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Impaired type I interferons (IFNs) production or signaling have been associated with severe COVID-19, further promoting the evaluation of recombinant type I IFNs as therapeutics against SARS-CoV-2 infection. In the Syrian hamster model, we show that intranasal administration of IFN-α starting one day pre-infection or one day post-infection limited weight loss and decreased viral lung titers. By contrast, intranasal administration of IFN-α starting at the onset of symptoms three days post-infection had no impact on the clinical course of SARS-CoV-2 infection. Our results provide evidence that early type I IFN treatment is beneficial, while late interventions are ineffective, although not associated with signs of enhanced disease.

European badgers ( Meles meles ) are reservoirs for animal tuberculosis (TB) in some European countries, complicating TB control in cattle. Badger vaccination and a deeper understanding of the subsequent protection mechanisms are necessary for effective TB control. In a previous study, two of eight badgers immunized with the heat-inactivated Mycobacterium bovis (HIMB) vaccine exhibited an unusual immune response (divergent), developing exacerbated lesions. The present study aimed to describe the local immune response in divergent badgers (those with severe disease progression), with respect to that observed in standard (where the vaccine showed efficacy) and control badgers. Immunohistochemistry was performed to evaluate immune cells (macrophages, T and B lymphocytes, plasma cells), and proteins (TGF-β, IL-10, Fox-P3) within TB granulomas in the lung and bronchial lymph node (LN), after TB challenge. Lung lesion volume, bacterial load and immunological response were also evaluated. The divergent immune response was characterized by elevated IL-10 and Fox-P3, few macrophages and high B lymphocytes (mainly in lungs), suggesting a Th1/Th2 imbalance with reduced Th1 cellular immunity leading to severe TB. In contrast, vaccinated badgers with a standard immune response showed a balanced response, with significantly lower bacterial loads (85.5% LN and 99.9% lung) than control group. This study provides new insights into the immune mechanisms in HIMB-vaccinated badgers, to improve TB control strategies.

Although control measures to tackle bovine tuberculosis (bTB) in cattle have been successful in many parts of Europe, this disease has not been eradicated in areas where Mycobacterium bovis circulates in multi-host systems. Here we analyzed the resurgence of 11 M . bovis genotypes (defined based on spoligotyping and MIRU-VNTR) detected in 141 farms between 2007 and 2019, in an area of Southwestern France where wildlife infection was also detected from 2012 in 65 badgers. We used a spatially-explicit model to reconstruct the simultaneous diffusion of the 11 genotypes in cattle farms and badger populations. Effective reproduction number R was estimated to be 1.34 in 2007–2011 indicating a self-sustained M. bovis transmission by a maintenance community although within-species R s were both < 1, indicating that neither cattle nor badger populations acted as separate reservoir hosts. From 2012, control measures were implemented, and we observed a decrease of R below 1. Spatial contrasts of the basic reproduction ratio suggested that local field conditions may favor (or penalize) local spread of bTB upon introduction into a new farm. Calculation of generation time distributions showed that the spread of M. bovis has been more rapid from cattle farms (0.5–0.7 year) than from badger groups (1.3–2.4 years). Although eradication of bTB appears possible in the study area (since R  < 1), the model suggests it is a long-term prospect, because of the prolonged persistence of infection in badger groups (2.9–5.7 years). Supplementary tools and efforts to better control bTB infection in badgers (including vaccination for instance) appear necessary.

In the UK and Ireland, the European badger is the main wildlife reservoir for Mycobacterium bovis ( M. bovis ), the causal agent of bovine tuberculosis (bTB). The ability to diagnose M. bovis infection in badgers is critical to understanding the epidemiology of the infection in this species and for informing control strategies. In this study we determined the sensitivity and specificity of a lateral flow assay (Dual Path Platform (DPP) VetTB assay) to identify infected live badgers using two blood sample types: fresh whole blood (suitable for immediate testing in the field without further processing) and serum (which can be stored frozen for batch testing). Two measures were used for the interpretation of test results: qualitative visual interpretation and quantitative measurement using an optical reader for a range of cut-offs. To overcome the absence of a gold standard comparison test, we used Bayesian latent class methods, applied to results from different sub-populations. Regardless of sample type, the highest sensitivity and specificity of the DPP under qualitative interpretation were obtained using Band 1 (MPB83 antigen) results. Median estimates (95% CIs) of sensitivity and specificity were 79.9% (66.1–91.4%) and 93.3% (90.7–95.7%), respectively for whole blood and 53.0% (43.0–63.7%) and 96.3% (94.7–97.7%), respectively for serum. Band 2 (ESAT-6/CFP-10), when interpreted on its own, had median sensitivity estimates of 21.4% (12.0–32.4%) for whole blood, and 6.8% (3.3–11.9%) for serum. When using Band 1 results from the optical reader, the estimate of sensitivity for whole blood was higher than for serum across the whole range of cut-offs, though with a concomitant reduction in specificity. This study provides reliable estimates of test characteristics for the DPP when applied to whole blood and serum. The results support the use of the DPP test in a field application to identify infected live badgers using whole blood samples.

Background Bovine tuberculosis (bTB) caused by Mycobacterium bovis is the most serious endemic disease affecting livestock in the UK. The European badger ( Meles meles ) is the most important wildlife reservoir of bTB transmission to cattle, making eradication particularly difficult. In this respect, oral vaccination with the attenuated M. bovis vaccine Bacillus Calmette-Guerin (BCG) has been suggested as a wide-scale intervention to reduce bTB infection in badgers. However, experimental studies show variable protection. Among the possibilities for this variation is that the resident gut bacteria may influence the success of oral vaccination in badgers; either through competitive exclusion and/or inhibition, or via effects on the host immune system. In order to explore this possibility, we have tested whether typical gut commensals such as Lactic Acid Bacteria (LAB) have the capacity to impact on the viability and survival rate of BCG and to modulate the immune response to BCG using an in vitro model. Results Twelve LAB isolated from badger faeces displayed inhibitory activity to BCG that was species-dependent. Weissella had a bacteriostatic effect, whereas isolates of enterococci, lactobacilli and pediococci had a more bactericidal activity. Furthermore, BCG-induced activation of the pro-inflammatory transcription factor NF-κB in human THP-1 macrophages was modulated by LAB in a strain-dependent manner. Most pediococci enhanced NF-κB activation but one strain had the opposite effect. Interestingly, isolates of enterococci, lactobacilli and weissella had different effects as immunomodulators of BCG-induced macrophage responses as some had no significant influence on NF-κB activation, but others increased it significantly. Conclusions Our in vitro results show that LAB isolated from badgers exhibit significant inhibitory activity against BCG and influence the immune activation mediated by BCG in a human macrophage assay. These findings suggest that gut commensal bacteria could play a role in influencing the outcome of oral BCG vaccination. Inactivated cells of LAB, or LAB that are bacteriostatic but have a synergistic immunostimulatory effect with BCG, could be potential adjuvants to be used for oral vaccination in badgers. Further work is needed to take into account the complex nature of the gut microbiome, specific immunity of the badger and the in vivo context.

In developing an oral bait BCG vaccine against tuberculosis in badgers we wanted to understand the conditions of the gastrointestinal tract and their impact on vaccine viability. Conditions mimicking stomach and small-intestine caused substantial reduction in BCG viability. We performed in vivo experiments using a telemetric pH monitoring system and used the data to parameterise a dynamic in vitro system (TIM-1) of the stomach and small intestine. Some BCG died in the stomach compartment and through the duodenum and jejunum compartments. BCG survival in the stomach was greatest when bait was absent but by the time BCG reached the jejunum, BCG viability was not significantly affected by the presence of bait. Our data suggest that from a starting quantity of 2.85 ± 0.45 x 108 colony-forming units of BCG around 2 log10 may be killed before delivery to the intestinal lymphoid tissue. There are economic arguments for reducing the dose of BCG to vaccinate badgers orally. Our findings imply this could be achieved if we can protect BCG from the harsh environment of the stomach and duodenum. TIM-1 is a valuable, non-animal model with which to evaluate and optimise formulations to maximise BCG survival in the gastrointestinal tract.

The introduction of European red foxes in Australia in the late mid-nineteenth century has resulted in the spread of this invasive species across the continent. The morphological and functional divergence of this relatively recently introduced population has not been explored to date, yet it may provide unique insights into adaptability of this widespread carnivore to very different environments. Here we used three-dimensional geometric morphometric approaches and dissections to explore differences in mandible form and function between two populations: one from France and the other from Western Australia. Bite force was predicted for Australian foxes using partial least squares (PLS) regression models based on the observed covariation between estimated bite force (from muscle dissections) and mandible form in French foxes. Muscle contributions were estimated based on Euclidean distances between landmarks that provide insights into muscle lever arms. Despite the greater sample size, Australian foxes show reduced variability in mandible shape compared with French foxes. The mandibles of adult French foxes tend to be slightly smaller and they also strongly differ in shape from the Australian foxes in functionally important areas of the mandible such as muscle insertion areas. This is accompanied by significant differences in the predicted bite force, even relative to size, and muscle contribution: the bite of Australian foxes is weaker and they show greater use of their temporalis muscle compared to French foxes. The reduced variability suggests a founder effect or stabilizing selection on a specific morphology, which was supported by statistical tests. The corresponding anatomical traits suggest different functional demands likely due to differences in diet or competition. Future studies investigating the drivers of variation in mandible shape in native and invasive populations, including data from the original source of the Australian introductions, are needed to better understand the observed differences.

Background Oral vaccination with Mycobacterium bovis Bacille of Calmette and Guerin (BCG) has provided protection against M. bovis to badgers both experimentally and in the field. There is also evidence suggesting that the persistence of live BCG within the host is important for maintaining protection against TB. Here we investigated the capacity of badger inductive mucosal sites to absorb and maintain live BCG. The targeted mucosae were the oropharyngeal cavity (tonsils and sublingual area) and the small intestine (ileum). Results We showed that significant quantities of live BCG persisted within badger in tissues of vaccinated badgers for at least 8 weeks following oral vaccination with only very mild pathological features and induced the circulation of IFNγ-producing mononuclear cells. The uptake of live BCG by tonsils and drainage to retro-pharyngeal lymph nodes was repeatable in the animal group vaccinated by oropharyngeal instillation whereas those vaccinated directly in the ileum displayed a lower frequency of BCG detection in the enteric wall or draining mesenteric lymph nodes. No faecal excretion of live BCG was observed, including when BCG was delivered directly in the ileum. Conclusions The apparent local loss of BCG viability suggests an unfavorable gastro-enteric environment for BCG in badgers, which should be taken in consideration when developing an oral vaccine for use in this species.

Bovine tuberculosis (TB) in Great Britain adversely affects animal health and welfare and is a cause of considerable economic loss. The situation is exacerbated by European badgers (Meles meles) acting as a wildlife source of recurrent Mycobacterium bovis infection to cattle. Vaccination of badgers against TB is a possible means to reduce and control bovine TB. The delivery of vaccine in oral bait holds the best prospect for vaccinating badgers over a wide geographical area. There are practical limitations over the volume and concentration of Bacillus of Calmette and Guérin (BCG) that can be prepared for inclusion in bait. The production of BCG in a bioreactor may overcome these issues. We evaluated the efficacy of oral, bioreactor-grown BCG against experimental TB in badgers. We demonstrated repeatable protection through the direct administration of at least 2.0 × 108 colony forming units of BCG to the oral cavity, whereas vaccination via voluntary consumption of bait containing the same preparation of BCG did not result in demonstrable protection at the group-level, although a minority of badgers consuming bait showed immunological responses and protection after challenge equivalent to badgers receiving oral vaccine by direct administration. The need to deliver oral BCG in the context of a palatable and environmentally robust bait appears to introduce such variation in BCG delivery to sites of immune induction in the badger as to render experimental studies variable and inconsistent.

European badgers are a wildlife reservoir of bovine tuberculosis in parts of Great Britain. Accurate diagnosis of tuberculosis in badgers is important for the development of strategies for the control of the disease. Sensitive serological tests for badger TB are needed for reasons such as cost and simplicity. Assay of mucosal IgA could be useful for diagnosing respiratory pathogens such as Mycobacterium bovis and for monitoring the response to mucosal vaccination. To develop an IgA assay, we purified secretory IgA from badger bile, identifying secretory component (SC), heavy chain (HC) and light chain (LC), at 66, 46 and 27 Kda, respectively, on the basis of size comparison with other species. Monoclonal antibodies (mAbs) were generated to purified IgA. We selected two for ELISA development. The detection limit of the IgA-specific mAbs was found to be approximately 20 ng/mL when titrated against purified badger bile. One monoclonal antibody specific for badger IgA was used to detect IgA in serum and tracheal aspirate with specificity to an immunodominant antigen of M. bovis. An M. bovis infection dose-dependent IgA response was observed in experimentally infected badgers. IgA was also detected by immunohistochemistry in the lungs of bTB-infected badgers. With further characterisation, these represent new reagents for the study of the IgA response in badgers.