vulpes) that were submitted with neurological symptoms between December of 2021 and February of 2022.

A histopathological analysis demonstrated that the virus was mainly present in the brain, with limited or no detection in the respiratory tract or other organs. Limited or no virus shedding was observed in throat and rectal swabs. A phylogenetic analysis showed that the three fox viruses were not closely related, but they were related to HPAI H5N1 clade viruses that are found in wild birds. This suggests that the virus was not transmitted between the foxes.

A genetic analysis demonstrated the presence of the mammalian adaptation E627K in the polymerase basic two (PB2) protein of the two fox viruses. In both foxes, the avian (PB2-627E) and the mammalian (PB2-627K) variants were present as a mixture in the virus population, which suggests that the mutation emerged in these specific animals. The two variant viruses were isolated, and virus replication and passaging experiments were performed. These experiments showed that the mutation PB2-627K increases the replication of the virus in mammalian cell lines, compared to the chicken cell line, and at the lower temperatures of the mammalian upper respiratory tract.

This study showed that the HPAI H5N1 virus is capable of adaptation to mammals; however, more adaptive mutations are required to allow for efficient transmission between mammals. Therefore, surveillance in mammals should be expanded to closely monitor the emergence of zoonotic mutations for pandemic preparedness.

IMPORTANCE Highly pathogenic avian influenza (HPAI) viruses caused high mortality among wild birds from 2021 to 2022 in the Netherlands. Recently, three wild foxes were found to be infected with HPAI H5N1 viruses, likely due to the foxes feeding on infected birds. Although HPAI is a respiratory virus, in these foxes, the viruses were mostly detected in the brain. Two viruses isolated from the foxes contained a mutation that is associated with adaptation to mammals. We show that the mutant virus replicates better in mammalian cells than in avian cells and at the lower body temperature of mammals.

More mutations are required before viruses can transmit between mammals or can be transmitted to humans. However, infections in mammalian species should be closely monitored to swiftly detect mutations that may increase the zoonotic potential of HPAI H5N1 viruses, as these may threaten public health.

          (Continue . . . )


Although there may be some unknown `species barrier' that prevents an H5 virus from sparking a human pandemic (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) - public health agencies like the CDC, ECDC, and WHO are taking the threat seriously. 

Last October the ECDC released a 32-page guidance document on testing and detection of zoonotic influenza viruses in humans, in November the UKHSA Issued Additional Guidance On Recognizing and Treating Novel Avian Influenza, while the CDC's Guidance can be found HERE.

While the future course and impact of HPAI H5N1 is unknowable, another pandemic is inevitable - and while we may have years before that happens -  nothing says it can't start tomorrow. 

And we can't afford to be caught flat-footed again.