A role for tetraspanin proteins in regulating fusion induced by Burkholderia thailandensis
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ORIGINAL INVESTIGATION
A role for tetraspanin proteins in regulating fusion induced by Burkholderia thailandensis Atiga Elgawidi1 · Muslim Idan Mohsin1,3 · Fawwaz Ali1,4 · Amyleigh Watts1 · Peter N. Monk2 · Mark S. Thomas2 · Lynda J. Partridge1 Received: 31 January 2020 / Accepted: 23 March 2020 © The Author(s) 2020
Abstract Burkholderia pseudomallei is the causative agent of melioidosis, a disease with high morbidity that is endemic in South East Asia and northern Australia. An unusual feature of the bacterium is its ability to induce multinucleated giant cell formation (MNGC), which appears to be related to bacterial pathogenicity. The mechanism of MNGC formation is not fully understood, but host cell factors as well as known bacterial virulence determinants are likely to contribute. Since members of the tetraspanin family of membrane proteins are involved in various types of cell:cell fusion, their role in MNGC formation induced by Burkholderia thailandensis, a mildly pathogenic species closely related to B. pseudomallei, was investigated. The effect of antibodies to tetraspanins CD9, CD81, and CD63 in MNGC formation induced by B. thailandensis in infected mouse J774.2 and RAW macrophage cell lines was assessed along with that of recombinant proteins corresponding to the large extracellular domain (EC2) of the tetraspanins. B. thailandensis-induced fusion was also examined in macrophages derived from CD9 null and corresponding WT mice, and in J774.2 macrophages over-expressing CD9. Antibodies to CD9 and CD81 promoted MNGC formation induced by B. thailandensis, whereas EC2 proteins of CD9, CD81, and CD63 inhibited MNGC formation. Enhanced MNGC formation was observed in CD9 null macrophages, whereas a decrease in MNGC formation was associated with overexpression of CD9. Overall our findings show that tetraspanins are involved in MNGC formation induced by B. thailandensis and by implication, B. pseudomallei, with CD9 and CD81 acting as negative regulators of this process. Keywords Burkholderia · Melioidosis · Tetraspanin · Multinucleated giant cell · CD9 · Cell:cell fusion
Introduction
Edited by Luise Florin. This article is part of the Special Issue on Tetraspanins in Infection and Immunity. * Lynda J. Partridge [email protected] 1
Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK
2
Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK
3
Present Address: Department of Pathological Analyses, University of Kufa, Kufa, Iraq
4
Present Address: Mosul Technical Institute, Northern Technical University, Mosul, Iraq
Melioidosis is a serious disease with a wide range of manifestations, depending on the route of infection. The causative agent, Burkholderia pseudomallei, is a Gram-negative bacillus that is endemic in the tropics [1, 2]. The bacterium is normally resident in soil and acts as an opportunistic pathogen. There is little evidence of person:person transmission and i
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