The LPS-code: uncovering meta-level chemical structures that establish LPS as friend or foe

Descripción del proyecto

Comprensión de las interacciones entre las endotoxinas lipopolisacáridas y los receptores del huésped

Las endotoxinas lipopolisacáridas (LPS) son glicolípidos microbianos presentes en bacterias Gram negativas. Aunque tradicionalmente se consideran perjudiciales debido a su papel en la sepsis, las LPS también pueden estar asociados con bacterias beneficiosas. Quedan preguntas clave sobre cómo interactúan las LPS con los receptores del huésped. Comprender estas interacciones podría conducir a nuevas aplicaciones terapéuticas tanto en medicina como en agricultura. El proyecto LPS-CODE, financiado por el Consejo Europeo de Investigación, tiene como objetivo descubrir las interacciones moleculares clave entre las LPS y los receptores del huésped, así como las vías de señalización implicadas tanto en animales como en plantas. Identificará microdominios esenciales dentro de las LPS que median interacciones beneficiosas o perjudiciales, influyendo así en la inmunidad innata del huésped. En última instancia, el proyecto busca descifrar el lenguaje microbiano e identificar epítopos químicos comunes a las LPS beneficiosas o patógenos en sus interacciones con los huéspedes.

Objetivo

The lipopolysaccharide endotoxins (LPSs) are ubiquitous microbial cell surface glycolipids of Gram-negative bacteria and are key molecular actors in the interaction with eukaryotic hosts. Traditionally, studies have focused on the role of LPS as dangerous and potent molecules with the ability to boost innate immunity in eukaryotes and cause sepsis in humans and severe pathologies in plants. In recent years, however, it has become clear that LPS is not always working as a microbial weapon. Indeed, LPS also covers the surface of symbiotic and beneficial bacteria. However, a precise chemical and molecular information on this duality remains elusive. Two central questions remain unsolved with the required chemical precision: i) which are the key features of the molecular interactions between LPSs and the host receptors; ii) how the subsequent signalling pathways lead to either pathogenicity or symbiosis in mammals and in plants. Indeed, despite the harmful image of LPS, disentangling these features of LPS chemistry could inspire new avenues for the employment of LPS and LPS-like molecules as a novel generation of therapeutics in medicine and agriculture.
Thus, the key objective of LPS-CODE is to unravel the key features of the molecular interactions between LPS and the host receptors and decipher the subsequent signalling pathways in both animals and plants. This will be achieved by identifying the key microdomains within the LPS molecules that establish beneficial or detrimental interactions with the host, eventually driving elicitation or suppression of host innate immunity.
LPS-CODE is grounded on (bio)-organic chemistry and chemical biology, with strong emphasis on glycan chemistry and structural glycosciences to decode the microbial language and thus decipher the chemical epitopes common to either all “friendly” or pathogenic LPS in the interaction with both plants and animals. With this, we will finally be able to make the conceptual leap to conceive new molec