Svenungsson, E

Abstract Background Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. Methods In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels and severe viral infection outcomes. Results In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the USA with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (Area under the curve (AUC) = 0.73, P = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including Coronavirus Disease 2019 (COVID-19), viral hepatitis and HIV [correlation coefficients: −0.79 (P = 4e-2), −0.94 (P = 6e-3) and −0.96 (P = 8e-2), respectively]. Conclusions This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.

Abstract Background: The objective of the study was to explore disease pathways activated in the inflammatory foci of skin lesions in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). Methods: Skin biopsies acquired from active CLE and DM lesions, patient (PC) and also healthy controls (HC) were investigated. Biopsy sections were examined by a pathologist and inflammatory foci were laser micro-dissected, captured and proteins within captured tissue were detected in a hypothesis free manner by mass-spectrometry. Protein pathway analysis was performed by string-db.org platform. Findings of interest were confirmed by immunohistochemistry (IHC).Results: Proteome investigation identified interleukin (IL)-16 to be the only detectable and abundant cytokine differentially expressed in CLE compared to DM. Caspase-3, enzyme that cleaves IL-16 into its active form, was detected in low levels. Significantly higher proportion of IL-16 and Caspase-3 positive cells were identified in CLE lesions in comparison to DM, PC and HC. Interferon-regulated proteins (IRP) were abundant in both CLE and DM. Proteomic results indicate more abundant complement deposition in CLE skin lesions. Conclusions: Using hypothesis free mass-spectrometry investigation of CLE inflammatory infiltrates, we identified that IL-16 is the only detectable and highly abundant cytokine, while IRP was a common feature of both CLE and DM. IHC confirmed high expression of IL-16 and caspase-3 in CLE. Our novel molecular findings indicate that IL-16 detection could be useful in differential diagnostics between the two conditions that can display similar histopathological appearance. Potentially, IL-16 could be of interest as a future therapeutic target for CLE.