권혁권 (Yale University)

한빛사논문

조회637

Yale University

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EMBO Mol. Med., 2022 Nov 10;e15284 | https://doi.org/10.15252/emmm.202115284 Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis

Hyuk-Kwon Kwon¹, Kristin E Yu^1,2, Sean V Cahill^1,3, Kareme D Alder^1,2, Christopher M Dussik^1,4, Sang-Hun Kim⁵, Lokesh Sharma⁵, Jungho Back¹, Irvin Oh¹ and Francis Y Lee ^*,1

¹Department of Orthopaedics and Rehabilitation, School of Medicine, Yale University, New Haven, CT, USA
²Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
³Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
⁴Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA
⁵Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

^*Corresponding author. Francis Y Lee

Abstract

Intracellular infiltration of bacteria into host cells complicates medical and surgical treatment of bacterial joint infections. Unlike soft tissue infections, septic arthritis and infection-associated inflammation destroy cartilage that does not regenerate once damaged. Herein, we show that glycolytic pathways are shared by methicillin-resistant Staphylococcus aureus (MRSA) proliferation and host inflammatory machinery in septic arthritis. MRSA readily penetrates host cells and induces proinflammatory cascades that persist after conventional antibiotic treatment. The glycolysis-targeting drug dimethyl fumarate (DMF) showed both bacteriostatic and anti-inflammatory effects by hindering the proliferation of intracellular MRSA and dampening excessive intraarticular inflammation. Combinatorial treatment with DMF and vancomycin further reduced the proliferation and re-emergence of intracellular MRSA. Combinatorial adjuvant administration of DMF with antibiotics alleviated clinical symptoms of septic arthritis by suppressing bacterial burden and curbing inflammation to protect cartilage and bone. Our results provide mechanistic insight into the regulation of glycolysis in the context of infection and host inflammation toward development of a novel therapeutic paradigm to ameliorate joint bioburden and destruction in septic arthritis.

논문정보

형식Research article
게재일2022년 11월 (BRIC 등록일 2022-11-11)
연구진국외 연구진
분야 생명과학 > 감염생물학

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