Biology subjects

Herder, V.

Publications and source records attributed to Herder, V..

11 recordsLinked to original sources

bioRxiv2026

Andes virus from the MV Hondius outbreak is highly pathogenic in hamsters and airborne shed

In May 2026, an outbreak of hantavirus pulmonary syndrome (HPS) caused by Andes virus (ANDV) was detected aboard the cruise ship MV Hondius, sparking public health measures in multiple countries. ANDV infections in humans are mostly sporadic, most often linked to exposure to infected rodents in South America, although small clusters of human cases, like the 2026 outbreak on the MV Hondius occur as well. It is not known whether virological factors may contribute to this distinct epidemiology, and no phenotypic characterisation of the newly emerged ANDV (ANDV2026) has been carried out to date. Here, using an ANDV isolate from a presymptomatic patient from the MV Hondius, we studied pathogenesis, identified sites of viral replication, characterized innate and adaptive immune responses, and quantified shedding in golden Syrian hamsters. ANDV2026 proved to be highly pathogenic in hamsters, causing severe pulmonary disease reminiscent of HPS. ANDV2026 triggered a delayed type-I IFN response and inflammatory response in the lungs consistent with the key pathological features of HPS, and we detected viral replication in both respiratory and extra-respiratory tissues, including the brain. Infected animals mounted neutralising antibodies and T cell responses, the latter directed predominantly against the L and N proteins. Importantly, ANDV2026-infected animals shed virus through multiple routes, and we detected infectious virus in air samplers connected to cages housing ANDV2026-infected hamsters. In contrast, control hamsters infected with a rodent-derived ANDV isolate (ANDV9717869) shed little virus and air samples were consistently negative. These findings consolidate established features of ANDV pathogenesis, while revealing properties not previously described. Phenotypic characterisation of patient-derived ANDV isolates in animal models can strengthen outbreak preparedness, identify markers of disease severity, and support the development of medical countermeasures.

microbiology↗

bioRxiv2026

Functional divergence of the NSs protein defines interferon antagonism and viral fitness across Bhanja virus lineages.

Bhanja virus (BHAV) is a tick-borne bandavirus (Family Phenuiviridae) with a broad geographic distribution and documented neuroinvasive capacity, yet its molecular biology remains poorly understood. Within the genus Bandavirus, the non-structural protein NSs functions as the primary antagonist of innate immune responses, although mechanistic details for BHAV remain unknown. We established a reverse genetics platform for BHAV by combining virion RNA sequencing with terminal untranslated region mapping, enabling generation of recombinant viruses and systematic investigation of viral determinants. Using this system, we characterized recombinant BHAV replication in mammalian and arthropod cell lines and demonstrated that interferon competence is a critical determinant of viral replication in mammalian cells. Notably, we observed substantial amino acid divergence within the NSs protein across geographically distinct BHAV isolates, despite higher conservation of other viral proteins. To investigate the functional significance of this variation, we generated recombinant viruses expressing heterologous NSs proteins from African and European isolates. Viruses expressing NSs from ibAr2709 or R1819 isolates exhibited enhanced capacity to suppress interferon-beta induction compared to the prototype IG690 strain, correlating with increased viral protein accumulation in interferon-competent cells. Mechanistic studies revealed that BHAV NSs proteins inhibit interferon induction upstream of IRF3, with ibAr2709 and R1819 NSs showing selective inhibition of TBK1 phosphorylation. However, unlike highly pathogenic bandaviruses such as severe fever with thrombocytopenia syndrome virus (SFTSV), BHAV NSs proteins exhibit comparatively weak antagonism of downstream interferon signalling. In vivo studies using interferon alpha/beta receptor-deficient mice demonstrated that NSs sequence variation influences viral replication in splenic tissue without substantially altering disease phenotype. Together, these findings establish BHAV reverse genetics tools for future investigation and reveal how naturally-occurring NSs divergence modulates innate immune antagonism and viral fitness while maintaining an overall attenuated disease phenotype. Author SummaryBhanja virus is a tick-borne virus distributed across Asia, Africa, and Europe that causes neurological disease, yet little is known about how it replicates or evades immunity. We developed the laboratory tools to create recombinant Bhanja viruses and investigate viral functions. We discovered that the virus replicates efficiently in cells lacking interferon responses but is severely restricted in normal immune-competent cells, revealing interferon as a major barrier to viral growth. We observed that Bhanja virus isolates from distinct geographic regions have different versions of a viral protein called NSs that suppresses interferon responses. Isolates from Africa and Europe were better at blocking interferon production than the original Asian strain, correlating with increased viral growth in immune-competent cells. However, unlike related viruses that cause more serious disease such as SFTSV, BHAV NSs proteins only partially antagonise interferon. While this weak antagonism likely contributes to the attenuated phenotype observed in our experimental systems, the natural pathogenesis of Bhanja virus in human hosts and tick vectors remains to be determined. This study provides tools for examining Bhanja virus biology and demonstrates that small viral differences in viral sequence can meaningfully influence evasion of innate immunity and viral fitness without triggering severe disease.

microbiology↗

bioRxiv2024

POLYGENIC DETERMINANTS OF H5N1 ADAPTATION TO BOVINE CELLS

Avian influenza H5N1 clade 2.3.4.4b viruses caused a global panzootic and, unexpectedly, widespread outbreaks in dairy cattle, therefore representing a pandemic threat. To inform effective control strategies, it is critical to determine whether the potential to adapt to bovine cells is a generalised feature of H5N1 viruses, or is specific to clade 2.3.4.4b, or even more restricted to specific genotypes within this clade (e.g., B3.13 and D1.1). Using a large panel of H5N1 viruses representing >60 years of their natural history and other IAV for comparative purposes, we demonstrate that virus adaptation to bovine cells is: (i) highly variable across 2.3.4.4b genotypes, (ii) limited in viruses predating the global expansion of this clade, (iii) determined by the viral internal gene cassette, and (iv) not restricted to udder epithelial cells. Mutations in the PB2 polymerase subunit, particularly M631L, emerge as key determinants of adaptation, although their phenotypic effects are context dependent and have limited enhanced viral polymerase activity in human cells. Bovine B3.13 and some avian genotypes also exhibit enhanced modulation of bovine interferon-induced antiviral responses, determined by at least the viral PB2, nucleoprotein, and the non-structural protein NS1. Our results highlight the polygenic nature of IAV host range and reveal that the potential to cross the species barrier varies during the evolutionary trajectory of H5N1, with some avian viruses more predisposed to spillover than others.

microbiology↗

bioRxiv2024

Lung structural cell dynamics are altered by influenza virus infection experience leading to rapid immune protection following viral re-challenge

Lung structural cells, including epithelial cells and fibroblasts, form barriers against pathogens and trigger immune responses following infections such as influenza A virus. This response leads to the recruitment of innate and adaptive immune cells required for viral clearance. Some of these recruited cells remain within the lung following infection and contribute to enhanced viral control following subsequent infections. There is growing evidence that structural cells can also display long-term changes following infection or insults. Here we investigate long-term changes to mouse lung epithelial cells, fibroblasts, and endothelial cells following influenza virus infection and find that all three cell types maintain an imprint of the infection, particularly in genes associated with communication with T cells. Lung epithelial cells from IAV-infected mice display functional changes by more rapidly controlling influenza virus than cells from naive animals. This rapid anti-viral response and increased expression of molecules required to communicate with T cells demonstrates sustained and enhanced functions following infection. These data suggest lung structural cells could be effective targets for vaccines to boost durable protective immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/604410v5_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@2774e0org.highwire.dtl.DTLVardef@6a39e6org.highwire.dtl.DTLVardef@1ff5863org.highwire.dtl.DTLVardef@103df12_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILung epithelial cells, fibroblasts, and blood endothelial cells maintain an inflammatory imprint of influenza A virus (IAV) infection for at least 40 days post-infection. C_LIO_LIIn vivo re-infection leads to a more spatially restricted anti-viral response compared to primary IAV-infected animals. C_LIO_LIT cells are not required for enhanced viral control early after re-infection in vivo C_LIO_LIEx vivo lung epithelial cells from IAV-infected mice more rapidly control IAV than cells from naive animals in the absence of immune cells. C_LI

immunology↗

bioRxiv2024

A Machine Learning Framework to Identify the Correlates of Disease Severity in Acute Arbovirus Infection

Most viral diseases display a variable clinical outcome due to differences in virus strain virulence and/or individual host susceptibility to infection. Understanding the biological mechanisms differentiating a viral infection displaying severe clinical manifestations from its milder forms can provide the intellectual framework toward therapies and early prognostic markers. This is especially true in arbovirus infections, where most clinical cases are present as mild febrile illness. Here, we used a naturally occurring vector-borne viral disease of ruminants, bluetongue, as an experimental system to uncover the fundamental mechanisms of virus-host interactions resulting in distinct clinical outcomes. As with most viral diseases, clinical symptoms in bluetongue can vary dramatically. We reproduced experimentally distinct clinical forms of bluetongue infection in sheep using three bluetongue virus (BTV) strains (BTV-1IT2006, BTV-1IT2013 and BTV-8FRA2017). Infected animals displayed clinical signs varying from clinically unapparent, to mild and severe disease. We collected and integrated clinical, haematological, virological, and histopathological data resulting in the analyses of 332 individual parameters from each infected and uninfected control animal. We subsequently used machine learning to identify the key viral and host processes associated with disease pathogenesis. We identified five different fundamental processes affecting the severity of bluetongue: (i) virus load and replication in target organs, (ii) modulation of the host type-I IFN response, (iii) pro-inflammatory responses, (iv) vascular damage, and (v) immunosuppression. Overall, our study using an agnostic machine learning approach, can be used to prioritise the different pathogenetic mechanisms affecting the disease outcome of an arbovirus infection.

microbiology↗

bioRxiv2023

Spatially resolved single-cell atlas of the lung in fatal Covid19 in an African population reveals a distinct cellular signature and an interferon gamma dominated response

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTD) including Covid19 but there is almost no data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. We used histology and high-dimensional imaging to characterise fatal lung disease in Malawian adults with (n=9) and without (n=7) Covid19, and generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved Covid19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in the Malawi cohort, by response to interferon-gamma (IFN-{gamma}) in lung-resident alveolar macrophages, in USA, European and Asian cohorts by type I/III interferon responses, particularly in blood-derived monocytes. HIV status had minimal impact on histology or immunopathology. Our study provides data resources and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.

immunology↗

bioRxiv2023

The SARS-CoV-2 Omicron sub-variant BA.2.86 is attenuated in hamsters

SARS-CoV-2 variants have emerged throughout the COVID-19 pandemic. There is a need to risk-assess newly emerged variants in near "real-time" to estimate their potential threat to public health. The recently emerged Omicron sub-variant BA.2.86 raised concerns as it carries a high number of mutations compared to its predecessors. Here, we assessed the virulence of BA.2.86 in hamsters. We compared the pathogenesis of BA.2.86 and BA.2.75, as the latter is one of the most virulent Omicron sub-variants in this animal model. Using digital pathology pipelines, we quantified the extent of pulmonary lesions measuring T cell and macrophage infiltrates, in addition to alveolar epithelial hyperplasia. We also assessed body weight loss, clinical symptoms, virus load in oropharyngeal swabs, and virus replication in the respiratory tract. Our data show that BA.2.86 displays an attenuated phenotype in hamsters, suggesting that it poses no greater risk to public health than its parental Omicron sub-variants. Article summary lineThe newly emerged Omicron sub-variant BA.2.86 is attenuated in hamsters.

microbiology↗

bioRxiv2023

Phenotyping the virulence of SARS-CoV-2 variants in hamsters by digital pathology and machine learning

SARS-CoV-2 has continued to evolve throughout the COVID-19 pandemic, giving rise to multiple variants of concern (VOCs) with different biological properties. As the pandemic progresses, it will be essential to test in near real time the potential of any new emerging variant to cause severe disease. BA.1 (Omicron) was shown to be attenuated compared to the previous VOCs like Delta, but it is possible that newly emerging variants may regain a virulent phenotype. Hamsters have been proven to be an exceedingly good model for SARS-CoV-2 pathogenesis. Here, we aimed to develop robust quantitative pipelines to assess the virulence of SARS-CoV-2 variants in hamsters. We used various approaches including RNAseq, RNA in situ hybridization, immunohistochemistry, and digital pathology, including software assisted whole section imaging and downstream automatic analyses enhanced by machine learning, to develop methods to assess and quantify virus-induced pulmonary lesions in an unbiased manner. Initially, we used Delta and Omicron to develop our experimental pipelines. We then assessed the virulence of recent Omicron sub-lineages including BA.5, XBB, BQ.1.18, BA.2 and BA.2.75. We show that in experimentally infected hamsters, accurate quantification of alveolar epithelial hyperplasia and macrophage infiltrates represent robust markers for assessing the extent of virus-induced pulmonary pathology, and hence virus virulence. In addition, using these pipelines, we could reveal how some Omicron sub-lineages (e.g., BA.2.75) have regained virulence compared to the original BA.1. Finally, to maximise the utility of the digital pathology pipelines reported in our study, we developed an online repository containing representative whole organ histopathology sections that can be visualised at variable magnifications (https://covid-atlas.cvr.gla.ac.uk). Overall, this pipeline can provide unbiased and invaluable data for rapidly assessing newly emerging variants and their potential to cause severe disease.

microbiology↗

bioRxiv2022

Zoonotic avian influenza viruses evade human BTN3A3 restriction

Cross-species transmission of avian influenza A viruses (IAVs) into humans could represent the first step of a future pandemic1. Multiple factors limiting the spillover and adaptation of avian IAVs in humans have been identified, but they are not sufficient to explain which virus lineages are more likely to cross the species barrier1,2. Here, we identified human BTN3A33 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human IAVs. We determined that BTN3A3 is constitutively expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts at the early stages of virus replication by inhibiting avian IAV vRNA transcription. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F, or rarely 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, several serotypes of avian IAVs that spilled over into humans in recent decades evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure4. Importantly, we identified more than 150 avian IAV lineages with a BTN3A3-resistant genotype. In conclusion, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

microbiology↗

bioRxiv2020

Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of the induction of IFN-mediated innate immune defences

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41{degrees}C. Fever is an evolutionarily conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general cellular transcription or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37{degrees}C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.

microbiology↗

bioRxiv2020

Respiratory disease in cats associated with human-to-cat transmission of SARS-CoV-2 in the UK

Two cats from different COVID-19-infected households in the UK were found to be infected with SARS-CoV-2 from humans, demonstrated by immunofluorescence, in situ hybridisation, reverse transcriptase quantitative PCR and viral genome sequencing. Lung tissue collected post-mortem from cat 1 displayed pathological and histological findings consistent with viral pneumonia and tested positive for SARS-CoV-2 antigens and RNA. SARS-CoV-2 RNA was detected in an oropharyngeal swab collected from cat 2 that presented with rhinitis and conjunctivitis. High throughput sequencing of the virus from cat 2 revealed that the feline viral genome contained five single nucleotide polymorphisms (SNPs) compared to the nearest UK human SARS-CoV-2 sequence. An analysis of cat 2s viral genome together with nine other feline-derived SARS-CoV-2 sequences from around the world revealed no shared catspecific mutations. These findings indicate that human-to-cat transmission of SARS-CoV-2 occurred during the COVID-19 pandemic in the UK, with the infected cats developing mild or severe respiratory disease. Given the versatility of the new coronavirus, it will be important to monitor for human-to-cat, cat-to-cat and cat-to-human transmission.

microbiology↗