Preprint: Enhanced Encephalitic Tropism of Bovine H5N1 Compared to the Vietnam H5N1 Isolate in Mice

 

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Although seasonal flu can occasionally cause neurological symptoms (see 2018's Neuroinfluenza: A Review Of Recently Published Studies) it is relatively rare phenomenon, and usually only results in mild, and transient symptoms. 

The exact mechanisms behind these neurological manifestations are largely unknown, as seasonal flu viruses are generally regarded as being non-neurotropic.

Some researchers have posited that neurological symptoms may be due to neuroinflammation induced by the host's immune response. Regardless of the mechanism, we've seen seen evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others.

Fifteen years ago H5N1 was considered primarily a respiratory disease, but in 2009 a PNAS study (link below) 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’.

Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration

In early 2014 we saw Alberta Canada Report a Fatal (Imported) H5N1 Infection, in a nurse who'd traveled to China for the holidays and succumbed to the virus shortly after her return.  This was Canada's 1st H5N1 infection, and in the following year we saw a study which described her infection as `neurotropic'. 

CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada

The patient presented with `. . . pleuritic chest and abdominal pain . . . , this was followed by headache, confusion and, ultimately, respiratory failure, coma and death.' After reviewing MRI imaging and histological analyses, the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.

Also in 2015 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.'

While clinical details of many H5Nx human infections go unpublished, in 2022, in Clinical Features of the First Critical Case of Acute Encephalitis Caused by Avian Influenza A (H5N6) Virus, we learned of the severe neurological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 certainly 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 human.

 Over the past few years we've seen numerous reports of mammals infected with the 2.3.4.4b subclade of H5Nx experiencing severe, and often fatal, neurological manifestations.  Often, cats and other small mammals were initially suspected being rabid, only to test positive for H5Nx.

Just over a year ago, in Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans, we looked at a review that looked at the history, and recent trends, of neuropathogenesis of avian H5 in mammals.

All of which brings us to a preprint, published yesterday by researchers at NIAID (NIH), which compares the neurotropism of a 20 year-old strain of H5N1 collected from Vietnam to a recent isolate of the `bovine' B3.13 genotype of H5N1. 

What they find is the `modern' version of H5N1 is far more neurotropic in lab animals (mice) than its ancestral strains.  

The authors do point out that `Importantly, the findings in this study appear to be mouse specific and likely not representative of what will occur in humans, as thus far there is no evidence of CNS infection in contemporary H5N1 patients.'

But it is further evidence that the H5N1 viruses circulating today are different from those that emerged two decades ago in Southeast Asia, and they continue to evolve in unpredictable ways.   

First the link and abstract from the 38-page preprint, then I'll return with a bit more.

Enhanced encephalitic tropism of bovine H5N1 compared to the Vietnam H5N1 isolate in mice

Kerry Goldin,  Sarah van Tol, Randall C Johnson, Reshma Koolaparambil Mukesh, Shane Gallogly, Jonathan E Schulz, Greg Saturday, Kwe Claude Yinda, Vincent J Munster, Emmie de Wit, Neeltje van Doremalen
doi: https://doi.org/10.1101/2024.11.19.624162

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Abstract

In recent years, the landscape of highly pathogenic avian influenza (HPAI) virus infections has shifted, as evidenced by an increase in infections among mammals. This includes the recent circulation of H5N1 in dairy cattle herds in the USA and a rise in associated human cases.

In this study, we investigated differences in tissue tropism of two HPAI H5N1 strains, the isolate A/Vietnam/1203/2004 (VN1203) isolated from a fatal human case in 2004 and the bovine isolate A/Bovine/Ohio/B24osu-342/2024 (Bov342) isolated in 2024, in C57BL/6J mice.

Infection with either HPAI H5N1 isolate was uniformly lethal in mice. However, tissue tropism differed significantly: while VN1203 replication was largely restricted to the respiratory tract, Bov342 successfully replicated in the respiratory tract as well as various regions of the brain.

Bov342-challenged animals exhibited clinical signs consistent with central nervous system (CNS) infection, and infectious virus was detected in brain tissue.

Correspondingly, cytokine profiles in the brain differed significantly between the isolates. Notably, in addition to abundant evidence of CNS infection in Bov342-challenged mice via immunohistochemistry, sporadic intranuclear and intracytoplasmic immunoreactivity was observed in other tissues in the head, including the choroid plexus, retina, and inner ear.

This study demonstrates that while both HPAI H5N1 isolates are uniformly lethal in C57BL/6J mice upon aerosol exposure, significant differences exist in tissue tropism, with Bov342 resulting in respiratory disease as well as increased neurotropism and inflammation in the brain and nasal turbinates compared to VN1203, which predominantly induces respiratory disease.

         (Continue . . . )

While there are still more questions than answers, over the years we've looked at numerous studies (some more compelling than others) linking severe and/or repeated viral infections (including flu) to a variety of neurological diagnoses later in life. 

In 2011 a study by Boise State biology professor Troy Rohn  appeared in PLOS ONE , which unexpectedly found immunohistochemical evidence of prior influenza A infection in the post-mortem brain tissues of 12 Parkinson’s patients they tested.

Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain

Troy T. Rohn*, Lindsey W. Catlin

The following year, in Revisiting The Influenza-Parkinson’s Link, we looked at another study, conducted by the University of British Columbia, that found a linkage between a past history of severe bouts of influenza and the likelihood of developing Parkinson’s disease later in life.

According to their research, a severe bout of influenza doubled a person’s chances of developing the neurological condition (Severe flu increases risk of Parkinson's: UBC research).

None of this is conclusive, but it does raise serious questions. 

As did a study published last year in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, which found statistical linkage between viral illnesses and developing neurodegenerative diseases later in life. 

Whenever we talk about long-term sequelae from influenza, the mysterious decade-long epidemic of Encephalitis Lethargica (EL) that followed the 1918 pandemic always comes to mind.

It is estimated that between 1 and 5 million people were affected with severe Parkinson's-like symptoms.  While some scientists have suggested they may have been linked to the pandemic virus, others have pointed to a post-streptococcal immune response, or believe it was an aberrant autoimmune response, and dismiss the link with the 1918 pandemic.

The cause remains a mystery.

Throughout history, there have been reports of similar outbreaks, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

And more recently, we've seen evidence that SARS-CoV-2 infection can produce persistent neurological manifestations (see CMAJ: Even Mild COVID-19 May Have Long-term Brain Impacts).

While the mild presentation of H5N1 in the United States thus far is reassuring, these viruses continue to mutate and evolve, and what we say about them today may not hold true tomorrow. 

Because with influenza viruses, the only constant is change.