bioRxiv Science⌕ Search

bioRxiv · 10.1101/2024.06.27.601069

LasR regulates protease IV expression at suboptimal growth temperatures in Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is a highly versatile bacterium capable of surviving and often thriving in stressful environmental conditions. Here we report the effect of two environmental conditions, temperature and growth phase, on the P. aeruginosa PAO1 transcriptome. As P. aeruginosa is well-known for its growth phase dependent phenotypes and gene regulation, our goal was to determine how temperature altered global gene expression at exponential versus stationary phase and to characterize how growth phase affects thermoregulation. To do this, we grew PAO1 in parallel at 25{degrees}C and 37{degrees}C and sampled the same populations first at exponential phase and then again at stationary phase and assessed gene expression by RNA-sequencing. We found that temperature regulated hundreds of genes at, and unique to, exponential and stationary phase. We also grew PAO1 and an isogenic {Delta}lasR mutant at 25{degrees}C and 37{degrees}C and sampled populations at stationary phase to define LasR-regulated genes at each temperature by RNA-sequencing. LasR regulated most of its target genes similarly at 25{degrees}C and 37{degrees}C, although we identified a subset of genes whose regulation by LasR was affected by temperature. This work provides a comprehensive thermoregulon for PAO1 at two distinct growth phases, as well as growth phase transcriptomics at two temperatures, and expands our understanding of quorum sensing regulation under different environmental conditions that P. aeruginosa encounters. IMPORTANCEPseudomonas aeruginosa is a highly adaptable opportunistic pathogen with a repertoire of mechanisms for surviving in diverse and often challenging environments yet is most often studied at 37{degrees}C as the optimum temperature for growth. To better understand how this bacterium survives in the environment versus the human body, we performed transcriptomics on P. aeruginosa grown at 25{degrees}C and 37{degrees}C. At each temperature, we examined both exponential and stationary phases. We also determined the LasRI quorum sensing regulon at 37{degrees}C compared to 25{degrees}C using a {Delta}lasR mutant, which uncovered a suite of previously unrecognized LasR-regulated genes. Our work provides a comprehensive transcriptomic resource for thermoregulation of P. aeruginosa at two growth phases, as well as growth phase and LasR regulation at two temperatures.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Done, R., Robertson, J., Prezioso, S., Goldberg, J. B.. 2024-06-28. LasR regulates protease IV expression at suboptimal growth temperatures in Pseudomonas aeruginosa. https://doi.org/10.1101/2024.06.27.601069

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

pTRIP, a novel integration plasmid for Listeria monocytogenes

In the past decades, several tools to genetically modify the human pathogen Listeria monocytogenes were developed. Here, we constructed a new integrative plasmid system for L. monocytogenes named pTRIP, for treB insertion plasmid. pTRIP is a vector which stably integrates into the treB locus of the wild type EGD-e. This locus encodes the sole trehalose-specific EIIB and EIIC component of a phosphotransferase system. Successful integration leads to the disruption of treB and thus, to an inability of the resulting L. monocytogenes strains to grow on trehalose as sole carbon source. Due to integration through double homologous recombination, it is the first integrative system which does not require antibiotic selection pressure. To assess functionality of the pTRIP system, prfA and its native promoter region were integrated into the treB locus of a {Delta}prfA strain. Complementation was confirmed in 78% of the isolated clones, indicating successful integration of prfA into the treB locus. We further constructed derivatives of pTRIP harboring the constitutive Pp60 (pTRIP1) and the inducible Prha (pTRIP2) promoter to further expand application possibilities. Microscopic analyses confirmed the functionality of both promoter constructs and showed dose-dependent induction for Prha. pTRIP is an efficient tool for stable gene expression as well as functional studies and expands genetic modification possibilities for L. monocytogenes.

microbiology↗

A rational design strategy and validation for protease-resistant fusion-inhibitor antiviral peptides

Peptide-based fusion inhibitors are promising pharmaceuticals in the fight against enveloped viruses relying on membrane fusion for host infection. However, peptide therapeutic applications have long been hindered by their poor stability in vivo. Here, we discovered that peptide inhibitors with the wildtype sequence of the heptad repeat 2 (HR2) domain of the SARS-CoV-2 spike protein are efficiently cleaved by Transmembrane Protease, Serine 2 (TMPRSS2), a key protease involved in the SARS-CoV-2 virus-cell fusion pathway. We then identified the corresponding cleavage sites and designed three protease-resistant peptides using ranking based on deep mutational scanning and natural occurrence. The three candidates all exhibit inhibitory activity in a cell-cell fusion assay. A high-resolution cryo-EM structure of the top candidate, HR2-NHN, bound to its HR1 target reveals the molecular basis for its potent activity. The top candidate of the cell-based screening assay significantly improved efficacy relative to the wildtype peptide when administered 12 h before infection in both an authentic virus-cell infection assay and a mouse assay. More broadly, our results suggest that the design strategies for protease-resistant peptides could be applied to a broad spectrum of other enveloped viruses and pave the way for the development of safe, prophylactic antivirals that can be administered before exposure.

microbiology↗

Host soluble inositol phosphate signaling promotes coronavirus replication

Coronaviruses rely extensively on host pathways for replication, making host-directed therapies an attractive strategy for broad-spectrum antivirals with reduced risk of viral resistance. Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.

microbiology↗