ETIDIOH - NEW

Editor’s summary The vast majority of the human population has immunity to influenza A virus (IAV) by prior infection, vaccination, or both . However, protection is generally subtype-specific , and it is not clear whether prior infection against one subtype could confer protection against clade 2.3.4.4b H5N1 IAVs , which are currently circulating in birds and dairy cows . Here, Restori et al. demonstrated that prior infection with the 2009 pandemic H1N1 IAV was protective against subsequent direct infection with H5N1 IAV in ferrets. Moreover, prior immunity reduced susceptibility to infection by transmission from an infected donor ferret. These data suggest that prior immunity to IAV, especially to the 2009 pandemic H1N1 virus, may offer a degree of protection against H5N1 infection. —Courtney Malo Abstract Zoonotic infections with emerging influenza viruses occur in the context of population-wide immunity to seasonal strains . Because of the worldwide spread of highly pathogenic clade...

Abstract Sudan virus (SUDV) causes highly lethal outbreaks of hemorrhagic disease throughout Africa , but there has yet to be an approved vaccine or therapeutic to combat this public health threat. The most common route of natural exposure to filoviruses is through mucosal contact which greatly impacts initial viral replication. Historically, SUDV animal models used an intramuscular infection route . Here, we sought to further characterize an animal model using mucosal challenge routes and compared the impact that intramuscular, intranasal, or aerosol exposure had on SUDV pathogenicity in a ferret model . We determined that the route of infection did not significantly impact overall SUDV pathogenicity; only subtle changes were detected in magnitude of viremia and oral viral shedding. Additionally, we sought to determine if preexisting Lloviu virus (LLOV) immunity could protect ferrets from lethal SUDV infection. We found that the previous immunity elicited by LLOV infection was not suf...

Abstract In March 2024, clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses were first detected in U.S. dairy cattle . Similar viruses have since caused 70 zoonotic human infections . To assess changes to zoonotic potential , we characterized A( H5N1 ) clade 2.3.4.4b viruses isolated from cows’ milk and birds . Bovine-derived viruses are lethal in mice and ferrets and transmit to direct but not airborne contact ferrets. All viruses replicate in human bronchial epithelial cells despite preferentially binding avian virus-like receptors. The bovine-derived viruses remain susceptible to FDA-approved antivirals , and they are inhibited by sera from ferrets vaccinated with WHO-recommended candidate vaccine viruses (CVV) or human sera from clade 2.3.4.4c vaccinees. While 2.3.4.4b viruses induce severe disease in mammalian models , they retain many avian virus-like characteristics. Combined, we conclude that the risk of contemporary bovine-derived viruses to humans not in contact ...

Abstract Collection of systemic tissues from influenza A virus (IAV)-infected ferrets at a fixed timepoint post-inoculation represents a frequent component of risk assessment activities to assess the capacity of IAV to replicate systemically. However, few studies have evaluated how the frequency and magnitude of IAV replication at discrete tissues contribute to within-host phenotypic outcomes, limiting our ability to fully contextualize results from scheduled necropsy into risk assessment settings. Employing aggregated data from ferrets inoculated with > 100 unique IAV ( both human- and avian-origin viruses, spanning H1, H2, H3, H5, H7, and H9 subtypes ), we examined relationships between infectious virus detection in four discrete tissue types ( nasal turbinate, lung, brain, and olfactory bulb [BnOB]) to clinical outcomes of IAV-inoculated ferrets, and the utility of including these discrete tissue data as features in machine learning (ML) models. We found that addition of viral ti...

  Abstract Highly pathogenic avian influenza A viruses subtype H5N1 (HPAIV H5N1), subclade 2.3.4.4b infect multiple avian and mammalian species , posing a potential pandemic risk . Here we describe the outcomes of infection of ferrets with a HPAIV H5N1 virus, isolated from a European grey seal in 2023, compared with an older HPAIV H5N1 (A/Indonesia/05/2005). Overall, infection of ferrets with A/grey seal/Netherlands/302603/2023 caused more rapid mortality than infection of ferrets with A/Indonesia/05/2005. Animals developed severe pneumonia and irreversible hypothermia , associated with high levels of virus replication and histopathological changes in the respiratory tract and peripheral organs. As animal models for severe avian influenza virus infections in humans play a key role in the development of intervention strategies against these infections, these findings highlight the importance of using updated ferret models based on circulating virus strains. Source: Journal of Infect...

LETTER Transmission among mammals of bovine highly pathogenic avian influenza (HPAI) H5N1 viruses , which have caused outbreaks in US dairy cattle (1–3), has been demonstrated in ferrets by our group (4, 5) and the US Centers for Disease Control and Prevention (CDC) (6). These studies showed that these viruses can be transmitted among ferrets via respiratory droplets , albeit with lower efficiency than seasonal human influenza viruses. In contrast, bovine HPAI H5N1 viruses spread easily among ferrets through direct contact (3 of 3 [100%] ferrets) (6). Although ferrets are frequently used for influenza virus transmission (7–9) and vaccine efficacy (10, 11) studies, they demand considerable housing space and personnel and can be difficult to handle. Here, we investigated the transmissibility of the bovine HPAI H5N1 virus A/Texas/37/2024 (TX/37), which was 100% lethal in ferrets inoculated with as little as 10 plaque-forming units (PFUs) (5) by using a hamster model .  (...) Bovine HP...

Abstract Ferrets are widely used to model airborne transmission of influenza viruses in humans. Airborne transmission is evaluated by infecting donor ferrets with a high virus dose (106 infectious units) and monitoring transmission to contact animals sharing the same airspace . However, humans can be infected with a broad range of influenza virus doses. Therefore, we evaluated the relationship between virus inoculation dose and transmission for two pandemic influenza viruses in ferrets. Donor ferrets were inoculated with 100 to 106 tissue culture infectious dose 50 (TCID50) of the 2009 pandemic H1N1 or 1968 H3N2 pandemic virus , and were then paired with respiratory contacts . Using the proportion of donors that became infected across virus doses, we calculated the infectious dose 50 (ID50). Subsequently, by comparing the proportion of respiratory contacts that became infected, we calculated the transmissible dose 50% (TD50): the donor inoculation dose that resulted in transmission to ...

ABSTRACT Recent avian-origin H3N8 influenza A virus (IAV) that have infected humans pose a potential public health concern . Alterations in the viral surface glycoprotein, hemagglutinin (HA), are typically required for IAVs to cross the species barrier for adaptation to a new host, but whether H3N8 has adapted to infect humans remains elusive. The observation of a degenerative codon in position 228 of HA in human H3N8 A/Henan/4-10/2022 protein sequence , which could be residue G or S, suggests a dynamic viral adaptation for human infection. Previously, we found this human-isolated virus has shown the ability to transmit between ferrets via respiratory droplets , with the HA-G228S substitution mutation emerging as a critical determinant for the airborne transmission of the virus in ferrets. Here, we investigated the receptor-binding properties of these two H3N8 HAs. Our results showed H3N8 HAs have dual receptor-binding properties with a preference for avian receptor binding , and G228S...

Abstract Reports of human infections with an influenza A(H5N1) clade 2.3.4.4b virus associated with outbreaks in dairy cows in the United States underscore the need to assess the potential cross-protection conferred by existing influenza immunity . We serologically evaluated ferrets previously infected with an influenza A(H1N1)pdm09 virus for cross-reactive antibodies and then challenged 3 months later with either highly pathogenic H5N1 clade 2.3.4.4b or low pathogenicity H7N9 virus . Our results showed that prior influenza A(H1N1)pdm09 virus infection more effectively reduced the replication and transmission of the H5N1 virus than did the H7N9 virus, a finding supported by the presence of group 1 hemagglutinin stalk and N1 neuraminidase antibodies in preimmune ferrets. Our findings suggest that prior influenza A(H1N1)pdm09 virus infection may confer some level of protection against influenza A(H5N1) clade 2.3.4.4.b virus. Source: US Centers for Disease Control and Prevention,  htt...

Abstract The emergence of highly pathogenic avian influenza A(H5N1) virus in dairy cattle herds across the United States in 2024 caused several human infections . Understanding the risk for spillover infections into humans is crucial for protecting public health. We investigated whether immunity from influenza A(H1N1)pdm09 (pH1N1) virus would provide protection from death and severe clinical disease among ferrets intranasally infected with H5N1 virus from dairy cows from the 2024 outbreak. We observed differential tissue tropism among pH1N1-immune ferrets. pH1N1-immune ferrets also had little H5N1 viral dissemination to organs outside the respiratory tract and much less H5N1 virus in nasal secretions and the respiratory tract than naive ferrets. In addition, ferrets with pH1N1 immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, our results suggest that humans with immunity to human seasonal influenza viruses may experience milder disease fro...

Abstract Influenza A virus (IAV) non-canonical replication products can be bound by host pathogen sensors , such as retinoic acid-inducible gene I (RIG-I). However, innate immune activation is infrequent in cell culture infection, in particular by adapted strains. Moreover, it is not understood why non-canonical IAV RNAs activate RIG-I in a sequence- or RNA structure-dependent manner. We therefore hypothesized that multiple errors need to occur before influenza virus RNA synthesis activates innate immune signaling . To test this idea, we investigated whether RIG-I activation is stimulated by the non-canonical or aberrant transcription of mini viral RNAs (mvRNA), a <125 nt long RNA that is overexpressed in pandemic and highly pathogenic IAV infections . Using mvRNA sequences identified in tissue culture and ferret infections , we find that mvRNAs can cause non-canonical transcription termination through a truncated 5ʹ polyadenylation signal or a 5ʹ transient RNA structure that interr...