한빛사 논문
Caleb J. Studstill1,#, Curtis J. Pritzl1,#, Young-Jin Seo2,#,*, Dae Young Kim3, Chuan Xia1, Jennifer J. Wolf1, Ravi Nistala4, Madhuvanthi Vijayan1, Yong-Bin Cho2, Kyung Won Kang5, Sang-Myeong Lee5,6, and Bumsuk Hahm1,*
1Departments of Surgery and Molecular Microbiology & Immunology, University of Missouri-Columbia, Medical Science Building M331, One Hospital Dr. Columbia, MO 65212, USA
2Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
3Veterinary Medical Diagnostic Laboratory, College of Veterinary Medicine, University of Missouri-Columbia
4Division of Nephrology, Department of Medicine, M754 Center for Precision Medicine, University of Missouri-Columbia, One Hospital Dr. Columbia, MO 65211, USA
5Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan 54596, Republic of Korea
6College of Veterinary Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
#These authors equally contributed to this work.
*Corresponding Authors
Abstract
Chronic viral infections are often established by the exploitation of immune regulatory mechanisms that result in non-functional T cell responses. Viruses that establish persistent infections remain a serious threat to human health. Sphingosine kinase (SphK) 2 generates sphingosine 1-phosphate, which is a molecule known to regulate multiple cellular processes. However, little is known about SphK2’s role during the host immune responses to viral infection. Here, we demonstrate that SphK2 functions during lymphocytic choriomeningitis virus Cl 13 (LCMV Cl 13) infection to limit T cell immune pathology, which subsequently aids in the establishment of virus-induced immunosuppression and the resultant viral persistence. The infection of Sphk2-deficient (Sphk2-/-) mice with LCMV Cl 13 led to the development of nephropathy and mortality via T cell-mediated immunopathology. Following LCMV infection, Sphk2-/- CD4+ T cells displayed increased activity and proliferation, and these cells promoted overactive LCMV Cl 13-specific CD8+ T cell responses. Notably, oral instillation of an SphK2-selective inhibitor promoted protective T cell responses and accelerated the termination of LCMV Cl 13 persistence in mice. Thus, SphK2 is indicated as an immunotherapeutic target for the control of persistent viral infections.
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