#18,253
Ten days ago, in Colorado: CVMA Statement On Influenza A (HPAI H5N1) in Domestic cats, we looked at an all-too-common report of cats infected with HPAI H5 that presented with both respiratory symptoms and severe neurological impairment.While occasional neurological involvement with H5N1 infection has been reported over the past 20 years, prior to 2020 it was considered a fairly unusual occurrence. A few highlights include:
- A 2009 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’.
- Six years later - following the 2014 death of the first imported H5N1 case in Canada - we saw a study (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'.
- In a 2015 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 described its neurotropic effects, and warned that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'
- In 2022, in Clinical Features of the First Critical Case of Acute Encephalitis Caused by Avian Influenza A (H5N6) Virus, we learned of the severe neurological impact of the virus on a 6 year-old girl in China. While not the typical presentation of H5Nx infection in humans, the authors wrote:
- In view of the fact that the clinical manifestations of this novel H5N6 reassortant are acute encephalitis, rather than previous respiratory symptoms, once these reassortants obtained the ability of human-to-human transmission through reassortment or mutations, it will bring great health threat for humans.
- Since 2020 we've seen increased HPAI H5Nx spillover into mammalian species, with many displaying severe neurological symptoms prior to death (see Emerging Microbes & Inf.: Neurotropic HPAI H5N1 Viruses with Mammalian Adaptive Mutations in Free-living Mesocarnivores in Canada).
- Last September a study (see Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans warned that` . . . highly pathogenic avian influenza (HPAI) H5Nx viruses can cause neurological complications in many mammalian species, including humans'.
To that end, we've a preprint today from researchers at the NIAID labs in Hamilton, MT that finds that the bovine (genotype B3.13) strain of HPAI H5 produces more severe neurological disease in C57BL/6J lab mice than did 3 other strains (two 2.3.4.4b isolates & a 20-year-old strain from Vietnam).
Curiously, tests on BALB/C mice produced more rapid onset of severe respiratory symptoms, but without the neurological involvement seen in C57BL/6J lab mice. While several plausible explanations were offered, the reasons remain unclear.
Due to its length (27 pages) I've only posted the link, abstract, and a brief excerpt from the study. Follow the link to read it in its entirety. I'll have a postscript after the break.
Recent Bovine HPAI H5N1 Isolate is Highly Virulent for Mice, Rapidly Causing Acute Pulmonary and Neurologic Disease
Thomas Tipih, Vignesh Mariappan, Kwe Claude Yinda, Kimberly Meade-White, Matthew Lewis, Atsushi Okumura, Natalie McCarthy, Chad Clancy, Emmie de Wit, Vincent Jacobus Munster, Heinz Ulrich Feldmann, Kyle Rosenke
doi: https://doi.org/10.1101/2024.08.19.608652
Abstract
The highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses, responsible for the current outbreak in dairy cows in the United States, pose a significant animal and public health threat.
In this study, we compared disease progression and pathology of three recent clade 2.3.4.4b isolates derived from a cow, mountain lion, and mink to a human HPAI A(H5N1) isolate from Vietnam in mice.
Inoculation of C57BL/6J and BALB/c mice with all four HPAI A(H5N1) isolates resulted in comparable levels of virus replication in the lung inducing severe respiratory disease.
C57BL/6J mice infected with the bovine isolate also developed high virus titers in the brain, resulting in a significant pro-inflammatory cytokine response and neurologic disease.
Our findings suggest the recent bovine isolate possesses enhanced respiratory and neuroinvasive/neurovirulent properties causing fatal respiratory and neurologic disease in C57BL/6J mice.
(SNIP)
Our study defined oral inoculations as a potent exposure route for HPAI A(H5N1) clade 2.3.4.4b viruses. This offers a plausible explanation for reported infections in wild and domesticated carnivores with HPAI A(H5N1) viruses that may get infected through hunting and scavenging as may be the case for the mountain lion from which one of the viruses used here was isolated. In addition, oral exposure may be a viable infection route for other mammals, such as cats and humans, when consuming raw milk from infected dairy cows. Oral exposure could also be a route supporting cattle-to-cattle transmission. More studies would be necessary to determine the risk of infection by the oral-gastric route.
In conclusion, the recent bovine isolate showed high virulence for mice when inoculated by the intranasal and oral routes. C57BL/6J and BALLB/c mice provide excellent in vivo screening models for efficacy testing of antiviral, therapeutic and vaccine candidates against infections with these emerging HPAI A(H5N1) viruses.
The C57BL/6J model allows studies on mechanisms of neuroinvasion and neurovirulence of the emerging HPAI A(H5N1) viruses. Both mouse models may be used to gain deeper insight into infection by the oral-gastric route, an exposure route of importance for cow-to-human as well as bird/poultry-to-carnivore transmission of emerging HPAI A(H5N1) isolates. Thus, the mouse models will be extremely beneficial for animal and public health responses to the current HPAI A(H5N1) outbreak.
Although we are currently focused on the bovine (B3.13) genotype of H5N1, there are literally dozens of genotypes of H5N1 in circulation around the world, with more being added over time.
And as we've discussed previously, even minor genetic variations between viruses can produce vastly different characteristics (see Differences In Virulence Between Closely Related H5N1 Strains).
While we may be comforted by the lack of severe H5N1 infection in the United States, the virus continues to rapidly evolve, making past performance no guarantee of future results.
