Mitochondrial chaperon TNF-receptor- associated protein 1 as a novel apoptotic regulator conferring susceptibility to Pneumocystis jirovecii pneumonia .

Autor:	Amali AA; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore., Paramasivam K; Mechanobiology Institute, National University of Singapore, Singapore, Singapore., Huang CH; Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, Singapore, Singapore., Joshi A; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD, United States., Hirpara JL; Cancer Science Institute, National University of Singapore, Singapore, Singapore., Ravikumar S; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore., Sam QH; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore.; Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore., Tan RYM; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore., Tan Z; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore., Kumar D; Singapore Immunology Network (SIgN), ASTAR (Agency for Science, Technology and Research), Singapore, Singapore., Neckers LM; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD, United States., Pervaiz S; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Foo R; Cardiovascular Research Institute, National University Health System, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chan CYY; Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore., Zhu J; Mechanobiology Institute, National University of Singapore, Singapore, Singapore., Lee C; Cardiovascular and Metabolic Disorders, Duke NUS Medical School, Singapore, Singapore., Chai LYA; Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore.; Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Aug 19; Vol. 15, pp. 1423086. Date of Electronic Publication: 2024 Aug 19 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1423086
Abstrakt:	Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infectious diseases relatable to defects in molecular chaperons have yet to be identified. To this end, we performed whole exome sequencing and functional immune assessment in a previously healthy Asian female, who experienced severe respiratory failure due to Pneumocystis jiroveci pneumonia and non-HIV-related CD4 lymphocytopenia. This revealed that a chaperon, the mitochondrial paralog of HSP90, TRAP1, may have been involved in the patient's susceptibility to an opportunistic infection. Two rare heterozygous variants in TRAP1, E93Q, and A64T were detected. The patient's peripheral blood mononuclear cells displayed diminished TRAP1 expression, but had increased active, cleaved caspase-3, caspase-7, and elevated IL-1β production. Transfection of A64T and E93Q variants in cell lines yielded decreased TRAP1 compared to transfected wildtype TRAP1 and re-capitulated the immunotypic phenotype of enhanced caspase-3 and caspase-7 activity. When infected with live P. jiroveci , the E93Q or A64T TRAP1 mutant expressing cells also exhibited reduced viability. Patient cells and cell lines transfected with the TRAP1 E93Q/A64T mutants had impaired respiration, glycolysis, and increased ROS production. Of note, co-expression of E93Q/A64T double mutants caused more functional aberration than either mutant singly. Taken together, our study uncovered a previously unrecognized role of TRAP1 in CD4 + lymphocytopenia, conferring susceptibility to opportunistic infections. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Amali, Paramasivam, Huang, Joshi, Hirpara, Ravikumar, Sam, Tan, Tan, Kumar, Neckers, Pervaiz, Foo, Chan, Zhu, Lee and Chai.)
Databáze:	MEDLINE
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