![[Carbohydrate Polymers 2023] [Carbohydrate Polymers 2023]](/sites/default/files/2023-12/1-s2.0-S0144861723005593-ga1_lrg.jpg)
Lipopolysaccharides (LPS) are major players in bacterial infection through the recognition by Toll-like receptor 4 (TLR4). Some atypical α-2 Proteobacteria LPSs may evade immune system activation by either preventing TLR4 complex formation or by disturbing the complex stability. The group of Dr. Sonsoles Martín Santamaría, from the Margarita Salas Center for Biological Research (CIB-CSIC), and Dr. Manuel Fresno, from the Severo Ochoa Center for Molecular Biology (CBM-CSIC), led the research to understand the atomic/molecular details of TLR4/LPS molecular recognition, which has been published in the journal Carbohydrate Polymers.
The LPS chemical structure, including the oligosaccharide core and the lipid A moiety, can be strongly influenced by adaptation and modulated to assure bacteria protection, evade immune surveillance, or reduce host immune responses. Deep structural understanding of TLRs signaling is essential for the modulation of the innate immune system in sepsis control and inflammation, during bacterial infection.
To advance this knowledge, the authors have employed computational techniques to characterize the TLR4 molecular recognition of atypical LPSs from different opportunistic members of α2-Proteobacteria, including Brucella melitensis, Ochrobactrum anthropi, and Ochrobactrum intermedium, with diverse immunostimulatory activities. Matamoros-Recio et al. have combined docking calculations, intensive all-atom molecular dynamics simulations, and energy analysis, with biological assays to unraveling the role of uncommon lipid A chemical features such as bearing very long-chain fatty acid chains, whose presence has been rarely reported, on modulating the proper heterodimerization of the TLR4 receptor complex. Moreover, the influence of the different oligosaccharide cores, including sugar composition and net charge has been evaluated on TLR4 activation.
“We cannot discard that its peculiar lipid A-core structures, different from typical LPS of Gram-negative bacteria, may also result in some cases, in the heterodimer formation with TLR2 as we described in the LPS of O. intermedium” indicated Dr. Martín Santamaría. “Despite that the LPSs of O. anthropi and Bm-wadC may stabilize the (TLR4/MD-2)2 system more efficiently than O. intermedium LPS, this LPS may compensate it through heterodimerization with TLR2, which could explain the biological results”, she added.
In conclusion, the results presented in this work clearly indicate that the biological activity of LPSs and their relationship with TLRs is more complex than generally thought. Thus, not only the well know interaction of lipid A with TLR4, which is affected by the number and length of acyl chains, but also subtle differences in LPS core structure affect TLR4/MD2 interaction, and homo and heterodimerization (with TLR2) of TLR4. A deep structural understanding of TLRs activation (and/or evasion) could help to modulate the innate immunity system in sepsis control, inflammation-based diseases, and cancer vaccines, among other relevant therapeutic applications.
Reference: Immune evasion through Toll-like receptor 4: The role of the core oligosaccharides from α2-Proteobacteria atypical lipopolysaccharides. A. Matamoros-Recio, J. Merino, A. Gallego-Jiménez, R. Conde-Álvarez, M. Fresno, S. Martín-Santamaría. Carbohydrate Polymers (2023). https://doi.org/10.1016/j.carbpol.2023.121094