Herder, Vanessa, Caporale, Marco, MacLean, Oscar A., Pintus, Davide, Huang, Xinyi, Nomikou, Kyriaki, Palmalux, Natasha, Nichols, Jenna, Scivoli, Rosario, Boutell, Chris, Taggart, Aislynn, Allan, Jay, Malik, Haris, Ilia, Georgios, Gu, Quan, Ronchi, Gaetano Federico, Furnon, Wilhelm, Zientara, Stephan, Bréard, Emmanuel, and Antonucci, Daniela
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 select the key viral and host processes associated with disease pathogenesis. We identified and experimentally validated 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, we showed that an agnostic machine learning approach can be used to prioritise the different pathogenetic mechanisms affecting the disease outcome of an arbovirus infection. Author summary: In this study we comprehensively investigated the pathogenetic mechanisms underlying the clinical outcomes of bluetongue, a viral disease of ruminants used as an experimental model for vector-borne infections. Arboviruses are the cause of major global health and economic burden. Each arbovirus infection induces its own distinctive clinical features. However, many of these vector-borne diseases are typically characterised by general symptoms such as mild febrile flu-like illness and rash, with only a minor proportion of cases exhibiting severe clinical manifestations. It is therefore critical to understand those biological processes distinguishing arbovirus infections resulting in mild or severe clinical diseases. Here, we used in vivo experiments in sheep, artificial intelligence and in vitro experiments to identify the key processes affecting the severity of bluetongue. We established that the clinical outcome of bluetongue in the infected animals is influenced by (i) levels of virus replication in target organs, (ii) modulation of the host innate immunity and (iii) pro-inflammatory responses, (iv) damage to the blood vessels, and (v) immunosuppression. This study provides an intellectual framework on how to prioritise experimentally the variety of biological processes determining the clinical outcome to a virus infection. [ABSTRACT FROM AUTHOR]