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=Volume 12 - 2021

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=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 (LPS). However, some atypical LPSs with different lipid A and core saccharide moieties structures and compositions than the well-studied enterobacterial LPSs, can induce a TLR2-dependent response in innate immune cells. Ochrobactrum intermedium, an opportunistic pathogen, presents an atypical LPS. In this study, we found that O. intermedium LPS exhibits a weak inflammatory activity compared to E. coli LPS, and more importantly is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of O. intermedium LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by 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.