#Species - and #variant - specific #ACE2 compatibility shapes #SARS-CoV-2 #spillover potential in North American #cervids

 

Abstract

Free-ranging white-tailed deer (WTD) are established SARS-CoV-2 reservoirs, but the susceptibility of other cervid species remains unclear. Here we integrate receptor analysis, structural modeling, and field surveillance to assess SARS-CoV-2 susceptibility across North American cervids. We identify species- and variant-specific differences in ACE2–spike compatibility. Elk ACE2 exhibits weak binding to the ancestral strain (Wuhan-Hu-1) and Delta spike receptor-binding domains (RBDs), likely due to a unique K31N substitution. In contrast, it shows stronger binding to Alpha, Beta, Gamma, and Omicron RBDs containing N501Y. Biophysical assays, gel filtration chromatography, and cryo-EM confirm stable complex formation between elk ACE2 and Alpha RBD, but not RBD from the ancestral strain. Despite weak binding, elk ACE2 supports viral entry and replication in vitro. However, surveillance revealed limited evidence of infection in the United States, contrasting with widespread WTD transmissions. These findings demonstrate that ACE2 compatibility alone is insufficient to predict reservoir potential and provide a framework for assessing species susceptibility to emerging coronaviruses.

Source: 

Link: https://www.nature.com/articles/s41467-026-71623-5

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#Norway - #Influenza A #HxNx viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

{A Canada Goose}

__

{A Greylag Goose}

___

A wild Greylag Goose and a wild Canada Goose in Innlandet and Østfold Regions.

Source: 

Link: https://wahis.woah.org/#/in-review/7424

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#Preclinical evaluation of an #mRNA #vaccine developed from the first #human isolate of #bovine #H5N1

 

Highlights

• SM102 and DB-Y ionizable lipids deliver H5 mRNA vaccine with high efficiency and safety

• Vaccine-induced antibody and T cell response protect mice from H5N1 challenge

• Pre-existing H1 immunity does not diminish H5-specific immunogenicity

• Vaccine fully protects chicken against clade 2.3.4.4b/h H5 virus challenge

Summary

Given the global threat posed by H5N1 clade 2.3.4.4b avian influenza, rapid development of effective vaccines is imperative. We design an mRNA vaccine encoding hemagglutinin (HA) from A/Texas/37/2024, the first bovine-to-human strain. In murine models, both wild-type and cleavage-site-modified HA vaccines elicit robust and durable humoral immunity, along with a balanced Th1/Th2 response, conferring complete protection against lethal homologous viral challenge. The vaccine, along with the World Health Organization (WHO)-recommended candidate (A/Astrakhan/3212/2020), elicits cross-clade binding antibody responses and demonstrates improvement against specific clades at a 1 μg dose. Pre-existing H1 immunity does not diminish H5-specific immunogenicity. In avian species, the vaccine also provides full protection against lethal clades (2.3.4.4b and 2.3.4.4h). Formulated with another ionizable lipid, the vaccine elicits responses comparable to benchmark lipid nanoparticles (LNPs) and shows a favorable safety profile in rats. This work establishes a rapidly adaptable mRNA-LNP vaccine prototype for pandemic preparedness against evolving avian influenza threats.

Source: 

Link: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00119-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666379126001199%3Fshowall%3Dtrue

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#Birth #imprinting effects on the #antibody responses of #H7N9 patients from 2013-2018 in #China

 

Abstract

Background

There is an urgent need to understand the immune correlates of protection against avian influenza viruses (AIV), where pre-existing immunity may be limited.

Methods

Here, we characterized the antibody response in 12 severely ill A(H7N9) patients and examined its association with early-life imprinting and clinical outcome.

Results

We find that A(H7N9) patients imprinted with A(H2N2) during early life show minimal H7-IgM and a rapid IgG response across diverse hemagglutinin subtypes. They also have more high avidity H7-antibodies compared to older or younger patients. Early antibody titers against seasonal H1, H3, and conserved stalk domains trend negatively with clinical severity in A(H7N9) infection, while an inverse pattern is observed following severe A(H1N1) infection, potentially suggesting a different mechanism of immune regulation between seasonal and avian influenza virus infections.

Conclusions

These data provide direct serological evidence that birth imprinting profoundly shapes the humoral immune landscape during zoonotic influenza infection and may influence subsequent disease outcome.

Source: 

Link: https://www.nature.com/articles/s43856-026-01554-1

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Genetic characterization of a novel triple - #reassortant #influenza #H1N2 virus from #pigs, #China, 2021

 

Abstract

Swine influenza virus (SIV) is a highly contagious respiratory pathogen in pigs, with bidirectional transmission posing a potential threat to human health. In this study, nasal swab samples were collected from pigs in Shandong Province, China, and yielded an H1N2 SIV strain, designated A/swine/Shandong/QD726/2021 (H1N2). Whole-genome sequencing was performed for Sw/SD/QD726/2021, and phylogenetic analysis was conducted together with 156 Chinese H1N2 reference sequences obtained from the Global Initiative on Sharing All Influenza Data (GISAID) database and the National Center for Biotechnology Information (NCBI) Influenza Virus Resource database. The results indicated that Sw/QD726/2021 represents a novel reassortant genotype (G21), with the HA gene derived from Eurasian avian-like H1N1 (EA H1N1), the NA and NS genes from triple-reassortant H1N2 (TR H1N2), and the remaining internal genes (PB2, PB1, PA, NP, M) from the 2009 pandemic H1N1 (pdm/09 H1N1). Key amino acid analysis revealed N31 in M2, responsible for adamantane resistance, and S42 in NS1, which influences viral virulence in mouse models. BALB/c mouse experiments demonstrated efficient viral replication in the lungs and nasal turbinates, accompanied by moderate body weight loss and lung lesions, indicating only moderate pathogenicity. These findings underscore the ongoing evolution of H1N2 SIV in pigs and emphasize the importance of enhanced surveillance and preventive strategies to mitigate public health risks.

Source: 

Link: https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2026.1779293/full

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Avian #Influenza #Report - From March 29 to April 4, 2026 (Wk 14) (#HK PRC SAR CHP, April 8 '26): 1 #H5N1 case in #Cambodia, 1 #H7H7 case in #Taiwan

{Excerpts}

(...)

1) H5N1

-- Date of report: 31/03/2026 

-- Country: Cambodia 

-- Province / Region: Oddar Meanchey province

-- District / City: Banteay Ampil district 

-- Sex: Male

-- Age: 3 

-- Condition at time of reporting: Hospitalised 

-- Subtype of virus  H5N1 

(...)

2) H7N7

-- Place of occurrence: Taiwan, China

-- No. of cases  (No. of deaths): 1(0)

-- Details:   

- Avian influenza A(H7N7): 

* Central Taiwan: A man in his 70s who works in a poultry farm with onset on March 20, 2026. 

* This is the first locally-acquired human case of avian influenza A(H7N7) reported in Taiwan, China. 

(...)

Source: 

Link: https://www.chp.gov.hk/files/pdf/2026_avian_influenza_report_vol22_wk14.pdf

____

#Chile - #Influenza A #H5N1 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

All [Backyard] birds at the site were culled; surveillance measures continue in the control zone. [Region: Libertador General Bernardo O'Higgins]

Source: 

Link: https://wahis.woah.org/#/in-review/7400

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#Genetic and #biological characterization of a #duck-origin clade 2.3.4.4b #H5N6 avian #influenza virus reveals partial #mammalian #adaptation

 

Highlights

• Duck-origin H5N6 virus A/Duck/Jiangsu/628/2022 shares high homology with the human strain A/Yangzhou/125/2022.

• The 628 strain shows mammalian adaptation markers: HA mutations enhance human receptors affinity and NA mutations reduce sensitivity to neuraminidase inhibitors.

• Limited airborne transmission but detectable droplet-mediated spread suggests increased mammalian transmission risk.

Abstract

Clade 2.3.4.4b H5Nx highly pathogenic avian influenza viruses (HPAIVs) have caused extensive outbreaks in poultry worldwide. H5 HPAIVs have caused sporadic but severe human infections in China, representing a persistent zoonotic threat. Here, we identified a duck-origin H5N6 HPAIV (A/Duck/Jiangsu/628/2022) through routine surveillance and assessed its biological characteristics and mammalian pathogenesis. Phylogenetic analysis revealed > 98% nucleotide identity between strain 628 and the concurrent human H5N6 strain A/Yangzhou/125/2022. Molecular characterization identified multiple mammalian adaptation markers: hemagglutinin substitutions (S137A, T160A, T192I) associated with enhanced human receptor binding; neuraminidase mutations (I117T, D198N) linked to reduced neuraminidase inhibitor susceptibility; and polymerase complex changes (PB1-D622G, PA-K142Q) conferring increased mammalian cell replication. In vitro studies demonstrated that 628 virus replicated more efficiently in mammalian than in avian cells and exhibited dual receptor-binding specificity. Mouse pathogenicity assays revealed moderate virulence with progressive lung pathology. Critically, transmission experiments confirmed both direct contact and airborne transmission capabilities of 628 in guinea pigs. These findings demonstrate that circulating H5N6 viruses have acquired partial mammalian adaptation while retaining avian fitness, significantly elevating pandemic potential. Enhanced surveillance of wild bird populations, poultry farms, and live poultry markets is urgently needed to develop effective prevention and control strategies.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S037811352600146X?via%3Dihub

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Using an evolutionary epidemiological #model of #pandemics to estimate the #infection #fatality ratio for #humans infected with avian #influenza viruses

 

Abstract

The risk of highly pathogenic avian influenza virus infection to humans is challenging to estimate as many human avian influenza virus (AIV) infections are undetected because infections may be asymptomatic, symptomatic but not tested, and difficult to identify through contact tracing, as human-to-human transmission is rare. We derive equations that consider the evolutionary mechanisms that give rise to pandemics and are parameterized to be consistent with records of past pandemics. We estimate that thousands of human AIV infections occur worldwide in an average year and estimate the infection fatality ratio as 32 deaths per 10,000 infections (95% confidence interval: [9.6, 75]). This estimate is comparable to SARS-CoV-2 during the recent pandemic and higher than seasonal human influenza. We estimate that preventing animal-to-human influenza spillovers would delay pandemic emergence by several years. Preventing human infections with AIV is necessary given the high risk of severe outcomes to individuals and to reduce the risk of pandemics occurring in the future.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

AH was supported by a Natural Sciences and Engineering Research Council of Canada Discovery Grant (RGPIN 023-05905) and a Catalyst Grant: Avian Influenza OneHealth Research, Enhanced tracking of the circulation of and risk from highly pathogenic avian influenza viruses at the human-wildlife interface from the Canadian Institutes of Health Research. JM, ML, and AH were support by an Atlantic Canada Research in the Mathematical Sciences Collaborative Research Group award.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.01.21.26344526v2

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#Genomic characterisation of Crimean-Congo haemorrhagic fever virus (#CCHFV) in #Tajikistan identifies a novel reassortant virus

 

Abstract

Crimean-Congo haemorrhagic fever virus (CCHFV) is an important human tick-borne pathogen, able to cause severe haemorrhagic fever. CCHFV is endemic in Tajikistan, which records between 5–38 cases of CCHF a year from southern regions. Molecular surveillance of CCHFV is crucial to implement effective prevention and control strategies, understand viral evolution, study transmission dynamics, and develop effective diagnostics, therapeutics, and vaccines. While the presence of Asia-1 and Asia-2 genotypes has been previously reported, only two historical samples from Tajikistan have been fully sequenced. In this study we developed and applied a genotype IV-specific tiling PCR enrichment approach recovering 52 CCHFV genome segment sequences from clinical and Hyalomma tick samples collected between 2017–2023. Most sequences belonged to the Asia-2 genotype, but one virus exhibited an Asia-1 S segment combined with Asia-2 M and L segments, representing the first evidence of such viral reassortment event in Tajikistan.

Source: 

Link: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014204

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Deep #disadvantage in #mortality on the frontlines of the #COVID19 #pandemic

 

Abstract

This study presents new evidence on the temporal and spatial impact of the COVID-19 pandemic on mortality among especially vulnerable New Yorkers. Using burial records from Hart Island—the City’s potter’s field—we study the distribution of unclaimed deaths over time and across boroughs in 2020 compared to pre-pandemic levels. We show that the Hart Island deaths began deviating from their historical pattern in early March 2020 and peaked five weeks later at 22 deaths for every death in the same week in 2019 (20:1 adjusted). COVID-19 excess death rates were more than twice as high in the Bronx compared to other boroughs. Citywide, we estimate that 10% of all COVID-related excess deaths during the initial outbreak (March–August 2020) were unclaimed. These findings suggest the pandemic greatly magnified existing inequalities in the City and, more broadly, illustrate the especially devastating impact of COVID-19 on economically and socially vulnerable populations.

Source: 

Link: https://www.nature.com/articles/s41598-026-41219-6

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#Russia - #Influenza A #H5N1 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification [FINAL]

 

A wild Greylag Goose in Kalmyk Region.

Source: 

Link: https://wahis.woah.org/#/in-review/7410

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MF59-adjuvanted A/Astrakhan #influenza #vaccine induces cross-neutralizing #H5N1 #antibodies in #ferrets against circulating clade 2.3.4.4b viruses

 

Abstract

The continued global spread of highly pathogenic avian influenza A(H5N1) viruses, particularly clade 2.3.4.4b, has increased zoonotic spillover risk and underscored the urgency of pandemic preparedness. Human vaccination is a key strategy for mitigating severe disease and limiting transmission, especially in a setting where avian influenza viruses pose a zoonotic threat. We evaluated the immunogenicity of the MF59-adjuvanted, egg-derived A/Astrakhan/3212/2020 (H5N8) influenza vaccine (CBER-RG8A) in ferrets. To assess cross-reactivity, we generated pseudoviruses bearing HA and NA from circulating A(H5N1) 2.3.4.4b viruses, including North American (B1.13 and D1.1) and Eurasian (DI.2) genotypes. Immunogenicity was assessed using hemagglutination inhibition and microneutralization assays. A single dose elicited robust neutralizing titers (GMT ≥ 160), while a second dose increased titers by ≥3.3-fold. Cross-reactivity was maintained across most strains; however, responses were reduced up to 8-fold against strains harboring the A156T HA mutation, which may introduce a glycosylation site at antigenic site B. Limited responses were detected against divergent clades, with modest titers against clade 2.3.2.1a. These findings suggest broad protection induced by the CSL Seqirus pandemic vaccine against contemporary clade 2.3.4.4b A(H5N1) viruses and underscore the value of ferret immunogenicity data in informing strain selection and regulatory preparedness when human clinical data are unavailable.

Source: 

Link: https://www.nature.com/articles/s41541-026-01438-4

____

#Genomic analysis of high pathogenicity avian #influenza viruses from #Antarctica reveals multiple introductions from South #America

 

Abstract

The spread of high pathogenic avian influenza virus (HPAIV) H5N1 clade 2.3.4.4b into Antarctica poses a major threat to polar wildlife. We report the detection of H5N1 in carcasses of eight species during the 2023-2024 and 2024-2025 austral summers in the South Shetland Islands: Antarctic shag, Antarctic tern, kelp gull, pintado petrel, Antarctic petrel, skuas, Antarctic fur seal, and southern elephant seal. Whole-genome sequencing, mutational profiling, and phylogenetic reconstruction revealed that the viruses detected in these hosts descended from distinct introduction events. One group of strains including complete and partial viral genomes from a gull, skuas, fur seals, an Antarctic tern, and a southern elephant seal clustered with H5N1 strains previously detected in marine mammals in South America and formed a polyphyletic lineage consistent with at least two independent introductions into Antarctica. A second group of strains including complete and partial viral genomes from petrels, shags, and skuas clustered with H5N1 strains previously detected in seabirds and marine mammals in South Georgia and with a previously reported HPAIV detection from Torgersen Island, Antarctic Peninsula. These findings reveal extensive epidemiological connectivity between South America and Antarctica, with South Georgia serving as a “stepping stone” for virus spread in the region.

Source: 

Link: https://www.nature.com/articles/s41467-026-71544-3

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#USA, DOH and #CDC Investigate Invasive Group A Streptococcal (#IGAS) Infections in West #Hawaii (April 7 '26)

 

HONOLULU — The Hawaiʻi Department of Health (DOH) and Hawaiʻi District Health Office are working with the Centers for Disease Control and Prevention (CDC) to investigate a report of high rates of a serious bacterial infection called invasive Group A Streptococcus (iGAS) in West Hawaiʻi.

This investigation began after a local physician identified a higher-than-expected number of patients with iGAS over a period of several months and informed DOH. 

While DOH routinely monitors these infections, historically Hawaiʻi has had higher rates than the national average. 

This investigation will help determine whether the number of people with iGAS is increasing in West Hawaiʻi and better understand possible causes and risk factors of this infection.

The goals of this investigation are to confirm whether there is an increase in the number of people with iGAS in West Hawaiʻi, identify risk factors, evaluate disease reporting, and better understand how infections may be occurring in the community. 

Investigators will also compare local trends with other areas of the state and analyze laboratory data to identify any patterns among people with iGAS infections.

Group A Streptococcus bacteria are commonly found on the skin or in the throat and often do not cause an infection. 

When infections do occur, they are usually mild illnesses such as strep throat or skin infection. 

In rare cases, the bacteria can enter the bloodstream or other normally sterile parts of the body. This is called invasive Group A Streptococcus (iGAS), which can be serious. Early treatment with antibiotics is effective, especially when care is given promptly.

Some people are at higher risk for severe illness. These include older adults and individuals with chronic medical conditions such as heart, kidney, or respiratory disease and diabetes. People with weakened immune systems, those with open wounds or skin infections — and people experiencing homelessness or who inject drugs may also be at increased risk. 

In addition, recent viral infections such as influenza or chickenpox can increase one’s risk. The specific causes of the elevated iGAS illnesses in West Hawaiʻi are not yet known, so DOH and CDC are investigating.

DOH encourages the public to take simple steps to reduce the risk of infection. 

- Keep cuts and wounds clean and covered until they heal and 

- wash hands regularly with soap and water. 

- Seek medical care if a wound becomes red, swollen, warm, or produces pus. 

- Anyone experiencing fever, severe pain, or rapidly worsening symptoms should seek medical attention immediately.

DOH and CDC are working closely with healthcare providers and community partners and will continue to provide updates as more information becomes available. At this time, the overall risk to the public is low; however, awareness and early treatment are important to prevent severe iGAS illness.

Source: 

Link: https://health.hawaii.gov/news/newsroom/doh-and-cdc-investigate-invasive-group-a-streptococcal-igas-infections-in-west-hawai%ca%bbi/

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Q1020R in the #spike proteins of #MERS-CoV from Arabian #camels confers resistance against soluble #human #DPP4

 

ABSTRACT

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a pre-pandemic coronavirus that is transmitted from camels, the natural reservoir, to humans and can cause severe disease. MERS cases have been documented in Arabia but not Africa, although the virus is circulating in both Arabian and African camels. Further, evidence has been provided that viruses in African camels might have a reduced capacity to cause disease. However, the underlying determinants are incompletely understood. Here, employing pseudotyped particles as model systems for MERS-CoV entry into cells, we compared cell entry of viruses from African and Arabian camels and its inhibition. We show that viruses found in Arabian camels and recent human cases are less susceptible to inhibition by human soluble DPP4 (sDPP4) than viruses from African camels, although both enter human cells efficiently and are comparably sensitive to inhibition by interferon-induced transmembrane (IFITM) proteins and neutralizing antibodies. Furthermore, relative resistance to sDPP4 was linked to mutation Q1020R, present in the spike proteins of recent Arabian but not African viruses. Finally, indirect evidence was obtained that sDPP4 in human plasma can inhibit MERS-CoV cell entry. These results support the concept that soluble DPP4 might constitute a natural barrier against human infection that is more efficiently overcome by viruses currently circulating in Arabian camels than those in African camels.

Source: 

Link: https://journals.asm.org/doi/10.1128/jvi.00282-26

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#Online monitoring and early #detection of #influenza #outbreaks using exponentially weighted spatial lasso: a case study in #China during 2014–2020

 

Abstract

Influenza poses a persistent public health threat in China, with substantial impacts on health and the economy, especially during seasonal epidemics and emerging outbreaks. Seasonality, local clustering, and serial correlation inherent in influenza data introduce spatio-temporal complexities that traditional statistical process control (SPC) methods cannot adequately capture. This study introduces a novel nonparametric framework for real-time influenza monitoring across 300+ Chinese cities from 2014 to 2020. Reference periods are selected to establish baseline incidence patterns and fit a nonparametric spatio-temporal model to estimate mean and covariance structures. These estimates enable the setting of dynamic outbreak thresholds. Next, exponentially weighted spatial LASSO (EWSL) charting statistics are computed for the monitoring period, prioritizing recent observations and detecting subtle mean shifts in small, clustered regions - well-suited to influenza's progression dynamics. Charting statistics exceeding control limits trigger timely outbreak warnings. Results demonstrate that our method consistently outperforms alternative methods, and existing literature corroborates that its early signals correspond to actual outbreaks - including those for H7N9 strains, influenza A and B viruses, and the initial spread of COVID-19. These findings highlight the potential of our approach as an effective epidemic monitoring tool, addressing complex spatio-temporal patterns and supporting timely, data-driven public health interventions.

Source: 

Link: https://www.tandfonline.com/doi/full/10.1080/02664763.2025.2534915

____

The #Mengla virus (Filoviridae: #Dianlovirus)

 

Abstract

Introduction. 

Filoviruses associated with various species of pteropodid bats (Chiroptera: Pteropodidae) are traditionally regarded as potential causative agents of hemorrhagic fevers with epidemic potential. The known agents of Ebola and Marburg fevers periodically cause sporadic cases and epidemic outbreaks in African countries. Recent discoveries of novel filoviruses associated with pteropodid bats in South and Southeast Asia highlight the necessity to investigate their genetic diversity and pathogenic potential.

The aim of this study was to investigate the genetic diversity and pathogenic potential of new filoviruses associated with bats, based on literature data.

Materials and methods. 

This review is based on an analysis of published literature describing the detection and molecular characterization of novel filoviruses identified in different geographic regions, with a particular focus on filoviruses associated with pteropodid bats in South and Southeast Asia. The analyzed studies include data on virus discovery, genome organization, taxonomic classification, and experimental assessment of biological properties. 

Results. 

Several novel filoviruses have been identified by metagenomic RNA sequencing of tissues from pteropodid bats captured in South and Southeast Asia. Among them, Mengla virus was detected in tissues of pteropodid bats (Rousettus spp.) captured in Mengla County, Yunnan Province, People’s Republic of China. Owing to a high level of genetic divergence, Mengla virus was classified as a representative of a new genus, Dianlovirus, within the family Filoviridae. Although a live isolate of Mengla virus has not yet been obtained, experimental studies using chimeric minigenome systems and virus-like particles suggest that the virus may exhibit tropism for tissues of various vertebrate hosts, including humans.

Conclusion. 

Members of the family Filoviridae are widely distributed within the geographic range of their natural reservoir–pteropodid bats–across South and Southeast Asia, including viruses evolutionarily related to Ebola and Marburg viruses. Although human disease caused by Mengla virus and other recently discovered filoviruses has not been documented, the potential for cross-species transmission and the emergence of novel filovirus infections in endemic regions remains.

Source: 

Link: https://virusjour.crie.ru/jour/article/view/16805

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#Bovine #H5N1 #influenza viruses have adapted to more efficiently use #receptors abundant in #cattle

 

Abstract

Sustained mammal-to-mammal transmission of high pathogenicity H5N1avian influenza viruses is reshaping the host range of these pathogens. One of the longest-running mammalian transmission chains involves the B3.13 genotype circulating in U.S. dairy cattle which was detected early in 2024. Genomic analysis revealed selection and rapid fixation of haemagglutinin mutations D104G and V147M. We demonstate, via glycomic profiling, that bovine tissues, including the mammary gland, are enriched in N- and O-linked glycans capped with N-glycolylneuraminic acid (NeuGc), a sialic acid absent in humans and birds, which instead express only N-acetylneuraminic acid (NeuAc). Early cattle H5 viruses poorly recognized NeuGc, but D104G and V147M enabled efficient engagement of both NeuAc- and NeuGc-containing receptors. These mutations enhanced replication in bovine mammary tissue without major attenuation of replication in human lung and primary nasal epithelial cells. NeuGc-driven receptor adaptation therefore promotes viral fitness in cattle while potentially limiting immediate zoonotic risk. Deep mutational scanning further identifies alternative haemagglutinin substitutions that confer NeuGc usage and represent surveillance markers for emerging cattle H5 lineages.

Competing Interest Statement

JDB and BD are inventors on Fred Hutch licensed patents related to deep mutational scanning. JDB consults for Pfizer, GSK, Apriori Bio, and Invivyd.

Funder Information Declared

Medical Research Council, MR/Y03368X/1, MR/R010757/1, MC_UU_0034/2, MC_UU_0034/3

BBSRC, BB/Y007298/1, BB/X006123/1, BB/X006166/1, BBS/E/PI/230002A, BBS/E/PI/230002B

BBSRC, BBS/E/PI/23NB0004, BBS/E/PI/23NB0003, UKRI2253, BB/V004697/1

Defra, SE2227

Royal Society, https://ror.org/03wnrjx87, RGS\R2\242118

Houghton Trust, HT/SPRG/23/04

Flanders, G005323N, G051322N, G010326N

CEIRR, 75N93021C00045

The Rockefeller Foundation, PC-2022-POP-005

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.04.02.715584v1

____

Next-generation #inhibitors of #SARS-CoV-2 #Mpro overcome the deficiencies of #Paxlovid

 

Abstract

It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (Mpro) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design iso-quinoline-containing inhibitors with high affinity for Mpro and its nirmatrelvir-resistant E166X mutants. Further optimization at P4 cultivates distinctive peptidomimetic inhibitors with drastically improved pharmacokinetic properties and significantly enhanced antiviral efficacy independent of ritonavir. Two such inhibitors, FD3-32 and FD3-36, also potent against SARS-CoV-1 and MERS-CoV Mpro, are more effective as a monotherapy regimen than Paxlovid in reducing viral loads in vivo and protecting infected male mice from acute lung injury. Here, we report the discovery of next-generation SARS-CoV-2 Mpro inhibitors that overcome the deficiencies of Paxlovid, promising efficacious antivirals critical for mitigating the current and future pandemics of coronaviruses.

Source: 

Link: https://www.nature.com/articles/s41467-026-71436-6

____