Multisystem Inflammation and Susceptibility to Viral infections in Human ZNFX1 Deficiency

BACKGROUND: The recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections, as a result of dysbalanced interferon production. NFX1-type zinc-finger-containing 1 (ZNFX1) is an interferon-stimulated double-strand RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1's role in the human immune response is not known. OBJECTIVE: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic-lymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease. METHODS: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, post-transcriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of ISGs mRNA and was associated with poorer clearance of virus infections by monocytes. CONCLUSION: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

• Vavassori, S.
• Chou, J.
• Faletti, L. E.
• Haunerdinger, V.
• Opitz, L.
• Joset, P.
• Fraser, C. J.
• Prader, S.
• Gao, X.
• Schuch, L. A.
• Wagner, M.
• Hoefele, J.
• Maccari, M. E.
• Zhu, Y.
• Elakis, G.
• Gabbett, M. T.
• Forstner, M.
• Omran, H.
• Kaiser, T.
• Kessler, C.
• Olbrich, H.
• Frosk, P.
• Almutairi, A.
• Platt, C. D.
• Elkins, M.
• Weeks, S.
• Rubin, T.
• Planas, R.
• Marchetti, T.
• Koovely, D.
• Klämbt, V.
• Soliman, N. A.
• von Hardenberg, S.
• Klemann, C.
• Baumann, U.
• Lenz, D.
• Klein-Franke, A.
• Schwemmle, M.
• Huber, M.
• Sturm, E.
• Hartleif, S.
• Häffner, K.
• Gimpel, C.
• Brotschi, B.
• Laube, G.
• Güngör, T.
• Buckley, M. F.
• Kottke, R.
• Staufner, C.
• Hildebrandt, F.
• Reu-Hofer, S.
• Moll, S.
• Weber, A.
• Kaur, H.
• Ehl, S.
• Hiller, S.
• Geha, R.
• Roscioli, T.
• Griese, M.
• Schmid, J. P.