Abstract
The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus–human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.
| Original language | English |
|---|---|
| Article number | 879 |
| Journal | Viruses |
| Volume | 14 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 05.2022 |
Funding
This work was supported by grants of the following funding agencies: Programa de Apoio a N?cleos de Excel?ncia (PRONEX)?Funda??o Arauc?ria (FA) and Conselho Nacional de Desen-volvimento Cient?fico e Tecnol?gico (CNPq), Conv?nio 116/2018?Protocolo 50530 provided support to M.L.P.-E.; the Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES/PROAP? Finance Code 001) provided financial support and scholarships to V.B.-B.H. and A.F.K. (CAPES-40001016006P1); the Swiss National Science Foundation CRSII5_202301/1; the University of L?beck; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany?s Excellence Strategy?EXC 22167-390884018 provided financial support to H.B. and E.S. M.L.P.-E. and A.B.W.B. receive research productivity scholarships from CNPq (protocol numbers 308783/2019-0 and 314288/2018?0, respectively). The funding agencies had no role in study design, sample collection, data analysis and interpretation, and manuscript drafting and submission. Acknowledgments: We deeply thank the patients and control individuals for their participation in this study. Our special thanks go to Marluci Aparecida da Silva and Esther Bordin Lupion who participated in the first stages of the work. We also thank the staff of the Laboratorio de Genetica Molecular Humana of the Federal University of Parana (UFPR) for their assistance, and the principal investigators of the German Autoimmune Bullous Diseases Study Group, who contributed less than five patients to this study and who were not granted coauthorships, i.e., Claudia Günther (Dresden), Michael Sticherling (Erlangen), Eva Hadaschik (Heidelberg), Kerstin Steinbrink (Mainz), Regine Gläser (Kiel) and Wiebke Ludwig-Peitsch (Mannheim). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. eQTL and sQTL effects of genetic variants associated in this study were obtained from https://gtexportal.org/home/snp/ (accessed on 2 December 2021). Funding: This work was supported by grants of the following funding agencies: Programa de Apoio a Núcleos de Excelência (PRONEX)—Fundação Araucária (FA) and Conselho Nacional de Desen-volvimento Científico e Tecnológico (CNPq), Convênio 116/2018—Protocolo 50530 provided support to M.L.P.-E.; the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROAP— Finance Code 001) provided financial support and scholarships to V.B.-B.H. and A.F.K. (CAPES-40001016006P1); the Swiss National Science Foundation CRSII5_202301/1; the University of Lübeck; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany‘s Excellence Strategy—EXC 22167-390884018 provided financial support to H.B. and E.S. M.L.P.-E. and A.B.W.B. receive research productivity scholarships from CNPq (protocol numbers 308783/2019-0 and 314288/2018–0, respectively). The funding agencies had no role in study design, sample collection, data analysis and interpretation, and manuscript drafting and submission.
Research Areas and Centers
- Centers: Center for Research on Inflammation of the Skin (CRIS)
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
