Biology subjects

Moran, J. C.

Publications and source records attributed to Moran, J. C..

3 recordsLinked to original sources

bioRxiv2021

Long term nasopharyngeal colonization by Staphylococcus aureus determinants of adaptation

Staphylococcus aureus nasal colonization is a risk factor for infection. A large proportion of the population are identified as potential S. aureus carriers yet we only partially understand the repertoire of genetic factors that promote long-term nasal colonization. Here we present a novel murine model of nasopharyngeal colonization that requires a low S. aureus inoculum and is amenable to experimental evolution approaches. We used this model to experimentally evolve S. aureus using successive passages in the nasopharynx to identify those genetic loci under selection. After 3 cycles of colonization, mutations were identified in mannitol, sorbitol, arginine, nitrite and lactate metabolism genes promoting key pathways in nasal colonization. Stress responses were identified as being under selective pressure, with mutations in DNA repair genes including dnaJ and recF and key stress response genes clpL, rpoB and ahpF. Peptidoglycan synthesis pathway genes also revealed mutations indicating potential selection for alteration of the cell surface. The infection model used here is versatile to assist decolonization and persistence studies.

microbiology↗

bioRxiv2021

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we established an optimized ribosome profiling approach tailored for the unique features of the human mitoribosome. Analysis of ribosome footprints in five cell types revealed that average mitochondrial synthesis rates corresponded precisely to cytosolic rates across OXPHOS complexes. Balanced mitochondrial and cytosolic synthesis did not rely on rapid feedback between the two translation systems. Rather, LRPPRC, a gene associated with Leighs syndrome, is required for the reciprocal translatomes and maintains cellular proteostasis. Based on our findings, we propose that human mitonuclear balance is enabled by matching OXPHOS subunit synthesis rates across cellular compartments, which may represent a vulnerability for cellular proteostasis.

cell biology↗

bioRxiv2020

Transcriptomic responses and survival mechanisms of staphylococci to the antimicrobial skin lipid sphingosine

Sphingosines are antimicrobial lipids that form part of the innate barrier to skin colonisation by microbes. Sphingosine deficiencies can result in increased epithelial infections by bacteria including Staphylococcus aureus. Recent studies have focused on the potential use of sphingosines as novel therapeutic agents, but there have been no investigations into sphingosine resistance or its potential mechanisms. We used RNA-Seq to identify the common D-sphingosine transcriptomic response of the transient skin coloniser S. aureus and the dominant skin coloniser S. epidermidis. A common D-sphingosine stimulon was identified that included downregulation of the SaeSR two-component system (TCS) regulon and upregulation of both the VraSR TCS and CtsR stress regulons. We show that the PstSCAB phosphate transporter, and VraSR offer intrinsic resistance to D-sphingosine. Further, we demonstrate increased sphingosine resistance in these staphylococci evolves readily through mutations in genes encoding the FarE-FarR efflux/regulator proteins. The ease of selecting mutants with resistance to sphingosine may impact upon staphylococcal colonisation of skin where the lipid is present and have implications with topical therapeutic applications.

microbiology↗