The Human-Associated Archaeon Methanosphaera stadtmanae Is Recognized through Its RNA and Induces TLR8-Dependent NLRP3 Inflammasome Activation

Abstract

The archaeon Methanosphaera stadtmanae is a member of the gut microbiota; yet, the molecular cross-talk between archaea and the human immune system and its potential contribution to inflammatory diseases has not been evaluated. Although archaea are as bacteria prokaryotes, they form a distinct domain having unique features such as different cell wall structures and membrane lipids. So far, no microbe-associated molecular patterns of archaea which activate innate immune receptors have been identified. By stimulating human myeloid cells with M. stadtmanae and purified archaeal nucleic acids, we identified both the microorganism and its RNA as potent stimuli for the innate immune system. To dissect the recognition and activation pathways induced by M. stadtmanae, human monocytic BLaER1 knockout cells were generated using the CRISPR/Cas9 system targeting components of TLR and inflammasome signaling. While the recognition of M. stadtmanae is mediated by TLR7 and TLR8, activation of the NLRP3 inflammasome depends solely on TLR8 engagement. Notably, this process resembles hallmarks of both the canonical and the recently described alternative inflammasome activation. Thus, we have demonstrated for the first time the specific recognition of and response to an archaeon by human cells at the molecular level.

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

“…Although there is ample knowledge about the function of PRRs and their respective bacterial ligands, the molecular mechanism of how archaea, and specifically M. stadtmanae , are detected remained elusive. We could recently demonstrate that M. stadtmanae is recognized through its RNA by TLR8, and to a lesser extent by TLR7 (Figure ) . Phagocytosis and lysosomal acidification are necessary for the access of TLR7 and TLR8 to archaeal RNA.…”

“…The efficacy of TLR7/8 ligands as potent adjuvants was already confirmed in different experimental setups including nonhuman primates . Interestingly, the archaeon M. stadtmanae is recognized by the innate immune system solely dependent on TLR8 and TLR7 and apparently without the involvement of any other innate immune receptors . Given the fact that to this day no pathogenic archaeon has been identified and that archaeal lipids have already been shown to hold adjuvant activity, the usage of archaea, such as M. stadtmanae , to target TLR8 in vaccine development could be considered.…”

“…Besides the role of TLR3, TLR7, and TLR8 in detection of viruses and bacteria, our group just recently identified another group of microbes which is recognized through its RNA—the archaea . Based on 16S rRNA analysis, archaea have been determined as an own prokaryotic domain by Carl Woese in 1977 .…”

“…Foreign and host‐derived DNA in the cytosol is detected by cyclic GMP‐AMP synthetase (cGAS) which activates stimulator of interferon genes (STING) through the second messenger 2′,3′‐cyclic GMP‐AMP (cGAMP) . The absent in melanoma 2 (AIM2) and gamma‐interferon‐inducible protein 16 (IFI16) inflammasomes are also activated by dsDNA, whereas various different NA species like RNA from bacteria, viruses, and archaea, as well as RNA:DNA hybrids, and oxidized mitochondrial DNA activate the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome. Inflammasome activation leads to maturation of caspase‐1, an enzyme that converts the inflammatory cytokines pro‐IL‐1β and pro‐IL‐18 into their active forms …”

Editorial: gut microbial profile associated with primary sclerosing cholangitis—what is new and how do we progress from here? Authors’ reply

“…The study of Lemoinne and colleagues showed for the first time that a fungus— Exophiala— is associated with bacterial dysbiosis in PSC and leverages the findings of formerly bacterial‐only to a trans‐kingdom dysbiosis in PSC . Recently it was highlighted that previous investigations of human‐associated archaea offered a rather biased picture of archaeal diversity and new approaches for investigating this kingdom were proposed, rendering archaea with its potential immunologic implication amenable to analysis in disease context.…”