AUTHOR=Francisco Sara , Billod Jean-Marc , Merino Javier , Punzón Carmen , Gallego Alicia , Arranz Alicia , Martin-Santamaria Sonsoles , Fresno Manuel 

TITLE=Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.748303

DOI=10.3389/fimmu.2021.748303

ISSN=1664-3224

ABSTRACT=<p>The Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex is considered the major receptor of the innate immune system to recognize lipopolysaccharides (LPSs). However, some atypical LPSs with different lipid A and core saccharide moiety structures and compositions than the well-studied enterobacterial LPSs can induce a TLR2-dependent response in innate immune cells. <italic>Ochrobactrum intermedium</italic>, an opportunistic pathogen, presents an atypical LPS. In this study, we found that <italic>O. intermedium</italic> LPS exhibits a weak inflammatory activity compared to <italic>Escherichia coli</italic> LPS and, more importantly, is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of <italic>O. intermedium</italic> LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by fluorescence resonance energy transfer (FRET) in cells. Interestingly, the core saccharide plays an important role in this interaction. This study reveals for the first time TLR4/TLR2 heterodimerization that is induced by atypical LPS and may help to escape from recognition by the innate immune system.</p>