Avian influenza A (H5N1) virus in dairy cattle: origin, evolution, and cross-species transmission

Abstract

Since the emergence of highly pathogenic avian influenza virus (HPAIV) H5N1 of clade 2.3.4.4b as a novel reassortant virus from subtype H5N8, the virus has led to a massive number of outbreaks worldwide in wild and domestic birds. Compared to the parental HPAIV H5N8 clade 2.3.4.4b, the novel reassortant HPAIV H5N1 displayed an increased ability to escape species barriers and infect multiple mammalian species, including humans. The virus host range has been recently expanded to include ruminants, particularly dairy cattle in the United States, where cattle-to-cattle transmission was reported. As with the avian 2.3.4.4.b H5N1 viruses, the cattle-infecting virus was found to transmit from cattle to other contact animals including cats, raccoons, rodents, opossums, and poultry. Although replication of the virus in cows appears to be mainly confined to the mammary tissue, with high levels of viral loads detected in milk, infected cats and poultry showed severe respiratory disease, neurologic signs, and eventually died. Furthermore, several human infections with HPAIV H5N1 have also been reported in dairy farm workers and were attributed to exposures to infected dairy cattle. This is believed to represent the first mammalian-to-human transmission report of the HPAIV H5N1. Fortunately, infection in humans and cows, as opposed to other animals, appears to be mild in most cases. Nevertheless, the H5N1 bovine outbreak represents the largest outbreak of the H5N1 in a domestic mammal close to humans, increasing the risk that this already mammalian adapted H5N1 further adapts to human-to-human transmission and starts a pandemic. Herein, we discuss the epidemiology, evolution, pathogenesis, and potential impact of the recently identified HPAIV H5N1 clade 2.3.4.4b in dairy cattle in the United States. Eventually, interdisciplinary cooperation under a One Health framework is required to be able to control this ongoing HPAIV H5N1 outbreak to stop it before further expansion of its host range and geographical distribution.

Keywords: H5N1; United States; avian viruses; cattle; highly pathogenic avian influenza virus.

Fig 1

Viral particle composition and host range of IAV, IBV, ICV, and IDV: (a) Schematic diagram showing the structure of IAV, IBV, ICV, and IDV. IAV and IBV are made of eight viral segments with two surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). ICV and IDV contain seven viral segments with a single surface glycoprotein, the hemagglutinin-esterase-fusion (HEF) protein; (b) Documented history of highly pathogenic avian influenza virus (HPAIV) H5N1 emergence in migratory birds in 1996 and key evolutionary occurrences until 2024. The figure has been created/assembled with BioRender.com.

Fig 2

Genesis of the cattle-origin HPAIV H5N1 strain clade 2.3.4.4b genotype B3.13 and cross-species transmission: (a) Schematic representation of major H5N1 clade 2.3.4.4b reassortment events with the internal proteins encoding segments from North American low pathogenic strains and genesis of the reassortant cattle-origin HPAIV H5N1 strain clade 2.3.4.4b genotype B3.13. The genetic constellation of the seven major reassortants, frequently detected in poultry since the introduction of the ancestor Eurasian HPAIV H5N1 (genotype A1), were designated as B1.1, B1.2, B2, B3.1, B3.2, B4, and B5 (33). The predicted origin of internal proteins encoding segments from North American low pathogenic strains has been visualized in different colors that correspond the predicted ancestor. The minor reassortant B3.9 was further subject to a multiple reassortant events, acquiring the PA, HA, NA, and M segments from the genotype A1 and the other segments from co-circulating low pathogenic North American strains to generate avian HPAIV H5N1 of genotype B3.13 that has been emerged in November 2023 (24, 34). The avian HPAIV H5N1 of B3.13 genotype has further an NP segment reassortment event with another low pathogenic strain in unknown host to generate the first cattle HPAIV H5N1 strains of B3.13 genotype that were detected in human, cats, raccoons, and opossums in Texas in March/April 2024; (b) amino acid variations between closely related human, feline, and bovine isolates during the cattle HPAIV H5N1 outbreak in the United States. Human influenza A/Texas/37/2024 (H5N1) (hTexas, red), bovine influenza A/bovine/Texas/24-029328-02/2024 (H5N1) (bTexas, blue), feline influenza A/feline/Texas/24-029329-01/2024 (H5N1) (fTexas, blue), and human influenza A/Michigan/90/2024 (H5N1) (hMichigan, green) have identical HA, NP, M1, M2, and NEP. The amino acid variations between human and bovine/feline isolates in the polymerase subunits PB2, PB1, and PA and its by-product PA-X, NA, and NS1 proteins are indicated. The bTexas and fTexas isolates have identical amino acid sequences in all viral segments; (c) detections of HPAIV H5N1 in mammals in the United States from May 2022 to August 2024. Besides the HPAIV H5N1 detections in cattle in 2024 (Fig. 2b), the United States Department of Agriculture (USDA) has frequently reported infections with the HPAIV H5N1 clade 2.3.4.4b in 373 mammals representing 27 animal species in 32 states between May 2022 and August 2024. The figure has been created/assembled with BioRender.com.

Fig 3

Updated host range of IAV, IBV, ICV, and IDV, and cattle H5N1 status in the United States: (a) documented hosts for influenza viruses show the broad-spectrum animal host species of IAV compared to IBV, ICV, and IDV; (b) confirmed cases of HPAIV H5N1 in dairy herds (CC) and human contact (HC) subjects. As of August 2024, HPAIV H5N1 has been detected in 189 dairy herds in 13 states (light blue, numbers between brackets represent the dairy herds affected). Three states, Colorado, Michigan, and Texas, have reported infections in dairy cattle as well as human infections in dairy herds’ workers (light red). The affected 13 states are Colorado (CO), Kansas (KS), Idaho (ID), Oklahoma (OK), Ohio (OH), New Mexico (NM), North Carolina (NC), Minnesota (MN), Michigan (MI), Iowa (IA), South Dakota (SD), Texas (TX), and Wyoming (WY). Numbers in the table indicate the cumulative numbers of dairy herd (CC) and human contact (HC) cases per affected state. The figure has been created/assembled with BioRender.com.