Wehkamp, J. | bioRxiv Science

bioRxiv2022

Gut microbiota bacterial strain richness is species specific and limits therapeutic engraftment

Despite the fundamental role of strain variation in gut microbiota function, the number of unique strains of a species that can stably colonize the human gut is still unknown. In this work, we determine the strain richness of common gut species using thousands of sequenced bacterial isolates and metagenomes. We find that strain richness varies across species, is transferable by fecal microbiota transplantation, and is low in the gut compared to other environments. Therapeutic administration of supraphysiologic numbers of strains per species only temporarily increases recipient strain richness, which subsequently converges back to the population average. These results suggest that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and provide a theoretical framework for strain engraftment and replacement in fecal microbiota transplantation and defined live biotherapeutic products.

microbiology↗

bioRxiv2019

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus.

Human cytomegalovirus (HCMV) infection causes severe illness in newborns and immunocompromised patients. Since treatment options are limited there is an unmet need for new therapeutic approaches. Defensins are cationic peptides, produced by various human tissues, which serve as antimicrobial effectors of the immune system. Furthermore, some defensins are proteolytically cleaved, resulting in the generation of smaller fragments with increased activity. Together, this led us to hypothesize that defensin-derived peptides are natural human inhibitors of virus infection with low toxicity. We screened several human defensin HNP4- and HD5-derived peptides and found HD5(1-9) to be antiviral without toxicity at high concentrations. HD5(1-9) inhibited HCMV cellular attachment and thereby entry and was active against primary as well as a multiresistant HCMV isolate. Moreover, cysteine and arginine residues were identified to mediate the antiviral activity of HD5(1-9). Altogether, defensin-derived peptides, in particular HD5(1-9), qualify as promising candidates for further development as a novel class of HCMV entry inhibitors.\n\nAUTHOR SUMMARYDefensins are peptides produced by various human organs which take part in the natural defense against pathogens. Recently, it has been shown that defensins are further cleaved to smaller peptides that have high intrinsic anti-microbial activity. We here challenged the hypothesis that these peptides might have antiviral activity, and due to their presumably natural occurrence, low toxicity. Indeed, we found one peptide fragment that turned out to block the attachment of the human cytomegalovirus (HCMV) to cells. Furthermore, this peptide did not show toxicity in various cellular assays or impede the embryonic development of zebrafish at the concentrations used to block HCMV. This is important, since HCMV is one of the most important viral congenital infections. Altogether, our results hold promise for the development of a new class of antivirals against HCMV.

microbiology↗