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African Swine Fever (ASF) is a viral disease that affects animals of the Suidae family, and soft ticks from the genus Ornithodoros can also be infected by the ASF virus (ASFV). The disease was first described in Africa at the beginning of the twentieth century as an acute disease characterized by high mortality and fatal hemorrhages. ASF has caused outbreaks in numerous countries and it continues to be devastating nowadays for the porcine sector in those countries affected, and a massive threat for those free of the disease. ASF can follow clinical courses from peracute to chronic in domestic pigs ( Sus scrofa ) depending on a variety of factors, including the immune status of the animals and the virulence of the ASFV strain. The key features of the pathogenesis of the disease in domestic swine are a) a severe lymphoid depletion including lymphopenia and a state of immunodeficiency, and b) hemorrhages. However, African wild swine like bushpigs ( Potamochoerus larvatus ), red river hogs ( Potamochoerus porcus ), and warthogs ( Phacochoerus africanus ) can be infected by ASFV showing no clinical signs of disease and acting as natural reservoir hosts. In this article we review the key features of the gross and microscopic pathology together with a description of the pathogenesis of ASFV infection in domestic pigs following the different clinical courses. The pathogenesis of ASF in wild and domestic swine is also described, what can provide important information for the design of control strategies, such as vaccines.

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection. Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

Vaccine-associated enhanced disease (VAED) is a difficult phenomenon to define and can be confused with vaccine failure. Using studies on respiratory syncytial virus (RSV) vaccination and dengue virus infection, we highlight known and theoretical mechanisms of VAED, including antibody-dependent enhancement (ADE), antibody-enhanced disease (AED) and Th2-mediated pathology. We also critically review the literature surrounding this phenomenon in pathogenic human coronaviruses, including MERS-CoV, SARS-CoV-1 and SARS-CoV-2. Poor quality histopathological data and a lack of consistency in defining severe pathology and VAED in preclinical studies of MERS-CoV and SARS-CoV-1 vaccines in particular make it difficult to interrogate potential cases of VAED. Fortuitously, there have been only few reports of mild VAED in SARS-CoV-2 vaccination in preclinical models and no observations in their clinical use. We describe the problem areas and discuss methods to improve the characterisation of VAED in the future.

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M . tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process.

Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.