The (#digestive) path less traveled: #influenza A virus and the #gastrointestinal tract

 

ABSTRACT

Influenza A virus (IAV) infection of the respiratory tract can cause both respiratory and non-respiratory symptoms. Gastrointestinal (GI) symptoms such as diarrhea, vomiting, and abdominal pain can occur in persons with seasonal influenza A or novel IAV infections, but the extent to which IAVs can infect and replicate in GI tissues is understudied. The ongoing outbreak of A(H5N1) IAV in US dairy cattle associated with sporadic human infections has highlighted the potential public health threat posed by the introduction of infectious virus into materials that may be consumed by humans, such as milk. Here, we review epidemiologic reports documenting the frequency of GI complications in humans infected with seasonal and novel IAVs and present laboratory studies supporting the capacity of IAV to replicate in mammalian GI tissues, with an emphasis on A(H5N1) viruses. Studies assessing the ability of IAV to cause mammalian infection following consumption of virus-containing material are also presented. Collectively, these studies suggest that gastric exposure represents a potential non-respiratory route for A(H5N1) IAVs in mammals that can lead to infection and support that IAV may be detected in mammalian intestinal tissues following multiple exposure routes.

Source: mBio, https://journals.asm.org/doi/full/10.1128/mbio.01017-25?af=R

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#Influenza #infection of the mammary #gland

 

ABSTRACT

The mammary gland is an essential organ for milk production, providing essential immune and nutritional support to offspring and supplying dairy products for human consumption. In both humans and animals, the lactating mammary gland is susceptible to bacterial and viral infections, which can lead to mastitis and, in some cases, vertical transmission to offspring, with potential adverse effects on infant health. However, until recently, the role of respiratory viruses in mammary gland infection has been relatively understudied, particularly their ability to infect mammary epithelial cells and transmit through lactation. The recent emergence of highly pathogenic avian influenza H5N1 clade 2.3.4.4b in dairy cattle has demonstrated the virus’s capacity to replicate in the mammary gland, cause mastitis, and produce high viral loads in milk. This raises significant concerns about the potential for zoonotic transmission to humans and other animals in contact with infected dairy cows and unpasteurized milk. In this mini-review, we highlight key studies that demonstrate the replication of influenza and other viruses in the mammary gland, summarize recent findings from experimental and natural H5N1 clade 2.3.4.4b infections in dairy cows and small animal models, and discuss the broader One Health implications of the current H5N1 outbreak. We emphasize the urgent need for an interdisciplinary collaboration across sectors to mitigate the risks posed by influenza viruses with pandemic potential.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.01940-24?af=R

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Estimated #transmission #dynamics of #SARS-CoV-2 #variants from #wastewater are unbiased and robust to differential shedding

 

Abstract

The COVID-19 pandemic has accelerated the development and adoption of wastewater-based epidemiology. Wastewater samples can provide genomic information for detecting and assessing the spread of SARS-CoV-2 variants in communities and for estimating important epidemiological parameters such as the selection advantage of a viral variant. However, despite demonstrated successes, epidemiological data derived from wastewater suffers from potential biases. Of particular concern are shedding profiles, which can affect the relationship between true viral incidence and viral loads in wastewater. Changes in shedding between variants may decouple the established relationship between wastewater loads and clinical test data. Using mathematical modeling, simulations, and Swiss surveillance data, we demonstrate that estimates of the selection advantage of a variant are not biased by shedding profiles. We show that they are robust to differences in shedding between variants under a wide range of assumptions, and identify specific conditions under which this robustness may break down. Additionally, we demonstrate that differences in shedding only briefly affect estimates of the effective reproduction number. Thus, estimates of selective advantage and reproduction numbers derived from wastewater maintain their advantages over traditional clinical data, even when there are differences in shedding among variants.

Source: Nature Communications, https://www.nature.com/articles/s41467-025-62790-y

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#Mpox: disease #manifestations and therapeutic #development

 

ABSTRACT

Mpox, caused by monkeypox virus (MPXV) infection, has emerged as a significant global health threat. The World Health Organization (WHO) has twice declared a Public Health Emergency of International Concern for mpox: first for the 2022–2023 global outbreak and subsequently for concurrent outbreaks in Africa. Beyond MPXV, other members of the Orthopoxvirus genus also pose growing risks of zoonotic spillover, with the potential to jump from animal reservoirs to humans. Clinically, mpox is distinguished from other Orthopoxvirus infections by its propensity to cause severe systemic manifestations alongside localized skin lesions, disproportionately affecting vulnerable groups such as children, pregnant women, and immunocompromised individuals. Although vaccines are available, effective therapeutics are equally essential in combating the mpox crisis. Current antiviral agents, including tecovirimat and brincidofovir, have demonstrated uncertain or disappointing efficacy in preclinical and clinical studies, underscoring the urgent need for further therapeutic development. This review provides a concise synthesis of recent advances in understanding mpox epidemiology and clinical features and offers an in-depth discussion of the current status and future directions in therapeutic development. We highlight the importance of innovative experimental models that can authentically replicate mpox disease manifestations and serve as robust platforms for therapeutic testing. Advancing these research efforts is critical for responding to the ongoing mpox emergency and for sustaining preparedness against future poxvirus epidemics.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.00152-25?af=R

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Quantifying viral #pandemic #potential from experimental #transmission studies

 

Abstract

In an effort to avert future pandemics, surveillance studies aimed at identifying zoonotic viruses at high risk of spilling over into humans act to monitor the "viral chatter" at the animal-human interface. These studies are hampered, however, by the diversity of zoonotic viruses and the limited tools available to assess pandemic risk. Methods currently in use include the characterization of candidate viruses using in vitro laboratory assays and experimental transmission studies in animal models. However, transmission experiments yield relatively low-resolution outputs that are not immediately translatable to projections of viral dynamics at the level of a host population. To address this gap, we present an analytical framework to extend the use of measurements from experimental transmission studies to generate more quantitative risk assessments. Specifically, we use within-host viral titer data from index and contact animals to estimate parameters relevant to transmission, including an estimate of transmissibility. We then extended this model to estimate epidemiological parameters, such as the basic reproductive number and generation interval. To illustrate these approaches, we present them in the context of two influenza A virus (IAV) ferret transmission experiments: one using influenza A/California/07/2009 (Cal/2009) and one using influenza A/Hong Kong/1/1968 (Hong Kong/1968). Despite estimating broadly similar transmissibilities for Cal/2009 and Hong Kong/1968, we conclude that Cal/2009 has a higher pandemic potential. This difference in pandemic potential seems to be primarily driven by its more robust within-host replication. Our results critically depend on several assumptions, namely that the within-host viral dynamics in humans and those in the model animal used (here, ferrets) share quantitative similarities and that viral transmissibility between model animals reflects viral transmissibility between humans. The methods we present to assess relative pandemic risk across viral isolates can be used to improve quantitative risk assessment of other emerging viruses of pandemic concern.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.24.645081v2

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#UK - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

 

{By gary noon - Flickr, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=4077294}

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{England, Devon} Premises with 5200 pheasants. Increased mortality, reduced water consumption and other clinical signs were reported. Samples were taken and were tested positive for HPAI H5N1.

Source: WOAH, https://wahis.woah.org/#/in-review/6716

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Decoding non-human #mammalian adaptive #signatures of 2.3.4.4b #H5N1 to assess its #human adaptive potential

ABSTRACT

The 2.3.4.4b clade highly pathogenic avian influenza H5N1 infected diverse non-human mammalian species, gained mammal-to-mammal transmission potential, and caused sporadic human infections. However, whether non-human mammals enable the human adaptation of 2.3.4.4b H5N1 to establish human infections is unclear. Gain-of-function research restrictions may hinder the assessment of 2.3.4.4b H5N1 human adaptations. Here, we tracked the evolution of 2.3.4.4b H5N1 that infected non-human mammals and evaluated their ability to gain human adaptations. The non-human mammal 2.3.4.4b H5N1 partly acquired classical human-adapting mutations, which are identical to the residues of H1N1pdm09 and seasonal human H3N2 viruses, while showing a few species-specific adaptations that might be potential barriers for successful human infections. The polymerase complex proteins, PA and PB2, acquired human adaptations in non-human mammals, with fox-infected viruses showing more positive selection in the polymerase complex. The human-adapting Q591K/R substitution in PB2 appeared only in the 2.3.4.4b clade but not in previously circulating H5N1 strains. Despite minimal changes in hemagglutinin (HA), A160T and T199I mutations near the receptor binding site of HA in dairy cattle viruses indicate the rapid HA glycan surface evolution affecting virus entry and immune evasion. The unbiased quantitative assessment of virus adaptations indicated that 2.3.4.4b H5N1 circulating in bears, cattle, dolphins, and foxes might show better human adaptive potential. Thus, 2.3.4.4b H5N1 appears to be acquiring human adaptations due to natural selection pressure in non-human mammals. Overall, our study delineates human adaptation and infection risk of specific non-human mammalian circulating 2.3.4.4b H5N1 strains.

IMPORTANCE

The 2.3.4.4b clade H5N1 virus emerged as a panzootic strain, leading to the unprecedented deaths of domestic and wild birds and diverse non-human mammalian species. Intriguingly, the 2.3.4.4b H5N1 transmitted to diverse mammalian species and gained mammal-to-mammal transmission, suggesting its pandemic potential. The H5N1 outbreaks in dairy cattle and sea lions are devastating, and they contributed to sporadic human infections. This indicates the ability of non-human mammal hosts, like dairy cattle, as potential sources for human transmission. However, the signatures of non-human mammal adaptations of 2.3.4.4b H5N1 and how these adaptations drive the human adaptive potential of 2.3.4.4b H5N1 are unclear. In this study, we show the specific molecular patterns of H5N1 proteins that determine species-specific adaptations in non-human mammals. We identified that 2.3.4.4b H5N1 circulating in non-human mammals is rapidly evolving with critical adaptations in PA, PB2, and HA and gaining human adaptive potential in specific non-human mammalian species.

Source: Microbiology Spectrum, https://journals.asm.org/doi/10.1128/spectrum.00948-25

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#COVID19 #pandemic resulted in more metastatic #breast #cancer cases at #diagnosis

Abstract

The study aimed to assess the impact of the COVID-19 pandemic on breast cancer diagnosis, tumor characteristics, and staging in an Eastern-European country. This retrospective study included 11,635 breast cancer patients and clients presenting between March 2019 and March 2022. Patients were categorized into pre-pandemic, pandemic, and post-pandemic groups. Data included age, sex, pathology, tumor characteristics (histologic type, grade, ER/PR/HER2 status), and TNM staging. Statistical analysis compared these parameters across the three-time intervals. During the pandemic, breast cancer diagnosis decreased significantly compared to the pre-pandemic period (9.1% vs. 13.17%, p < 0.001) but increased post-pandemic (11%, p = 0.013). Invasive ductal carcinoma of non-special type (IDC-NST) was predominant in all three-time periods. Aggressive tumors (Nottingham grade 3, ER negative) increased during the pandemic and post-pandemic times. Molecular subtypes showed variations across time intervals, with triple-negative tumors rising significantly. Larger tumors, increased lymph node involvement (9–19%), and distant metastasis characterized the pandemic and post-pandemic periods. Compared to pre-pandemic patients, post-pandemic ones were 7 times more likely to be metastatic at diagnosis (p < 0.05). The COVID-19 pandemic led to a significant decrease in breast cancer diagnosis, particularly during the pandemic period. Tumors appeared more aggressive, with higher lymph node and distant metastatic involvement. The long-term prognosis and healthcare cost implications remain uncertain. These findings emphasize the need for adapted cancer screening programs and healthcare system readiness during pandemics. COVID-19 pandemic has resulted in a lower detection rate among patients diagnosed with breast cancer and increased TNM stage.

Source: Scientific Reports, https://www.nature.com/articles/s41598-025-14582-z

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The Abbey in the Oakwood, Caspar David Friedrich (1809 - 1810)

 

Public Domain.

Source: WikiArt, https://www.wikiart.org/en/caspar-david-friedrich/the-abbey-in-the-oakwood

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History of Mass Transportation: The DB VT 11.5 Autotrain

 

By Benedikt Dohmen (User:Benedictus), Archiv-Nr. 92/39 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=496875

Source: Wikipedia, https://en.wikipedia.org/wiki/DB_Class_VT_11.5

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Companion #animals and #H5N1 highly pathogenic avian #influenza: cause for #concern?

Abstract

The first known human infection with a highly pathogenic H5N1 influenza A virus appeared in China in 1997. Between 2003 and 2017, the WHO documented an additional 862 human cases, mainly from southeast Asia and Egypt, with a mean annual case fatality rate of 56%. By 2006, the susceptibility of cats to severe respiratory and neurologic disease became apparent. Scientists raised concerns regarding the potential for domestic cats to transmit novel pathogenic strains to humans. But after 2006, reports of new H5N1 infections in companion animals dwindled, and human cases fell after 2016. In 2021, H5N1 clade 2.3.4.4b viruses suddenly appeared in Europe and spread rapidly to the Americas, wreaking havoc on wildlife and crippling the poultry and dairy industries. Between 2022 and 2025, dozens of domestic cats died, most often following raw food consumption. Unease regarding the transmission potential of pets resurfaced. Although most human infections in the Americas were mild and associated with poultry or dairy contact, the recent detection of genotype D1.1 in association with severe illness or death is cause for concern. Genotype D1.1 has now also been detected in dairy cattle and domestic cats. Reports of H5N1 clade 2.3.2.1a viruses in India suggest a new potential threat. Successful control of H5N1 infections is strongly dependent on a One Health approach. Small animal veterinarians play a key role in this approach through recognition of cases and education of pet owners, thus preserving the human-animal bond.

Source: Journal of American Veterinary Medicine Association, https://avmajournals.avma.org/view/journals/javma/aop/javma.25.06.0388/javma.25.06.0388.xml?tab_body=abstract

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A multivalent #mRNA #vaccine elicits robust immune responses and confers #protection in a murine #model of #monkeypox virus infection

Abstract

Monkeypox virus (MPXV) has re-emerged globally since May 2022, posing a significant public health threat. To address this, we develop two multivalent mRNA vaccine candidates—AAL, encoding three MPXV antigens, and AALI, which combines AAL with an immune-enhancing IFN-α protein. Both vaccines are delivered via mannose-modified lipid nanoparticles to target dendritic cells. Here we show that these vaccines elicit strong antibody responses against vaccinia virus and multiple MPXV clades, induce robust memory B-cell and T-cell responses, and promote dendritic cell maturation. In mouse challenge models, both vaccines provide protection against clade IIb MPXV and vaccinia virus, significantly reducing viral loads and preventing lung damage. Immune profiling reveals enhanced B- and T-cell receptor diversity and distinct CDR3 motifs post-vaccination. These findings demonstrate the potential of using mRNA-based multivalent vaccines as an effective strategy for preventing mpox and related Orthopoxvirus infections.

Source: Nature Communications, https://www.nature.com/articles/s41467-025-61699-w

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#Sialic Acid #Receptors in #Human Mammary Tissue: Implications for #Infection with Novel #Influenza Strains

 

Abstract

Importance: 

Highly pathogenic avian influenza (HPAI) A H5N1 has been recognized for nearly three decades as a threat to avian species and as a virus with pandemic potential if spillover into human populations occurs. Recently the virus has evolved capacity to infect many mammalian species, including dairy cattle, increasing the risk for human exposure and the pandemic threat. Sialic acids (SA) serve as binding sites for influenza viruses. The distribution of SA determines infectivity of specific influenza viruses across species and tissue tropism. Hemagglutinin (HA) of human and swine adapted influenza viruses bind primarily to SA with α2,6-galactose linkages and avian influenza viruses preferentially bind to SA with α2,3-galactose linkages. Recently, the bovine udder was found to contain SA with α2,3 linkages which allow the H5N1 virus to bind to bovine udder epithelium and to infect milk. The distribution of SA receptors in the human mammary gland is unknown. 

Objective: 

Evaluate normal human mammary tissue for the presence of both human and avian SA receptors. 

Design: 

Retrospective evaluation of lectin binding to sialic acids in human mammary tissue. 

Setting: 

US academic health center. 

Participants: 

Specimens obtained from de-identified women with residual non-malignant tissue following breast surgery at the University of California, San Diego. 

Exposures: 

Lectin affinity-staining of human tissue for the presence of SA. 

Main Outcomes and Measures: 

Presence or absence of lectin staining. 

Results: 

All mammary tissue samples demonstrated lectin staining for both SA receptors with α2,6-galactose and α2,3-galactose linkages. 

Conclusions and Relevance: 

The presence of SA receptors that can bind HPAI A H5N1 in human mammary tissue indicates that human milk could be infected during severe avian influenza infection. Pandemic preparedness must prioritize mechanisms to protect the safety of human milk.

Competing Interest Statement

Dr. Byington has intellectual property in and receives royalties from BioFire (biomerieux) through the University of Utah. Dr. Byington is a member of the board of directors of Becton Dickinson.

Funding Statement

This study did not receive any funding

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.08.06.25333154v1

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Subtype-specific neutralizing #antibodies promote #antigenic #shift during #influenza virus co-infection

 

Abstract

Reassortment between different influenza strains occurs when they co-infect the same host cell. The emergence of a reassortant virus depends on both its intrinsic fitness and extrinsic factors, including pre-existing humoral immunity. The generation of pandemic strains, such as H2N2 and H3N2, and zoonotic influenza A viruses, like H5N6, H5N8, and H7N9, in birds is suggested to be the result of extensive selection by pre-existing antibodies. To further explore the role of humoral immunity in reassortment, we generated two divergent fluorescent protein-expressing viruses and used strain-specific and cross-reactive monoclonal antibodies (mAbs) to assess the impact of cross-immunity on reassortment. Our results indicate that all mAbs altered the genotypic diversity and significantly reduced the release of progeny virions in co-infected cells both in vitro and in vivo. Moreover, antibody transfer studies in mice revealed protection from challenge with divergent pathogenicity profiles. Notably, selection driven by a strain-specific mAb depended on its neutralizing specificity, whereas the selection driven by broadly reactive mAbs was independent of neutralization specificity. Our findings demonstrate that pre-existing neutralizing antibodies shape reassortment and that strain-specific neutralizing antibodies promote antigenic shift during co-infection, which is not the case for broadly cross-reactive antibodies that recognize influenza viruses from different subtypes.

Competing Interest Statement

The authors have declared no competing interest.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.08.08.669311v1

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#Cytokine Regulation of #Human #Antibody Responses to #Influenza #Vaccines

 

Abstract

Vaccine responses vary widely in human studies. Here we pooled data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-β concentrations and the antibody response on day 28. We investigated this further in human tonsil and spleen organoids, and found that several cytokines, including multiple Type I IFNs (IFN-β and others), IL-21, IL-12, IL-10, but not IL-18 or its downstream Type II IFN (IFN-β), could adjuvant the IIV vaccine to enhance the antibody response. The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-β, recapitulated most of the live vaccine-specific cytokine activation program and increased the antibody response of the inactivated vaccine to that of the live vaccine. Thus, the human vaccinees and the organoid data showed that IFN-β is a natural adjuvant. Two other antibody-boosting cytokines, IL-12 and IL-21, were induced by LAIV but not by Type I IFNs, which suggested parallel regulatory pathways. Moreover, IL-21 mRNA lipid nanoparticles (LNPs) greatly augmented the quantity and breadth of antibody responses in a mouse model of IIV vaccination, while IFN-β LNPs enhanced durability. These findings identified parallel cytokine pathways regulating human vaccine responses and provide a rationale for using cytokines as adjuvants to mimic the effectiveness of live-attenuated vaccines- without the risk of side effects.

Competing Interest Statement

The authors have declared no competing interest.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.08.07.668218v1

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History of Mass Transportation: The FS Ale 501 Electric Multiple Unit

 

De user:axpde - Opera propia, GFDL, https://commons.wikimedia.org/w/index.php?curid=11625891

Source: Wikipedia, https://it.wikipedia.org/wiki/Minuetto_(treno)

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A versatile #H5N1-VSV #platform for safe #influenza virus #research applications

 

ABSTRACT

The H5N1 strain of influenza A virus (IAV) continues to cause severe infections in a range of avian and mammalian species, including sporadic but concerning cases in humans. There is growing concern that circulating H5N1 strains could lead to widespread human outbreaks. Research with highly pathogenic H5N1 viruses is restricted to Biosafety Level 3 (BSL-3) laboratories. Vesicular stomatitis virus (VSV)-based vaccine vectors expressing heterologous viral proteins from Ebola, SARS-CoV-2, Lassa virus, etc., have previously been shown to be safe and effective in animal models and human clinical trials. Here, we report the development of a recombinant VSV expressing the hemagglutinin (HA) and neuraminidase (NA) genes of H5N1 IAV (H5N1-VSV), which serves as a versatile platform to study various aspects of H5N1 IAV biology. H5N1-VSV replicated robustly to titers comparable to those of the full H5N1 virus in multiple cell lines. In mice, H5N1-VSV vaccination was safe, elicited strong immunity, and conferred protection against a circulating H5N1 strain. Notably, we found that polymorphisms in antigenic site Sa of circulating strains emerged under immune selection pressure in cattle, resembling the evolution of pandemic IAV in humans. These findings suggest that H5N1-VSV can serve as a safe, adaptable platform for influenza research.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.00975-25?af=R

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#Inflammatory, transcriptomic, and #cell fate responses underlying the #mammalian #transmission of avian #influenza viruses

 

ABSTRACT

Airborne transmissibility of avian influenza viruses (AIVs) in humans is considered an essential component of their pandemic risk. Although several viral factors regulating airborne transmission (AT) have been delineated, it is not known what, if any, responses at the respiratory epithelia are determinants of AIV AT. Using responses in the ferret nasal epithelium to a panel of H1N1 AIVs, we describe host responses that segregate with AT phenotypes. AIV infection upregulated interferon alpha and gamma responses and IL-6 JAK-STAT signaling and downregulated oxidative phosphorylation. Single-cell transcriptomics revealed that cellular genotoxic stress and NF-kB, interferon, and cell fate pathways differentiated host responses to AIVs with different transmissibilities. These responses culminated in greater AIV antigen-containing exudate and debris in the respiratory spaces of the nasal epithelium of ferrets inoculated with AT AIVs. More abundant CMPK2, SP100, and CXCL10 transcription in infected epithelia was a hallmark of AT viruses. Overall, our study reveals host responses associated with AIV infection and transmission in the nasal epithelium, the determinant anatomical site of influenza virus transmission.

IMPORTANCE

Airborne transmission (AT) is a critical component of the pandemic risks posed by avian influenza A viruses (AIVs). However, the host responses ultimately dictating transmissibility elicited by AIVs in the upper respiratory tract of mammals, the determinant site of influenza virus AT, are largely unknown. We identified host responses in the nasal epithelium of the upper respiratory tract differentially expressed in response to infection by AIVs of different mammalian ATs. Our data indicate that a definable host response was associated with AT of AIVs. These data would serve as an important basis for future mechanistic studies of AIV zoonosis and potentially have implications for understanding the mechanisms of transmission of respiratory viruses between humans.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.00647-25?af=R

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