#17,541
Until relatively recently, severe avian influenza A infection in mammals (including humans) has been regarded as primarily a respiratory infection; commonly presenting as a viral pneumonia.
It wasn't an absolute, of course, since even seasonal flu can occasionally produce a variety of subtle, and sometimes profound, neurological symptoms.
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| Credit CDC 2018 COCA Call On Severe Influenza |
The exact mechanisms behind these neurological manifestations are unknown. Seasonal flu viruses are generally regarded as being non-neurotropic, but some studies have suggested there is a risk of long-term neurological impacts of severe (or repeated) influenza infections (see Nature Comms: Revisiting The Influenza-Parkinson's Link).
While there had been some rumors of neurological involvement in some H5N1 cases in Indonesia during the first decade of the 21st century, information was sparse.
In 2009 a PNAS study (Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.
Our first detailed look at an extrapulmonary H5N1 infection came in 2015, after the death of the first imported H5N1 case in Canada the previous year (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), where the authors wrote:`These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.
Similarly, in a Scientific Reports study on the genetics of the H5N1 clade 2.3.2.1c virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors warned of its neurotropic effects, and that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'
More recently, in 2022's Clinical Features of the First Critical Case of Acute Encephalitis Caused by Avian Influenza A (H5N6) Virus, we looked at the case of a 6 year-old girl in China who presented with severe neurological symptoms following H5N6 infection.
Preprint: Pathology Of HPAI H5N1 clade 2.3.4.4b in Wild Terrestrial Mammals in the United States in 2022
Emerging Microbes & Inf.: Neurotropic HPAI H5N1 Viruses with Mammalian Adaptive Mutations in Free-living Mesocarnivores in Canada
Pathogens: Zoonotic Mutation of Highly Pathogenic Avian Influenza H5N1 Virus Identified in the Brain of Multiple Wild Carnivore Species
Exactly why we are seeing more reports of neurotropic avian influenza isn't clear. As we've discussed in the past, within each subtype (e.g. H5N1, H5N6, etc) of influenza there can be dozens of clades, each with dozens or scores of genotypes.
Within each of these subgroups can exist individual mutations (e.g. E627K, D710N, etc.), which can add to, or detract from, its virulence or transmissibility.
Most of these variants are destined to end up evolutionary failures, and will be unable to compete against their parental strains. But a few may prove more biological `fit', establish themselves, and present greater risks to humans.
In an attempt to better understand the pathogenesis of avian flu in mammals, researchers in the Netherlands inoculated ferrets with an H5N6 virus collected from local black-headed gulls in 2017. While this particular strain did not spread from ferret-to-ferret via the air, it produced unusually severe extrapulmonary infection in these lab animals.
Other than a D701N substitution in the PB2 - which has previously been linked to adaptation and increased virulence in mammals (see Dual E627K and D701N mutations in the PB2 protein of A(H7N9), no other AA changes of note were detected.
Research Article 10 July 2023
A Dutch highly pathogenic H5N6 avian influenza virus showed remarkable tropism for extra-respiratory organs and caused severe disease but was not transmissible via air in the ferret model
Authors: Sander Herfst https://orcid.org/0000-0001-9866-8903 s.herfst@erasmusmc.nl, Lineke Begeman, Monique I. Spronken, Marjolein J. Poen, Dirk Eggink, Dennis de Meulder, Pascal Lexmond, Theo M. Bestebroer, Marion P. G. Koopmans, Thijs Kuiken, Mathilde Richard https://orcid.org/0000-0003-0240-9312, Ron A. M. Fouchier
ABSTRACT
Continued circulation of A/H5N1 influenza viruses of the A/goose/Guangdong/1/96 lineage in poultry has resulted in the diversification in multiple genetic and antigenic clades. Since 2009, clade 2.3.4.4 hemagglutinin (HA) containing viruses harboring the internal and neuraminidase (NA) genes of other avian influenza A viruses have been detected. As a result, various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8 have been identified.
As of January 2023, 83 humans have been infected with A/H5N6 viruses, thereby posing an apparent risk for public health. Here, as part of a risk assessment, the in vitro and in vivo characterization of A/H5N6 A/black-headed gull/Netherlands/29/2017 is described. This A/H5N6 virus was not transmitted between ferrets via the air but was of unexpectedly high pathogenicity compared to other described A/H5N6 viruses.
The virus replicated and caused severe lesions not only in respiratory tissues but also in multiple extra-respiratory tissues, including brain, liver, pancreas, spleen, lymph nodes, and adrenal gland. Sequence analyses demonstrated that the well-known mammalian adaptation substitution D701N was positively selected in almost all ferrets. In the in vitro experiments, no other known viral phenotypic properties associated with mammalian adaptation or increased pathogenicity were identified. The lack of transmission via the air and the absence of mammalian adaptation markers suggest that the public health risk of this virus is low. The high pathogenicity of this virus in ferrets could not be explained by the known mammalian pathogenicity factors and should be further studied.
IMPORTANCE
Avian influenza A/H5 viruses can cross the species barrier and infect humans. These infections can have a fatal outcome, but fortunately these influenza A/H5 viruses do not spread between humans. However, the extensive circulation and reassortment of A/H5N6 viruses in poultry and wild birds warrant risk assessments of circulating strains. Here an in-depth characterization of the properties of an avian A/H5N6 influenza virus isolated from a black-headed gull in the Netherlands was performed in vitro and in vivo, in ferrets. The virus was not transmissible via the air but caused severe disease and spread to extra-respiratory organs. Apart from the detection in ferrets of a mutation that increased virus replication, no other mammalian adaptation phenotypes were identified. Our results suggest that the risk of this avian A/H5N6 virus for public health is low. The underlying reasons for the high pathogenicity of this virus are unexplained and should be further studied.
(SNIP)
Collectively, our results demonstrated that the Dutch HPAI H5N6 A/black-headed gull/Netherlands/29/2017 virus replicated systemically in ferrets with an unusual lymphotropism and neurotropism, had high pathogenicity but lacked the ability to transmit via the airborne route in the ferret model. The high pathogenicity could not be explained by our phenotypical in vitro analyses and warrants further investigation.
Careful extrapolation from animal models to humans suggests that the public health threat of the HPAI H5N6 viruses is low. However, given the rapid geographical spread of HPAI clade 2.3.4.4 A/H5Nx viruses, including recent clade 2.3.4.4b A/H5N1 viruses, their ability to infect various species of birds and mammals including humans, and the tendency of influenza A viruses to mutate and reassort, the phenotypic properties of HPAI H5Nx viruses should be monitored closely (47)
Humans are obviously not ferrets, and there are too many moving genetic parts to know whether a current day human-adapted H5N1 virus would produce the same neurological impacts in people as this older H5N6 virus did in ferrets.
Nevertheless, the findings in mammals around the world are concerning, and we need to understand why it appears to be happening with more frequency over the past 24 months.
While it is still unknown whether H5Nx can spark a pandemic, should it happen we need to go into it with as much knowledge as possible.
