Unexpected viral reservoir: influenza A thrives in cattle mammary glands

By Dr. Chinta SidharthanReviewed by Susha Cheriyedath, M.Sc.Jan 15 2025

Scientists reveal the mammary gland's hidden role in influenza A infections, spotlighting the urgent need for targeted vaccines to protect cattle, milk safety, and public health.

Review: Influenza A virus in dairy cattle: infection biology and potential mammary gland-targeted vaccines. Image Credit: Aleksandar Malivuk / Shutterstock

In a recent review published in the journal NPJ Vaccines, researchers in France explored the impact of influenza A virus (IAV) infections in dairy cattle. They specifically examined the biology of the virus, virus-mammalian host interactions, and the unexpected role of the bovine mammary gland in viral replication. The review emphasized the potential for vaccines targeting the mammary gland to control infection and prevent milk-associated spread.

Influenza A Virus

Influenza A virus is a highly contagious pathogen that infects a wide range of avian and mammalian species. Migratory birds serve as its natural reservoir, facilitating global spread and sporadic outbreaks in domestic animals and humans. The virus's segmented genome enables it to reassort alleles, leading to new variants capable of crossing species barriers. In mammals, IAV infections often result from spillovers of avian-origin strains, which sometimes adapt to their new hosts, leading to epidemics or pandemics.

While cattle have historically been considered resistant to infection due to low expression of avian-type receptors, recent outbreaks of highly pathogenic avian influenza (HPAI) in dairy cattle have challenged this assumption. These outbreaks revealed not only viral replication in the mammary glands of cattle but also its potential for cow-to-human transmission, with documented cases in farm workers. This has made it imperative to understand the behavior of IAV in cattle and highlighted the need for targeted vaccines to mitigate these risks.

Influenza A Infections in Cattle

The review reported on recent studies that have found that IAVs rely on sialic acid receptors for cell entry and have demonstrated the ability to infect bovine tissues due to the presence of both avian- and mammalian-type receptors in the respiratory tract and mammary glands of cattle. This dual receptor compatibility enables cross-species transmission in IAV, a significant factor in the virus's adaptability.

Furthermore, experimental infections in dairy cattle have revealed that IAV can replicate in the mammary gland, with viral entry possible through intranasal and intramammary routes. Post-mortem analyses have confirmed the replication of the virus in mammary epithelial cells, and viral titers have been detected in milk, underscoring the mammary gland's role as both a reservoir and transmission vector.

Additionally, studies that conducted cytokine profiling and receptor expression analyses revealed that the mammary gland activates innate immunity through pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I). However, the mammary gland's distinct immune environment presents challenges, such as low levels of IgA and insufficient natural antibody activity, limiting immune defense mechanisms.

The researchers noted that the emergence of H5N1 infections in cattle, particularly the clade 2.3.4.4b lineage, marks a significant development in IAV research. This strain is known for its ability to adapt to mammalian hosts and causes mastitis-like symptoms. Furthermore, the systemic spread of the strain in cattle has raised numerous concerns about zoonotic risks and viral dissemination. Of particular concern are the documented human cases linked to milk-associated transmission, highlighting occupational risks for farm workers. The review highlighted the importance of developing targeted vaccines and management strategies to control IAV replication in cattle and mitigate potential public health risks.

Vaccination Strategies

The researchers discussed various strategies, including intranasal, subcutaneous, and intramammary administration, that have been explored in vaccination trials. While intramammary vaccination has shown promise in enhancing local immunity, it faces limitations due to the mammary gland's distinct immune characteristics.

Findings from recent studies have also demonstrated that influenza vaccines in cattle must overcome challenges such as low levels of immunoglobulins in bovine milk, which limit the immune response. Immunoglobulin G1 (IgG) dominates in milk but does not enhance neutrophil activity, requiring innovative approaches such as adjuvant-enhanced vaccines to boost local and systemic immunity.

Furthermore, existing vaccines against influenza in humans and animals rely mainly on inactivated or live attenuated viruses. These target humoral immunity, inducing IgG responses and limiting viral spread. However, antigenic drift necessitates frequent reformulation, reducing their reliability against new strains.

The review suggested that effective bovine vaccines might require eliciting strong mucosal and cellular immune responses in the mammary gland to prevent viral replication and milk transmission. For instance, establishing resident memory T-cells in the mammary tissue through intramammary immunization could offer site-specific defense. However, this approach requires careful balancing of efficacy and milk production concerns.

Conclusions

Overall, the review provided critical insights into the biology of IAV infections in dairy cattle, especially the role of the mammary gland in viral replication and milk-associated transmission. It also highlighted the potential of intramammary vaccination strategies to control infections but acknowledged significant challenges in achieving effective immunity. Given the zoonotic potential of IAV infections in cattle, these findings underscore the urgency for developing "One Health" solutions that integrate virology, immunology, and public health expertise.