Usutu virus (USUV) is an emerging arbovirus belonging to the Flavivirus genus transmitted to the host during a mosquito’s blood meal. The infection can be asymptomatic or lead to meningoencephalitis in humans. Following the bite of an infected mosquito, the skin represents the initial site of inoculation of this virus and provides the first line of host defense. Currently, few data are available on the interactions between skin cells and USUV as well as on the inflammatory and antiviral responses induced. In order to study the pathophysiology of USUV skin infection, the permissivity of primary resident skin cells to USUV infection and the pathways involved in viral recognition and innate immune response activation were characterized. Our results showed an early viral replication during the first 24 hours in human epidermal keratinocytes, dermal fibroblast and skin explants leading to the induction of antiviral and pro-inflammatory targets. In vivo, following cutaneous inoculation, we demonstrated that USUV can rapidly spread, replicate and persist in all distal cutaneous tissues in mice, a phenomenon associated with a generalized skin inflammatory response. Moreover, a main role of the RIG-I receptor in USUV sensing, induction of the inflammatory and antiviral response and restriction of the infectious viral particle production was shown. Finally, type I interferon signaling has been shown to be essential to prevent USUV dissemination to the peripheral organs. Together, these data provide a better understanding of the pathophysiology of the early stages of USUV infection and highlight the key amplifying and immunological role of the skin during USUV infection.

The Exploring Inflammation in Health and Disease (X-HiDE) consortium was developed with the aim of unraveling commonalities and differences of inflammatory processes across diseases. Although inflammatory pathways share common attributes across clinical conditions, most conditions are studied separately, resulting in disease-specific drugs and treatment algorithms. However, both broad immunosuppressants and targeted therapies appear effective in multiple conditions. X-HiDE has followed a two-way methodology: (i) characterisation of inflammatory phenotypes determined based on geneset databases (i.e., acute inflammation, low-grade chronic inflammation, immunoparalysis) through curation of publicly available data; and (ii) investigation of inflammatory pathways within and across model diseases. Characterisation of inflammatory phenotypes and identification of model diseases followed a molecular and a clinical approach. Briefly, gene ontology was used as a basis to identify genes of relevance, and each gene and corresponding protein (mediator) were scored as a contributors, inhibitors, or irrelevant for each one of the inflammatory phenotypes. Data curation was independently performed by 6 experts through review of mechanistic studies, with recurrent calibration meetings. Next, relevant diseases were individually scored by 3 clinicians for the presence of components of acute or low-grade chronic inflammation, or resolution. Model diseases were selected, the first ones being sepsis, representative for acute inflammation and immunoparalysis, and systemic lupus erythematosus, representative for acute and low-grade chronic inflammation. Study of the lupus transcriptome pointed to STAT1, PLK1, and B and plasma cell signatures as important for pathogenesis and relevant for drug repurposing, but molecular patterns from cluster analysis were not indicative of the organ manifestations. Another study showed small overlap between geneset enrichment and the molecules identified in each phenotype. These results imply that inflammation is characterised by a multilevel complexity of mechanisms. How inflammatory processes interact with each other remains elusive.

In experimental and clinical studies, the role of nonspecific neutrophil proteinases (elastase-like & trypsin-like activity) and their endogenous inhibitors (antitrypsin activity & acid-stable inhibitors) in the development of local inflammation in the lungs, endometrial hyperplasia (EH) and systemic inflammation in critical conditions was studied.The results showed that the development of local inflammation leads for nonspecific reaction of proteinases and their inhibitors in the blood serum with increase of proteinases and their inhibitors levels. Investigation of the bronchoalveolar lavage fluid showed more specific changes, which are characterized by a phase reactions: in the acute period the changes can be characterized as compensatory, in chronic – the level of proteinases increases with a decrease activity of local inhibitors.These studies made it possible to characterize the types of reactions of nonspecific proteinases and their inhibitors at the systemic and local levels. At the blood level, compensated and decompensated types of reactions were described. At the local level, 4 types of changes are described, which can be characterized as potentiated, compensated, destructive and decompensated. Depending on the types of reactions, it is possible to evaluate compensatory potential and decide on the use of proteinase inhibitors for therapeutic purposes. In addition, in critical conditions, the assessment of the proteinase-inhibitory balance made it possible to propose an original classification of shock: with primary and secondary formation of the systemic inflammatory response syndrome (SIRS).