Archaeal cell envelopes selectively activate innate immunity through TLR2 in contrasts with multi-receptor bacterial sensing

Abstract

The cell envelope of bacteria and fungi is a major source of microbial-associated molecular patterns (MAMPs), which are recognised by multiple host pattern recognition receptors (PRRs) such as TLRs and NODs. The key role of this recognition in protecting against infection and regulating diverse physiological processes has been studied for decades. In contrast, although the archaea are growingly recognised as an important component of the animal and human microbiome, their interaction with the innate immune system has been largely understudied. Here, we asked whether the archaeal cell envelope acts as MAMP. We selected 15 archaeal species from different environments, including the human microbiome, and harbouring diverse envelope characteristics, and we tested their ability to activate innate immune responses in human and murine immune cells. We first show that archaeal cells activate the innate immune transcription factor NF-kB and induce IL-6 secretion. Using whole archaeal cells, supernatants, and purified envelope components, we then find that none of the main PRR receptors which recognise the bacterial envelope (TLR4, TLR5, NOD1 and NOD2) are involved in this activation. We only detected activation of TLR2, regardless of the environmental origins of the archaea tested, although with overall lower activity compared to bacteria. We further demonstrate that different TLR2 heterodimers are involved, depending on the species, although the archaeal agonist remains unknown. Altogether, our results highlight a surprising paucity of interaction of archaeal cell envelope components with host PPRs, in contrast to bacteria, and open new avenues of research toward further investigation of archaea/host interplay.