The cytomegalovirus protein US31 induces inflammation through mono-macrophages in systemic lupus erythematosus by promoting NF-\u03baB2 activation

Gangqiang Guo,Xiangyang Xue,Cong Lin,Chaosheng Chen,Fangyan Wang,Ming Li,Shangdan Xie,Lele Ye,Lifang Zhang,Baoqing Li,Min Yang,Sisi Ye,Huidi Zhang,Xinyu Shi

doi:10.1038/s41419-017-0122-4

Abstract

It has been hypothesized that human cytomegalovirus (HCMV) infection, especially in monocyte and CD34 (+) myeloid cells, acts as a important regulator of immune system to promote inflammation in multiple autoimmune diseases. The aim of this study was to elucidate the HCMV gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of SLE patients and demonstrate the effect and mechanism of viral gene associated with SLE in mono-macrophages functions. Using two RNA-Seq techniques in combination with RT-PCR, 11 viral genes mainly associated with latent HCMV infection were identified in the PBMCs of SLE patients. Among these viral genes, US31 with previously unknown function was highly expressed in the PBMCs of SLE patients compared to healthy controls. Analysis of function indicated that US31 expression could induce inflammation in monocyte and macrophage and stimulate macrophage differentiation toward an M1 macrophage phenotype. Screening via protein chips in combination with bioinformatic analysis and consequent detection of mono-macrophages function indicates that the direct interaction between US31 and NF-κB2 contributed the NF-kB2 activation. Consequent analysis indicated US31 directly interacted with NF-κB2, contribute to the polyubiquitination of the phosphorylated p100 and consequent activation of NF-κB2. Taken together, our data uncovered a previously unknown role of the HCMV protein US31 in inducing NF-κB-mediated mono-macrophage inflammation in the pathogenesis and development of SLE. Our findings provide a foundation for the continued investigation of novel therapeutic targets for SLE patients.

Highlights

Increasing evidence suggests that human cytomegalovirus (HCMV), which commonly infects human populations, constitutes an important trigger of systemic lupus erythematosus (SLE) and can further aggravate disease progression[1,2,3]
Our data showed that 18 viral genes (UL29, UL32, UL34, UL36, UL37, UL44, UL50, UL56, UL82, UL84, UL95, UL105, UL112, UL117, UL123, US3, US31, and TRS1) were detected in the peripheral blood mononuclear cells (PBMCs) of at least one of the three SLE patients
UL36, UL123, and US31 were only detected during whole transcriptome sequencing, whereas UL29, UL32, UL37, UL50, UL56, UL105, UL117, and US3 were only detected during mRNA sequencing, respectively

Summary

Introduction

Increasing evidence suggests that human cytomegalovirus (HCMV), which commonly infects human populations, constitutes an important trigger of SLE and can further aggravate disease progression[1,2,3]. HCMV infection[4], resulting in a vicious cycle. There is currently very little information available regarding the mechenisms after HCMV infection with the immunological function and SLE morbidity. Monocytes and consequent differentiation are verified as playing a decisive and crucial role in the systemic spread of HCMV as well as establishment of effective and persistent infection 6.

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