#animalmodels

Polygenic #Determinants of #H5N1 #Adaptation to Bovine Cells

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.29.626120v1

Abstract
H5N1 avian influenza virus (lineage 2.3.4.4b, B3.13 genotype) has caused, unexpectedly, a large outbreak in dairy cattle in North America. It is critical to ascertain how this virus has specifically adapted to bovine cells and the molecular determinants of this process. Here, we focused on the contribution of the viral internal genomic segments of H5N1 B3.13 to bovine cells adaptation. We generated 45 reassortant viruses harbouring the haemagglutinin and neuraminidase from A/Puerto Rico/8/1934 and internal gene constellations from several influenza A viruses (IAV) or carrying segment swaps between distinct H5N1 strains. The recombinant B3.13 viruses displayed faster replication kinetics in bovine cells compared to other IAV. Importantly, multiple genomic segments of B3.13 viruses contribute to their faster replicative fitness. Further, recombinants with the B3.13 internal genes were less susceptible than ancestral 2.3.4.4b strain to the bovine IFN response. However, bovine (and human) MX1, a key restriction factor for avian IAV, restricted both ancestral 2.3.4.4b and B3.13 recombinant viruses. Interestingly, the latter escape restriction from human BTN3A3. Finally, recombinant B3.13 was virulent in mice unlike the ancestor 2.3.4.4b recombinant virus. Our results highlight the polygenic nature of influenza host range as multiple internal genes of B3.13 contribute to bovine adaptation.

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#aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #dairyCow #h5n1 #health #news #research #viralPathogenesis

A #vaccine #platform targeting #lung-resident memory #CD4+ T-cells provides #protection against heterosubtypic #influenza infections in mice and #ferrets

Source: Nature Communications, https://www.nature.com/articles/s41467-024-54620-4

Abstract
Lung tissue-resident memory T (TRM) cells induced by influenza vaccination are crucial for heterosubtypic immunity upon re-exposure to the influenza virus, enabling rapid and robust responses upon reactivation. To enhance the efficacy of influenza vaccines, we induce the generation of lung TRM cells following intranasal vaccination with a commercial influenza vaccine adjuvanted with NexaVant (NVT), a TLR3 agonist-based adjuvant. We demonstrate that intranasal immunization with the NVT-adjuvanted vaccine provides improved protection against influenza virus infections by inducing the generation of CD4+ TRM cells in the lungs in a type I interferon-dependent manner. These pulmonary CD4+ TRM cells provide potent mucosal immunity and cross-protection against heterosubtypic infections in both mouse and ferret models. This vaccine platform has the potential to significantly improve conventional intramuscular influenza vaccines by providing broader protection.

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#abstract #animalModels #ferrets #research #SEASONALINFLUENZA #vaccines

Lack of #Lloviu Virus #Disease #Development in #Ferret Model

Source: Emerging Infectious Diseases Journal, https://wwwnc.cdc.gov/eid/article/30/12/24-0818_article

Abstract
The first isolate of the emerging filovirus Lloviu virus (LLOV) was obtained in 2022. No animal disease models have been established. We assessed the pathogenic potential of LLOV in ferrets after intranasal, intramuscular, or aerosol exposure. The lack of disease development shows ferrets are not a disease model for LLOV.

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#abstract #animalModels #filovirus #lloviuVirus #research

Single-dose avian #influenza A(#H5N1) Clade 2.3.4.4b #hemagglutinin-Matrix-M nanoparticle #vaccine induces neutralizing responses in nonhuman #primates

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.21.624712v1?rss=1

Abstract
With the recent rise in cases of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b infection in humans and animals, there is an associated increase in the risk of human-to-human transmission. In this study, we characterize recombinant A(H5N1) A/American Wigeon/South Carolina/22/000345-001/2021 (A/AW/SC/2021) clade 2.3.4.4b vaccine. Purified recombinant A/AW/SC/2021 HA trimers upon formulation with Matrix-M™ adjuvant, saponin-cholesterol-phospholipid icosahedral particles, non-covalently anchored to the vertices of the Matrix-M forming A(H5N1) HA–Matrix-M nanoparticles (H5-MNPs). In naive mice, two intranasal (IN) or intramuscular (IM) doses of A/AW/SC/2021 H5-MNP vaccine induced robust antibody- and cell-mediated immune responses, including neutralizing antibodies against A(H5N1). In non-human primates (NHPs) primed with seasonal influenza vaccine, a single IM or IN dose of the A/AW/SC/2021 H5-MNP vaccine induced geometric mean serum A(H5N1) clade 2.3.4.4b pseudovirus neutralizing titers of 1:1160 and 1:54, respectively; above the generally accepted seroconverting neutralizing titer of 1:40. Immunization with H5-MNP vaccine induced antibody responses against conserved epitopes in the A(H5N1) HA stem, vestigial esterase subdomain, and receptor binding site. This novel A(H5N1) H5-MNP IN and IM vaccine was immunogenic in rodents and NHPs as a potential A(H5N1) pandemic single-dose vaccine.

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#aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #h5n1 #health #news #pandemicPreparedness #research #vaccines

#Chicken ANP32A-independent #replication of highly pathogenic avian #influenza viruses potentially leads to #mammalian #adaptation-related amino acid substitutions in viral #PB2 and #PA proteins

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.01840-24?af=R

ABSTRACT
Acidic nuclear phosphoprotein 32 family member A (ANP32A) is an important host factor that supports the efficient replication of avian influenza viruses (AIVs). To develop an antiviral strategy against Gs/Gd-lineage H5 highly pathogenic avian influenza (HPAI) viruses in chickens, we established chicken ANP32-knockout (chANP32A-KO) DF-1 cells and evaluated their antiviral efficacy through in vitro validation. The replication of all HPAI viruses tested in chANP32A-KO cells was significantly lower compared to that of wild-type DF-1 cells. However, when HPAI strains A/mountain hawk-eagle/Kumamoto/1/2007 (H5N1; MHE) and A/chicken/Aichi/2/2011 (H5N1; H5Aichi) were passed in chANP32A-KO cells, mutant viruses were generated, which exhibited comparable replication levels in both chANP32A-KO and wild-type DF-1 cells. Sequence analysis revealed that mammalian-adaptive amino acid mutations PB2_D256G and PA_T97I were present in the MHE mutant virus, and the PB2_E627K mutation was identified in the H5Aichi mutant virus. These mutations have also been reported to enhance the polymerase activity of AIVs in mammalian cells; however, the minigenome assay in the present study showed that the polymerase activity of mutant viruses in chANP32A-KO cells was not restored to levels comparable to those in wild-type DF-1 cells. These findings suggest that ANP32A-independent viral replication may induce amino acid substitutions associated with mammalian adaptation in AIVs. They also imply that the high efficiency of viral replication mediated by these amino acid mutations may not result from enhanced polymerase activity but rather involve other undefined mechanisms.

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#aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #biology #birdFlu #health #research #science

#Age-Dependent #Pathogenesis of #Influenza A Virus #H7N9 Mediated Through #PB1-F2-Induced Mitochondrial DNA Release and Activation of cGAS-STING-NF-κB Signaling

Source: Journal of Medical Virology, https://onlinelibrary.wiley.com/doi/10.1002/jmv.70062

ABSTRACT
Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1-F2 is a pathogenic factor in 15–18-month-old BALB/C mice (aged mice) but not in 6–8-week-old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1-F2-knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2′3′-cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2′3′-cGAMP to boost proinflammatory cytokine expression through STING-NF-κB signaling. We found that H7N9 PB1-F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA-cGAS-STING-NF-κB pathway. H7N9 PB1-F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V-dependent electron transport dysfunction, reverse electron transfer-dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS-STING-NF-κB signaling. PB1-F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1-F2-mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1-F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human-adapted descendants. Our findings provide one explanation to age-dependent pathogenesis of H7N9 infection.

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#aH7n9 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #h5n1 #health #news #research #viralPathogenesis

Boosting #neuraminidase #immunity in the presence of #hemagglutinin with the next generation of #influenza #vaccines

Source: npj Vaccines, https://www.nature.com/articles/s41541-024-01011-x

Abstract
Neuraminidase (NA), the second most abundant surface glycoprotein on the influenza virus, plays a key role in viral replication and propagation. Despite growing evidence showing that NA-specific antibodies correlate with resistance to disease in humans, current licensed vaccines focus almost entirely on the hemagglutinin (HA) antigen. Here, we demonstrate that recombinant NA (rNA) protein is highly immunogenic in both naïve mice and ferrets, as well as in pre-immune ferrets, irrespective of the level of match with preexisting immunity. Ferrets vaccinated with rNA developed mild influenza disease symptoms upon challenge with human H3N2 influenza virus, and anti-NA antibody responses appeared correlated with reduction in disease severity. The addition of rNA to a quadrivalent HA-based vaccine induced robust NA-specific humoral immunity in ferrets, while retaining the ability to induce HA-specific immunity. These results demonstrate that the addition of rNA is a viable option to increase immunogenicity and potentially efficacy versus currently licensed influenza vaccines by means of boosting NA immunity.

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#aH1n1 #aH3n2 #abstract #animalModels #health #influenzaA #mrna #news #research #vaccine #vaccines

Enhanced #encephalitic #tropism of #bovine #H5N1 compared to the #Vietnam #H5N1 isolate in #mice

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.19.624162v1

Abstract
In recent years, the landscape of highly pathogenic avian influenza (HPAI) virus infections has shifted, as evidenced by an increase in infections among mammals. This includes the recent circulation of H5N1 in dairy cattle herds in the USA and a rise in associated human cases. In this study, we investigated differences in tissue tropism of two HPAI H5N1 strains, the isolate A/Vietnam/1203/2004 (VN1203) isolated from a fatal human case in 2004 and the bovine isolate A/Bovine/Ohio/B24osu-342/2024 (Bov342) isolated in 2024, in C57BL/6J mice. Infection with either HPAI H5N1 isolate was uniformly lethal in mice. However, tissue tropism differed significantly: while VN1203 replication was largely restricted to the respiratory tract, Bov342 successfully replicated in the respiratory tract as well as various regions of the brain. Bov342-challenged animals exhibited clinical signs consistent with central nervous system (CNS) infection, and infectious virus was detected in brain tissue. Correspondingly, cytokine profiles in the brain differed significantly between the isolates. Notably, in addition to abundant evidence of CNS infection in Bov342-challenged mice via immunohistochemistry, sporadic intranuclear and intracytoplasmic immunoreactivity was observed in other tissues in the head, including the choroid plexus, retina, and inner ear. This study demonstrates that while both HPAI H5N1 isolates are uniformly lethal in C57BL/6J mice upon aerosol exposure, significant differences exist in tissue tropism, with Bov342 resulting in respiratory disease as well as increased neurotropism and inflammation in the brain and nasal turbinates compared to VN1203, which predominantly induces respiratory disease.

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#aH5n1 #abstract #animalHealth #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #dairyCow #h5n1 #health #neuroinvasion #news #research

Protective threshold of a potent neutralizing #Zika virus monoclonal #antibody in rhesus #macaques

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.01429-24?af=R

ABSTRACT
Zika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016–2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117-LALA-YTE, which has been engineered to reduce Fc receptor binding and to extend half-life, in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117-LALA-YTE, which resulted in median serum concentrations of 0.13 µg/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV.

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#abstract #animalModels #monoclonalAntibodies #research #zikaVirus

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.07.622580v1?rss=1

Abstract
JN.1 is a subvariant of SARS-CoV-2 Omicron BA.2.86 lineage that was predominant worldwide in early 2024, of which the in vivo characteristics are largely unknown. Our results demonstrated that the replication of JN.1 was more efficient than that of the parental BA.2 in Vero cells, which demonstrated low dependence on TMPRSS2. Compared to Omicron variants BA.2 and XBB EG.5.1, JN.1 replicated less efficiently in hACE2 mouse lungs of which the intranasal infection was not lethal to hACE2 mice and led to weaker immune dysregulation in lungs. On a more sensitive, aged hACE2 hamster model, JN.1 led to a lower mortality rate and no weight loss, corresponding well with the low preference in lower airways. Lower amounts of viruses in nasal washes and exhaled aerosols were detected in JN.1 infected wildtype hamsters than EG.5.1, and consistently, JN.1 also exhibited largely reduced airborne transmission. Moreover, the poor transmission was also clearly demonstrated even by using hamsters expressing hACE2 receptors in the whole airways. Thus both pathogenicity and airborne transmission of JN.1 were demonstrated to be largely attenuated.

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https://etidioh.wordpress.com/2024/11/09/sars-cov-2-jn1-reveals-attenuated-pathogenicity-and-airborne-transmission/

#abstract #animalModels #COVID19 #research #sarsCov2

Source: Journal of Virology, https://journals.asm.org/doi/10.1128/jvi.00928-24

ABSTRACT
A better understanding of viral factors that contribute to influenza A virus (IAV) airborne transmission is crucial for pandemic preparedness. A limited capacity for airborne transmission was recently observed in a human A(H9N2) virus isolate (A/Anhui-Lujiang/39/2018, AL/39) that possesses a leucine (L) residue at position HA1-226 (H3 numbering), indicative of human-like receptor binding potential. To evaluate the roles of the residue at this position in virus fitness and airborne transmission, a wild-type AL/39 (AL/39-wt) and a mutant virus (AL/39-HA1-L226Q) with a single substitution at position HA1-226 from leucine to glutamine (Q), a consensus residue in avian influenza viruses, were rescued and assessed in the ferret model. The AL/39-HA1-L226Q virus lost the ability to transmit by air, although the virus had a comparable capacity for replication, induced similar levels of host innate immune responses, and was detected at comparable levels in the air surrounding the inoculated ferrets relative to AL/39-wt virus. However, ferrets showed a lower susceptibility to AL/39-HA1-L226Q virus infection compared to the AL/39-wt virus. Furthermore, the AL/39-wt and AL/39-HA1-L226Q viruses each gained dominance in different anatomic sites in the respiratory tract in a co-infection competition model in ferrets. Taken together, our findings demonstrate that the increasing dominance of HA1-L226 residue in an avian A(H9N2) virus plays multifaceted roles in virus infection and transmission in the ferret model, including improved virus fitness and infectivity.

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https://etidioh.wordpress.com/2024/11/04/dissecting-the-role-of-the-ha1-226-leucine-residue-in-the-fitness-and-airborne-transmission-of-an-ah9n2-avian-influenza-virus/

#aH9n2 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #ferrets #h5n1 #health #news #research

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.01.621606v1?rss=1

Abstract
The ongoing outbreak of highly pathogenic avian influenza (HPAI) H5N1 of the clade 2.3.4.4b in dairy cows has led to numerous questions including how the virus transmits amongst cattle given the limited respiratory infection. One hypothesis is that the virus is spreading through fomites from udder to udder. In these studies, we demonstrate that intraductal inoculation of H5N1 but not H1N1 influenza virus results in infection in mice. This model will be useful to our understanding of the impact of influenza virus on the mammary gland, the potential as a new route of transmission, and can be used to assess if antiviral treatments prevent infections in the mammary gland.

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https://etidioh.wordpress.com/2024/11/03/intraductal-infection-with-h5n1-clade-2-3-4-4b-influenza-virus/

#aH5n1 #abstract #animalModels #avianInfluenza #dairyCow #research

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.10.29.620905v1

Abstract
The host range of HPAIV H5N1 was recently expanded to include ruminants, particularly dairy cattle in the United States. Shortly after, human H5N1 infection was reported in a dairy worker in Texas following exposure to infected cattle. Herein, we rescued the cattle-origin influenza A/bovine/Texas/24-029328-02/2024(H5N1, rHPbTX) and A/Texas/37/2024(H5N1, rHPhTX) viruses, identified in dairy cattle and human, respectively, and their low pathogenic forms, rLPbTX and rLPhTX, with monobasic HA cleavage sites. Intriguingly, rHPhTX replicated more efficiently than rHPbTX in mammalian and avian cells. Still, variations in the PA and NA proteins did not affect their antiviral susceptibility to PA and NA inhibitors. Compared to rHPbTX and rLPbTX, the rHPhTX and rLPhTX exhibited higher pathogenicity and efficient replication in infected C57BL/6J mice. The lungs of rHPhTX-infected mice produced higher inflammatory cytokines/chemokines than rHPbTX-infected mice. Our results highlight potential risk of HPAIV H5N1 virus adaptation in human and/or dairy cattle during the current multistate/multispecies outbreak.

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https://etidioh.wordpress.com/2024/10/30/replication-kinetics-pathogenicity-and-virus-induced-cellular-responses-of-cattle-origin-influenza-ah5n1-isolates-from-texas-united-states/

#aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #dairyCow #h5n1 #health #human #news #research

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.10.23.619695v1

Abstract
The most recent outbreak of highly pathogenic avian H5 influenza (HPAI) virus in cattle is now widespread across the U.S. with spillover events happening to other mammals, including humans. Several human cases have been reported with clinical signs ranging from conjunctivitis to respiratory illness. However, most of those infected report mild to moderate symptoms, while previously reported HPAI H5Nx infections in humans have had mortality rates upwards of 50%. We recently reported that mice with pre-existing immunity to A/Puerto Rico/08/1934 H1N1 virus were protected from lethal challenge from highly pathogenic clade 2.3.4.4b H5N1 influenza virus. Here, we demonstrate that mice infected with the 2009 pandemic H1N1 virus strain A/California/04/2009 (Cal09) or vaccinated with a live-attenuated influenza vaccine (LAIV) were moderately-to-highly protected against a lethal A/bovine/Ohio/2024 H5N1 virus challenge. We also observed that ferrets with mixed pre-existing immunity, either from LAIV vaccination and/or from Cal09 infection, showed protection against a HPAI H5N1 clade 2.3.4.4b virus isolated from a cat. Notably, this protection occurred independently of any detectable hemagglutination inhibition titers (HAIs) against the H5N1 virus. To explore factors that may contribute to protection, we conducted detailed T cell epitope mapping using previously published sequences from H1N1 strains. This analysis revealed a high conservation of amino acid sequences within the internal proteins of our bovine HPAI H5N1 virus strain. These data highlight the necessity to explore additional factors that contribute to protection against HPAI H5N1 viruses, such as memory T cell responses, in addition to HA-inhibition or neutralizing antibodies.

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https://etidioh.wordpress.com/2024/10/24/immune-history-modifies-disease-severity-to-hpai-h5n1-clade-2-3-4-4b-viral-challenge/

#aH1n1 #aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #ferrets #h1n1pdm09 #h5n1 #health #immuneSystem #news #research

Applications are OPEN for our Gnotobiotic Workshop, happening May 8-10, 2024 at the University of Calgary! Head to our website for details, and don't wait to apply because space is extremely limited! https://www.impactt-microbiome.ca/gnotobiotic-workshop/

#gnotobiotic #workshop #germfree #animalmodels #animalresearch #microbiome #microbiota #microbiology

Save the date! Our next IMPACTT/IMC Gnotobiotic Workshop will be held May 8-10, 2024 at the University of Calgary. Learn to conduct research with germ-free and gnotobiotic animal models in this hands-on 2.5 day workshop. Registration opens early 2024. Learn more at our website: https://www.impactt-microbiome.ca/gnotobiotic-workshop/

#gnotobiotic #GermFree #research #AnimalModels #workshop #microbiome

This study strengthens caution of quickly extrapolating animal model studies to humans, and vice versa.
“…the assessment of human–animal relationships is important for translational studies. We believe that our data will also help to identify which species should be used in specific settings or as an animal model.” #physiology #animalmodels #Proteomics #biology #translationalscience

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338492/

@dustcircle

from ^ article: "Rats are unable to vomit to purge themselves of toxic substances, and hence taste aversion is an important adaptation that helps them avoid drinking or eating potentially noxious substances. Taste aversion is rapid and persists for over a month ... "

Yet another difference between rats & humans.

#AnimalModels #vomiting
#neuroscience #immunology #gastroenterology

WORKSHOP ANNOUNCEMENT: Our next Gnotobiotic Workshop is happening May 4-5, 2023 at the University of Calgary! Registration is open and space is extremely limited so click the link to apply today: https://www.impactt-microbiome.ca/gnotobiotic-workshop/

#workshop #gnotobiotic #germ-free #axenic #animalmodels #animalresearch #microbiome #microbiota

@albertcardona
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#Drosophila
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