Bovine H5N1 displays pronounced neurotropism in many mammals

A study investigated and compared the tissue tropism of a 2004 H5N1 strain isolated from a fatal human case and the 2024 bovine strain of H5N1 that is currently circulating in mice and found that the two strains displayed significantly different abilities to infect different tissues. While replication of the 2004 virus was largely in the respiratory tract with “limited” replication in the central nervous system, the 2024 bovine strain successfully replicated in the respiratory tract as well as various regions of the brain. Also, mice challenged with the 2024 bovine H5N1 isolates exhibited clinical signs consistent with central nervous system infection, and infectious viruses were detected in the brain tissue. The 2004 H5N1 virus was used for comparison as the virus strain has been extensively studied in animal models.

The study demonstrated that both the 2004 and the 2024 H5N1 isolates were uniformly fatal in mice when infected through aerosol exposure. But the tissue tropism was vastly different — the 2004 strain was largely restricted to the respiratory tract and predominantly caused respiratory disease, while the 2024 bovine strain showed preference to both the respiratory tract and the brain and caused inflammation in the brain and nasal cavity.

“Our findings reveal that the bovine isolate exhibits enhanced neurotropism, unlike the respiratory-restricted replication observed with the H5N1 isolate from 2004. This difference in tissue tropism, accompanied by distinct cytokine responses in the brain, underscores the potential for altered disease outcomes in other mammalian hosts,” the authors of a study posted in a preprint server BioRxiv write. Preprints are yet to be peer-reviewed.

The H5N1 clade 2.3.4.4b has caused widespread infection in over 90 species of wild and domestic birds and more than 21 mammalian species, including several human infections. The virus has caused fatal infections in many different mammals. In March 2024, the 2.3.4.4b clade was first detected in dairy cattle in Texas. The virus has since spread rapidly; as of December 12, the virus has spread to 832 cattle herds across 16 States in the U.S., with 617 herds in California alone.

Mice were exposed to one of the two H5N1 isolates via aerosols to mimic a more natural route of infection. Upon exposure, mice in both groups displayed reduced activity, rapidly lost weight, and died. While the mice exposed to the 2024 bovine strain showed neurological signs of disease, neurological disease was absent in mice exposed to the 2004 isolate. Therefore, unsurprisingly, the virus titers were high in the brain tissue of mice exposed to the bovine strain compared with mice exposed to the 2004 strain.

‘Heavily linked’

In April this year, 10 cats died in a rural South Dakota residence, showing respiratory and neurological symptoms. Lab testing of two cats confirmed H5N1 clade 2.3.4.4b infection. As per a paper accepted for publication in the journal Emerging Microbes & Infections, dead cats showed systemic infection with lesions and viral antigens in multiple organs. “Higher viral RNA and antigen in the brain indicated pronounced neurotropism,” they write.

The authors note that while earlier H5N1 clades in cats caused subclinical infections or clinical disease characterised by pneumonia and encephalitis, the 2.3.4.4b H5N1 virus strain has also been “heavily linked to respiratory and neurological signs in cats in France, Poland, South Korea, and the U.S.”.

The authors of the accepted paper note that animals infected with clade 2.3.4.4b H5N1 viruses commonly exhibited pneumonia and meningoencephalitis, with neurological signs predominating in several animal species. Mammals such as dolphins, skunks, minks, red foxes, and sea lions have displayed significant neurological signs such as tremors, convulsions, and ataxia, with viral presence mainly in the brain. “Though neurotropism and neurological signs were observed during the outbreaks of previous clades of H5N1 viruses, the pronounced neurotropism of the current H5N1 clade 2.3.4.4b is highlighted by high viral loads in the brain and minimal or no viral presence in the lungs of several species, suggesting a significant shift in virus behaviour,” they write.

It must be noted that unlike in mice, central nervous system involvement has not yet been reported for dairy cows, either via natural or experimental infection by the bovine H5N1 strain (2.3.4.4b clade). The H5N1 transmission within and between cattle herds is hypothesised to be associated with milking practices. In cows, the H5N1 virus replication has been limited to the mammary glands when lactating cows were inoculated via the mammary gland.

“The growing list of susceptible mammalian hosts highlights the virus’s ability to cross species barriers, raising concerns about its potential impact on wildlife and domestic animal populations,” the authors of the accepted paper write. “There is a notable shift in the neurotropism of H5N1 viruses, particularly with the emergence of clade 2.3.4.4b in cats and wild carnivores like foxes… These cases have documented viral adaptations that facilitate central nervous system involvement, with some infections exhibiting viral mutations indicative of enhanced neurotropism.”