The systemic lupus erythematosus-associated NCF190H allele synergizes with viral infection to cause mouse lupus but also limits virus spread

Yanpeng Li, Ana Coelho, Zhilei Li, Malin Alsved, Qixing Li, Rui Xu, Huqiao Luo, Dongxia Liang, Jing Xu, Kutty Selva Nandakumar, Liesu Meng, Jakob Löndahl and Rikard Holmdahl ()
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Yanpeng Li: Karolinska Institute
Ana Coelho: Karolinska Institute
Zhilei Li: Southern University of Science and Technology Hospital
Malin Alsved: Lund University
Qixing Li: Southern Medical University
Rui Xu: Southern Medical University
Huqiao Luo: Karolinska Institute
Dongxia Liang: Second Affiliated Hospital of Xi’ an Jiaotong University (Xibei Hospital)
Jing Xu: Ministry of Education
Kutty Selva Nandakumar: Southern Medical University
Liesu Meng: Second Affiliated Hospital of Xi’ an Jiaotong University (Xibei Hospital)
Jakob Löndahl: Lund University
Rikard Holmdahl: Karolinska Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Studying how single nucleotide polymorphisms (SNPs) crosstalk with non-autologous factors to cause complex autoimmune diseases is challenging. An amino acid replacement in the neutrophil cytosolic factor 1 (NCF1-339/NCF1R90H) leading to lower reactive oxygen species induction has been reported as the major SNP for systemic lupus erythematosus (SLE). Here we show that infection with the murine norovirus (MNV) contributes to the induction of lupus in Ncf190H mice. Mutant NCF190H upregulates the IFN-α/JAK1/STAT1 pathway in macrophages and anti-MNV-antibody production. In parallel, the MNV infection of NCF190H mice upregulates Toll-like receptor 7 in macrophages, plasmacytoid dendritic cells and B220+ splenocytes, thereby promoting germinal center formation and lupus-associated autoantibodies production. These compounded effects lead to protection against MNV infection but also glomeruloneph ritis with proteinuria and lupus arthritis in the absence of chemical inducers such as pristane. Our data thus suggest that this SLE-associated SNP, NCF190H, synergizes with MNV infection to induce the development of mouse lupus.

Date: 2025
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DOI: 10.1038/s41467-025-56857-z

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