Biology subjects

Averhoff, B.

Publications and source records attributed to Averhoff, B..

3 recordsLinked to original sources

bioRxiv2023

Domain-architecture aware phylogenetic profiling indicates a functional diversification of type IVa pili in the nosocomial pathogen Acinetobacter baumannii

The Gram-negative bacterial pathogen Acinetobacter baumannii is a major cause of hospital-acquired opportunistic infections. The increasing spread of pan-drug resistant strains, paired with a surge in virulence, makes A. baumannii top-ranking among the ESKAPE pathogens for which novel routes of treatment are urgently needed. Comparative genomics approaches have successfully identified genetic changes that coincide with the emergence of pathogenicity in Acinetobacter. Genes that are prevalent both in pathogenic and a-pathogenic Acinetobacter species were not considered ignoring that virulence factors may emerge by the modification of evolutionarily old and widespread proteins. Here, we increased the resolution of comparative genomics analyses to also include lineage-specific changes in protein domain architectures. Using type IVa pili (T4aP) as an example, we show that two pilus components, FimU and the pilus tip adhesin ComC, exist with markedly differing domain architectures in pathogenic Acinetobacter species. ComC, has gained a von Willebrand Factor type A domain displaying a finger-like protrusion, and we provide experimental evidence that this finger conveys virulence-related functions in A. baumannii. Both genes together form an evolutionary cassette, which has been replaced at least twice during A. baumannii diversification. The resulting strain-specific differences in T4aP layout suggests differences in the way how individual strains interact with their host. Our study underpins the hypothesis that A. baumannii uses T4aP for host infection as it was shown previously for other pathogens. It also indicates that many more functional complexes may exist whose precise function can be rapidly adjusted by changing the domain architecture of individual proteins. Author SummaryType IVa pili (T4aP) are hair-like, extendable, and retractable appendages that many bacteria use for interacting with their environment. Several human pathogens have independently recruited these pili for processes related to host infection, but the modifications necessary to turn T4aP into virulence factors are largely unknown. Here, we studied if and how T4aP components have changed in the nosocomial pathogen A. baumannii compared to its largely a-pathogenic relatives in the Acinetobacter genus. Most A. baumannii isolates have T4aP with a pilus tip adhesin containing a protein domain not seen outside the pathogenic clade. This domain is essential for bacterial motility and contributes to host cell adhesion and natural competence. However, some isolates have T4aP resembling those of largely a-pathogenic species in this genus. This indicates that the way these pili are used during infection processes differs between A. baumannii isolates probably as a result of niche adaptation. In a broader perspective, our findings highlight that many relevant genetic differences between pathogens and their a-pathogenic relatives emerge only on the domain- and sub-domain level. This suggests that comparative genomics studies have only uncovered the tip of the iceberg of genetic determinants that contribute to A. baumannii virulence.

microbiology↗

bioRxiv2022

Evolutionarily stable gene clusters shed light on the common grounds of pathogenicity in the Acinetobacter calcoaceticus-baumanniicomplex

Nosocomial pathogens of the Acinetobacter calcoaceticus-baumannii (ACB) complex are a cautionary example for the world-wide spread of multi- and pan-drug resistant bacteria. Aiding the urgent demand for novel therapeutic targets, comparative genomics studies between pathogens and their apathogenic relatives shed light on the genetic basis of human-pathogen interaction. Yet, existing studies are limited in taxonomic scope, sensing of the phylogenetic signal, and resolution by largely analyzing genes isolated from their functional contexts. Here, we explored more than 3,000 Acinetobacter genomes in a phylogenomic framework integrating orthology-based phylogenetic profiling and microsynteny conservation analyses. This allowed to delineate gene clusters in the type strain A. baumannii ATCC 19606 whose evolutionary conservation indicates a functional integration of the subsumed genes. These evolutionarily stable gene clusters (ESGCs) reveal metabolic pathways, transcriptional regulators residing next to their targets but also tie together sub-clusters with distinct functions to form higher-order functional modules. We shortlisted 150 ESGCs that either co-emerged with, or are found preferentially in, the pathogenic ACB clade. They unveil, at an unprecedented resolution, the genetic makeup that coincides with the manifestation of the pathogenic phenotype in the last common ancestor of the ACB clade. Key innovations are the remodeling of the regulatory-effector cascade connecting LuxR/LuxI quorum sensing via an intermediate messenger to biofilm formation, the extension of micronutrient scavenging systems, and the increase of metabolic flexibility by exploiting carbon sources that are provided by the human host. Specifically, we could show that only members of the ACB clade use kynurenine as a sole carbon and energy source, a substance produced by humans to fine-tune the antimicrobial innate immune response. In summary, this study provides a rich and unbiased set of novel testable hypotheses on how pathogenic Acinetobacter interact with and ultimately infect their human host. They disclose promising routes for future therapeutic strategies. Author SummaryThe spread of multi- and pan-drug resistant bacterial pathogens is a world-wide threat to human health. Understanding the genetics of host colonization and infection is essential for devising novel ways of treatment. Acinetobacter baumannii, a nosocomial pathogen ranked top by the World Health Organization in the list of bacteria for which novel therapeutic approaches are needed, is a prime example. Here, we have carved out the genetic make-up that distinguishes A. baumannii and its pathogenic next relatives comprising the A. baumannii-calcoaceticus complex from other and mostly apathogenic Acinetobacter species. We found a rich spectrum of pathways and regulatory modules that reveals how the pathogens have modified biofilm formation, iron scavenging, and their carbohydrate metabolism to adapt to their human host. Among these, the capability to metabolize kynurenine is particularly intriguing. Humans produce this substance to contain bacterial invaders and to fine-tune the innate immune response. But A. baumannii and its allies have turned the table. They feed on kynurenine, and thus most likely also dysregulate human immune response. In summary, our study substantially deepens the understanding of how a highly critical pathogen interacts with its host, which substantially eases the identification of novel targets for innovative therapeutic strategies.

genomics↗

bioRxiv2019

A new twist on bacterial motility - Two distinct type IV pili revealed by cryoEM

Many bacteria express flexible protein filaments on their surface that enable a variety of important cellular functions. Type IV pili are examples of such filaments and are comprised of a helical assembly of repeating pilin subunits. Type IV pili are involved in motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). They are therefore powerful structures that enable bacterial proliferation and genetic adaptation, potentially leading to the development of pathogenicity and antibiotic resistance. They are also targets for drug development.\n\nBy a complement of experimental approaches, we show that the bacterium Thermus thermophilus produces two different forms of type IV pilus. We have determined the structures of both and built atomic models. The structures answer key unresolved questions regarding the molecular architecture of type IV pili and identify a new type of pilin. We also delineate the roles of the two filaments in promoting twitching and natural transformation.

biophysics↗