Avian Influenza in Humans: Zoonotic Transmission, Clinical Presentation, and One Health Surveillance

Introduction

Avian influenza viruses (AIVs) are type A influenza viruses belonging to the family Orthomyxoviridae that primarily circulate in wild waterfowl and shorebirds [1]. These viruses are classified into low pathogenicity (LPAI) and highly pathogenic (HPAI) forms based on the cleavability of the hemagglutinin (HA) glycoprotein and the resulting systemic disease in gallinaceous poultry [2, 3]. AIVs of subtypes H5, H7, and H9 have repeatedly crossed the species barrier to infect mammals, including humans, with variable clinical outcomes [4, 5, 6]. The zoonotic potential of AIVs is determined by a constellation of viral genetic markers that facilitate receptor binding, replication, and immune evasion in mammalian hosts [2, 7, 8]. Since the first documented human H5N1 infections in 1997, multiple subtypes (H5N1, H5N6, H7N9, H9N2, H3N8, H10N3, H10N8) have caused sporadic human cases, and the ongoing circulation of clade 2.3.4.4b H5N1 viruses in diverse avian and mammalian species has elevated pandemic risk assessments [5, 9, 10, 8]. This article provides a veterinary-focused review of the virological, ecological, and clinical dimensions of avian influenza zoonosis, with emphasis on molecular mechanisms of host adaptation, transmission pathways, and the role of integrated One Health surveillance in early detection and risk mitigation.

Virology and Molecular Determinants of Zoonotic Transmission

Receptor Binding Specificity

The primary barrier to AIV infection of humans is the differential distribution of sialic acid (SA) receptors in the respiratory tract. Avian influenza viruses preferentially bind to SA linked to galactose by an alpha-2,3 linkage (SA-alpha-2,3-Gal), which is abundant on epithelial cells of the avian intestinal tract and on human lower respiratory tract epithelia [2, 11]. Human-adapted influenza viruses bind SA-alpha-2,6-Gal, which predominates on human upper respiratory tract epithelia [11, 12]. Mutations in the HA receptor binding site (RBS) that shift affinity toward SA-alpha-2,6-Gal are critical for efficient human-to-human transmission [2, 13]. For H5N1 viruses, substitutions such as Q226L and G228S (H3 numbering) have been shown to enhance binding to human-type receptors [2, 14]. Similarly, H9N2 viruses circulating in poultry in Asia have acquired HA mutations that confer dual receptor specificity, increasing their zoonotic potential [15, 16, 17]. The HA of H7N9 viruses that caused human infections in China already possessed a natural affinity for SA-alpha-2,6-Gal, facilitating direct spillover [3, 6].

Polymerase Complex Adaptations

The viral RNA-dependent RNA polymerase complex, composed of PB1, PB2, and PA subunits, must function efficiently in mammalian cells for productive infection [18, 19]. The PB2 subunit harbors several well-characterized mammalian adaptation markers. The substitution PB2 E627K is a canonical adaptation that enhances polymerase activity at the lower temperatures of the mammalian upper respiratory tract (approximately 33 degrees Celsius) compared to the avian intestinal tract (approximately 41 degrees Celsius) [18, 19, 13]. PB2 D701N similarly promotes nuclear import of the polymerase complex in mammalian cells [19, 13]. A triad of mutations (I147T, K339T, A588T) identified in avian viruses has been associated with increased polymerase activity and virulence in mammalian models [19]. PB2 A588V and T271A have also been detected in mammalian-adapted AIVs [18, 13]. The PA protein can acquire mutations such as T97I and I38T that enhance replication efficiency and, in the case of I38T, confer resistance to baloxavir marboxil [13].

Hemagglutinin Cleavage Site and Pathogenicity

The HA0 precursor protein must be cleaved by host proteases to activate membrane fusion activity [2, 1]. LPAI viruses possess a monobasic cleavage site (e.g., -R-X-R/G-) that is cleaved only by trypsin-like proteases present in the respiratory and intestinal tracts, restricting infection to these sites [2]. HPAI viruses, including H5 and H7 subtypes, acquire a multibasic cleavage site (e.g., -R-X-R/K-R-R/G-) through insertion of basic amino acids, allowing cleavage by ubiquitous furin-like proteases and enabling systemic dissemination [2, 3]. The presence of a multibasic cleavage site is a defining feature of HPAI and is associated with high mortality in poultry and, in some cases, severe disease in mammals [2, 10]. However, the multibasic cleavage site alone is not sufficient for mammalian virulence; additional HA glycosylation patterns and receptor binding properties modulate pathogenicity [2, 14].

NS1 and Immune Evasion

The nonstructural protein NS1 of AIVs counteracts the host interferon response [20, 1]. Following avian-to-seal transmission, the NS1 protein undergoes host-specific functional evolution to optimize antagonism of the mammalian innate immune system [20]. Mutations in NS1 that enhance binding to the mammalian PDZ domain protein network have been linked to increased virulence in mice and ferrets [20, 13]. The NS1 protein also modulates the host inflammatory response, and certain alleles are associated with enhanced cytokine dysregulation in mammalian infections [20, 1].

Subtypes and Geographic Distribution of Zoonotic AIVs

H5N1 and Clade 2.3.4.4b

H5N1 HPAI viruses of the A/goose/Guangdong/1/1996 lineage have caused the majority of documented human AIV infections since 1997 [5, 8]. The emergence of clade 2.3.4.4b H5N1 viruses around 2016 marked a significant expansion in host range and geographic distribution [7, 8]. These viruses have been detected in over 100 avian species and numerous mammalian taxa, including felids, canids, mustelids, pinnipeds, cetaceans, and bovids [7, 10, 21, 8, 22]. Clade 2.3.4.4b H5N1 viruses have caused outbreaks in dairy cattle in the United States, with spillover to humans via occupational exposure [23, 22]. The virus has also been detected in raw milk and raw pet foods, raising concerns about foodborne transmission [24, 25, 26]. In South Asia, clade 2.3.4.4b viruses co-circulate with clade 2.3.2.1a viruses, increasing the risk of reassortment [9, 27]. Ratites (ostriches, emus) infected with clade 2.3.4.4b H5N1 have shown high viral loads, suggesting potential for zoonotic spillover in farming settings [28].

H5N6, H5N8, and Other H5 Subtypes

H5N6 HPAI viruses, particularly those of clade 2.3.4.4, have caused human infections in China since 2014 [29, 30]. A duck-origin clade 2.3.4.4b H5N6 virus was shown to possess partial mammalian adaptation markers, including PB2 E627K, and replicated efficiently in mammalian cell lines and mice [29]. H5N8 HPAI viruses, while primarily affecting poultry, have demonstrated zoonotic potential through experimental infections and serological evidence in exposed workers [31]. H5N8 viruses isolated from Egyptian poultry farms carried mammalian adaptation markers in PB2 and HA [31].

H7N9 and H9N2

H7N9 LPAI viruses emerged in China in 2013 and caused five epidemic waves of human infections, with a case fatality rate of approximately 39 percent [3, 6]. These viruses possessed a natural affinity for human-type receptors and acquired mammalian adaptation markers over time [3]. H9N2 LPAI viruses are enzootic in poultry across Asia, the Middle East, and Africa, and have donated internal gene segments to multiple zoonotic AIVs, including H5N1, H7N9, and H10N8 [15, 16, 17]. H9N2 viruses from Laos and Xinjiang, China, have shown increasing genetic diversity and the acquisition of mammalian adaptation markers [15, 16]. Human infections with H9N2 are typically mild but underscore the pandemic potential of this subtype [6].

H3N8, H3Nx, and Other Subtypes

H3N8 AIVs, typically of low pathogenicity in birds, have caused fatal human infections in China, with the index case reported in 2022 [32, 33]. A risk assessment indicated that the fatal human H3N8 virus had a moderate pandemic potential, with the ability to bind human-type receptors and replicate in human airway epithelial cells [32]. H3Nx viruses, including H3N2 and H3N3 reassortants, have been detected in poultry and wild birds in China, with some isolates showing partial mammalian adaptation [34, 35]. H11 AIVs, while rarely associated with human infection, have been isolated from wild birds in Xinjiang and may represent an underappreciated zoonotic reservoir [36].

Transmission Pathways to Humans

Direct Contact with Infected Poultry

The predominant route of AIV transmission to humans is direct or indirect contact with infected poultry, particularly in live bird markets (LBMs) and backyard flocks [37, 38, 39, 40]. Occupational exposure among poultry workers, cullers, and veterinarians carries the highest risk [41, 23, 42]. In Washington State, USA, poultry farm workers exposed to clade 2.3.4.4b H5N1-infected flocks developed conjunctivitis and mild respiratory symptoms [23]. In Germany, veterinary first responders and cat owners were exposed to H5N1 during outbreaks in poultry and domestic cats [41]. Biosecurity practices, including the use of personal protective equipment, are critical for reducing occupational risk [39, 42].

Environmental Persistence and Indirect Transmission

AIVs can persist in the environment, particularly in water, feces, and on fomites, facilitating indirect transmission [43, 44]. H3N8 viruses have been shown to remain infectious on surfaces for extended periods under appropriate temperature and humidity conditions [43]. Environmental metagenomic surveillance of LBMs in Cambodia detected AIV RNA in water, floor swabs, and feather samples, demonstrating the utility of environmental sampling for early warning [45]. Waterbird activity entropy has been used to map global AIV risk patterns, linking environmental viral persistence to spillover potential [46].

Foodborne Transmission

The detection of H5N1 virus in raw milk from infected dairy cattle has raised concerns about foodborne transmission to humans [24, 26, 22]. Experimental studies demonstrated that H5N1 virus in raw milk can be inactivated by pasteurization but remains infectious in unpasteurized products [24]. Raw meat-based diets for companion animals have been found to contain H9N2 AIV RNA in South Korea, indicating a potential route of exposure for pets and their owners [25]. The bovine mammary gland has been proposed as a crucible for zoonotic influenza virus emergence, as it expresses both SA-alpha-2,3 and SA-alpha-2,6 receptors and supports high-titer viral replication [11, 47, 22].

Companion Animals as Bridge Hosts

Cats, dogs, and other companion animals can become infected with AIVs and may serve as bridge hosts for human exposure [48, 49, 50, 51, 12]. H5N1 clade 2.3.4.4b infection in domestic cats has been documented in Poland, Germany, and the United States, with some cases involving severe neurological and respiratory disease [41, 50, 51]. Canine influenza viruses (e.g., H3N2, H3N8) originated from avian sources and have established sustained transmission in dogs, with occasional spillback to humans [49, 12]. Hunting dogs in the United States may be exposed to H5N1 through contact with infected waterfowl, creating a potential pathway for zoonotic transmission [48].

Clinical Presentation in Humans

Spectrum of Disease

Human AIV infections range from asymptomatic or mild upper respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, and death [4, 5, 2, 10]. Conjunctivitis is a frequent presenting sign, particularly in H5N1 and H7N9 infections acquired through ocular exposure [4, 23, 52]. Gastrointestinal symptoms, including diarrhea and vomiting, are reported in a subset of H5N1 cases [4, 2]. Neurological complications, such as encephalitis and seizures, have been observed in severe H5N1 infections [2, 10].

Comparative Pathology in Mammalian Models

Ferrets are the preferred animal model for studying AIV pathogenesis and transmission because their respiratory tract receptor distribution closely resembles that of humans [53, 54, 8]. In ferrets, clade 2.3.4.4b H5N1 viruses cause severe respiratory disease with high viral titers in nasal washes and lung tissue, and some strains transmit via direct contact but not via aerosol [10, 54]. Mice are used for virulence assessment and vaccine efficacy studies, with lethality depending on viral strain and mouse strain [55, 56, 57]. Bovine models have been developed to study H5N1 infection in dairy cattle, revealing that the mammary gland supports high-level replication without severe systemic disease in adult cows [55, 58, 22].

Immunological Factors

Severe outcomes in human AIV infections are associated with dysregulated innate immune responses, including hypercytokinemia (cytokine storm) [2, 59]. Autoantibodies neutralizing type I interferons have been identified in a fatal case of H5N1 infection, suggesting that pre-existing immune deficiencies may predispose individuals to severe disease [60]. Pre-existing memory T and B cells recognizing avian influenza hemagglutinins are present at low levels in the human population and are poorly boosted by seasonal influenza vaccination [61]. This immunological naivety contributes to the pandemic potential of novel AIV subtypes [59, 61].

One Health Surveillance

Integrated Surveillance Framework

One Health surveillance for AIVs requires coordinated monitoring of wild birds, poultry, livestock, companion animals, and humans, with data sharing across veterinary and public health sectors [9, 62, 63]. The World Health Organization (WHO) Public Health Research Agenda for Influenza emphasizes the need for enhanced surveillance at the animal-human interface [64]. District-level joint risk assessments, such as those conducted in live bird markets in Bogor, Indonesia, integrate environmental, animal, and human health data to identify high-risk practices and locations [38]. High-resolution digital twins of interacting livestock, wild bird, and human ecosystems have been developed to model multihost epidemic spread and evaluate intervention strategies [65].

Molecular and Genomic Surveillance

Real-time reverse transcription polymerase chain reaction (RT-qPCR) assays targeting the matrix gene and subtype-specific HA genes are the standard for AIV detection in clinical and environmental samples [66, 67]. Subtyping RT-qPCR assays for H5 have been validated and deployed in influenza surveillance networks [67]. Whole-genome sequencing of AIV isolates enables the identification of mammalian adaptation markers, reassortment events, and phylogenetic relationships [68, 29, 69, 70, 31, 27, 33, 71, 16, 14]. Environmental metagenomics, using shotgun sequencing of samples from LBMs, enhances the detection of circulating viruses without prior knowledge of subtype [45]. Smartphone-assisted upconversion nanoparticle assays have been developed for rapid multiplex detection of H5, H7, and H10 AIVs at the point of care [72].

Serological Surveillance

Serological surveys in occupationally exposed populations and in wild birds provide evidence of past AIV infections that may not have been detected clinically [73, 74]. In Switzerland, a national program for surveillance of influenza A viruses in pigs and humans from 2010 to 2022 revealed sporadic zoonotic transmissions of swine-origin viruses and provided baseline seroprevalence data [74]. Serological evidence of flavivirus and limited AIV exposure was found in urban house martins in Spain, highlighting the role of synanthropic birds in pathogen maintenance [73].

Risk Modeling and Forecasting

Computational models integrating ecological, climatic, and land-use data are used to forecast AIV spillover risk [46, 75, 76]. Waterbird activity entropy derived from satellite tracking data has been used to map global AIV risk patterns [46]. Region-specific models for Asia incorporate El Niño-Southern Oscillation (ENSO) forecasts to predict H5 AIV outbreaks [75]. Climate and land-use change projections for Bangladesh indicate that AIV suitability may increase in the future, particularly in areas with intensive poultry production [76]. Artificial intelligence (AI) tools are being developed to assess potential zoonotic threats by analyzing viral genomic sequences and ecological data [77].

Biosecurity and Control Measures

Biosecurity interventions in poultry production, including the segregation of species in LBMs, regular cleaning and disinfection, and the use of personal protective equipment by workers, reduce the risk of AIV spillover [37, 38, 39, 78]. Vaccination of poultry against H5 and H7 subtypes is employed in several countries as a control measure, but vaccine efficacy must be monitored against emerging antigenic variants [79, 64]. In mammals, experimental vaccines for H5N1 have been developed using mRNA platforms, virus-like particles, and adjuvanted inactivated vaccines, with promising results in ferret and bovine models [80, 79, 55, 53, 56, 81, 57, 54]. Monoclonal antibodies targeting the HA stem region have shown prophylactic and therapeutic efficacy against H5N1 in animal models [82, 57].

Conclusion

Avian influenza viruses continue to pose a significant zoonotic threat due to their genetic plasticity, expanding host range, and increasing geographic distribution. The emergence of clade 2.3.4.4b H5N1 viruses with documented transmission to dairy cattle and humans underscores the need for robust One Health surveillance systems that integrate molecular, ecological, and epidemiological data. Continued monitoring of mammalian adaptation markers in AIV genomes, coupled with risk modeling and enhanced biosecurity in animal production systems, is essential for pandemic preparedness. The development of broadly protective vaccines and antiviral strategies remains a priority for mitigating the impact of future zoonotic AIV events.

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Disclaimer: This article is for educational and informational purposes only. It is not intended to substitute for professional veterinary advice, diagnosis, treatment, or regulatory guidance. Always consult a licensed veterinarian or qualified specialist regarding animal health, disease diagnosis, and therapeutic decisions.