Distinct influenza interfaces in cattle: repeated spillovers of highly pathogenic avian influenza A(H5N1) from wild birds and enzootic circulation of influenza D virus.

Cattle now occupy two epidemiologically distinct influenza interfaces. This Mini Review comparatively synthesizes epidemiological, pathological, experimental-transmission, genomic, and surveillance evidence for highly pathogenic avian influenza A(H5N1) and influenza D virus (IDV), asking how source ecology, tissue tropism, shedding, transmission, persistence, and zoonotic evidence differ between the two viruses. Genetically distinct H5N1 viruses have spilled over repeatedly from wild birds into United States dairy cattle. In lactating cows, infection is prominent in mammary alveolar epithelium and produces high titers of infectious virus in raw milk; inter-herd cattle movements have disseminated genotype B3.13 through dairy production networks. On affected farms, viral RNA has been detected in milk and respiratory specimens; infectious virus is recovered consistently from raw milk and mammary tissues but only sporadically from respiratory or environmental samples such as milking-parlour air and wastewater. These findings identify exposure settings but do not resolve the dominant natural cow-to-cow transmission route or how the virus reaches the mammary gland. Occupational infections have occurred, but sustained cattle adaptation or long-term reservoir status has not been demonstrated. In contrast, IDV is a cattle-adapted respiratory virus maintained through direct contact and short-range airborne transmission, with interlineage reassortment among IDV genome segments and frequent association with bovine respiratory disease complex (BRDC), although an independent causal role in BRDC remains unproven. Human seroreactivity and efficient replication in human airway models indicate exposure and biological compatibility, but not confirmed productive human infection or onward transmission. These contrasts support event-triggered, milk-centered investigation for H5N1 and longitudinal respiratory and genomic surveillance for IDV, built on shared One Health diagnostic, sequencing, epidemiological, and occupational-health infrastructure.