A Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in Mice

Abstract

We previously generated STING N153S knock-in mice that have a human disease-associated gain-of-function mutation in STING. Patients with this mutation (STING N154S in humans) develop STING-associated vasculopathy with onset in infancy (SAVI), a severe pediatric autoinflammatory disease characterized by pulmonary fibrosis. Since this mutation promotes the upregulation of antiviral type I interferon-stimulated genes (ISGs), we hypothesized that STING N153S knock-in mice may develop more severe autoinflammatory disease in response to a virus challenge. To test this hypothesis, we infected heterozygous STING N153S mice with murine gammaherpesvirus 68 (γHV68). STING N153S mice were highly vulnerable to infection and developed pulmonary fibrosis after infection. In addition to impairing CD8+ T cell responses and humoral immunity, STING N153S also promoted the replication of γHV68 in cultured macrophages. In further support of a combined innate and adaptive immunodeficiency, γHV68 infection was more severe in Rag1–/– STING N153S mice than in Rag1–/– littermate mice, which completely lack adaptive immunity. Thus, a gain-of-function STING mutation creates a combined innate and adaptive immunodeficiency that leads to virus-induced pulmonary fibrosis. IMPORTANCE A variety of human rheumatologic disease-causing mutations have recently been identified. Some of these mutations are found in viral nucleic acid-sensing proteins, but whether viruses can influence the onset or progression of these human diseases is less well understood. One such autoinflammatory disease, called STING-associated vasculopathy with onset in infancy (SAVI), affects children and leads to severe lung disease. We generated mice with a SAVI-associated STING mutation and infected them with γHV68, a common DNA virus that is related to human Epstein-Barr virus. Mice with the human disease-causing STING mutation were more vulnerable to infection than wild-type littermate control animals. Furthermore, the STING mutant mice developed lung fibrosis similar to that of patients with SAVI. These findings reveal that a human STING mutation creates severe immunodeficiency, leading to virus-induced lung disease in mice.

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

“…Although the aforementioned features mimic SLE, the authors reported that none of the subjects met the SLE criteria [129]. Interestingly, mice who carry one of the SAVI-associated mutations developed features of severe combined immunodeficiency [68,140].…”

A Human STAT1 Gain-of-Function Mutation Impairs CD8 + T Cell Responses against Gammaherpesvirus 68

“…IFN-␥ and T cells are critical for control of ␥HV68 infection (21)(22)(23)(24)(25)(26)(27)(28). Upon examination of IFN-␥-expressing T cells, we observed a consistent ϳ2or 3-fold reduction in the total number of IFN-␥-producing CD4 ϩ and CD8 ϩ T cells in infected but not in naive STAT1 R274W animals compared to that in WT littermate controls (Fig.…”

“…8). Antiviral CD4 ϩ and CD8 ϩ T cells are already known to play a major role in controlling ␥HV68 infection (21)(22)(23)(24)(25)(26)(27)(28). However, it is not known whether a similar defect in antigenspecific T cell responses may occur during virus infection in humans, so this could be a topic of future study.…”

“…Although we are not able to conclude definitively whether these adaptive immune defects are responsible for STAT1 R274W-associated susceptibility to viral infection, our studies of mixed bone marrow chimeric mice support the conclusion that STAT1 R274W impairs control of infection because of effects on antigen-specific CD8 ϩ T cells. Furthermore, CD8 ϩ T cells were previously demonstrated to play a major role in controlling ␥HV68 infection (21)(22)(23)(24)(25)(26)(27)(28).…”

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

“…However, these phenotypes do not depend on either IFN-α/β receptor signaling or mixed lineage kinase domain-like pseudokinase (MLKL)dependent necroptotic cell death pathways as reported in humans. [143][144][145] Unexpectedly, V154M mutant mice have more robust STING activation and develop lung fibrosis, while N153S mutant mice have a weaker STING activation and only develop lung inflammation, indicating murine models of SAVI mutations reflect different aspects of the human disease. 144 Because lung fibrosis is a common complication of SAVI patients, the V154M mouse is a useful tool for dissecting the role of the STING pathway in pulmonary disease and provides an excellent model for assessing possible STING antagonists for the treatment of SAVI patients.…”