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Revealing 29 sets of independently modulated genes in Staphylococcus aureus, their regulators, and role in key physiological response.

ABSTRACT: The ability of Staphylococcus aureus to infect many different tissue sites is enabled, in part, by its transcriptional regulatory network (TRN) that coordinates its gene expression to respond to different environments. We elucidated the organization and activity of this TRN by applying independent component analysis to a compendium of 108 RNA-sequencing expression profiles from two S. aureus clinical strains (TCH1516 and LAC). ICA decomposed the S. aureus transcriptome into 29 independently modulated sets of genes (i-modulons) that revealed: 1) High confidence associations between 21 i-modulons and known regulators; 2) an association between an i-modulon and ?S, whose regulatory role was previously undefined; 3) the regulatory organization of 65 virulence factors in the form of three i-modulons associated with AgrR, SaeR, and Vim-3; 4) the roles of three key transcription factors (CodY, Fur, and CcpA) in coordinating the metabolic and regulatory networks; and 5) a low-dimensional representation, involving the function of few transcription factors of changes in gene expression between two laboratory media (RPMI, cation adjust Mueller Hinton broth) and two physiological media (blood and serum). This representation of the TRN covers 842 genes representing 76% of the variance in gene expression that provides a quantitative reconstruction of transcriptional modules in S. aureus, and a platform enabling its full elucidation.

SUBMITTER: Poudel S

PROVIDER: S-EPMC7382225 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Revealing 29 sets of independently modulated genes in Staphylococcus aureus, their regulators, and role in key physiological response.

Poudel Saugat S Tsunemoto Hannah H Seif Yara Y Sastry Anand V AV Szubin Richard R Xu Sibei S Machado Henrique H Olson Connor A CA Anand Amitesh A Pogliano Joe J Nizet Victor V Palsson Bernhard O BO

Proceedings of the National Academy of Sciences of the United States of America 20200702 29

The ability of Staphylococcus aureus to infect many different tissue sites is enabled, in part, by its transcriptional regulatory network (TRN) that coordinates its gene expression to respond to different environments. We elucidated the organization and activity of this TRN by applying independent component analysis to a compendium of 108 RNA-sequencing expression profiles from two S. aureus clinical strains (TCH1516 and LAC). ICA decomposed the S. aureus transcriptome into ...[more]

PMID: 32616573

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Project description:The complex cross talk between metabolism and gene regulatory networks makes it difficult to untangle individual constituents and study their precise roles and interactions. To address this issue, we modularized the transcriptional regulatory network (TRN) of the Staphylococcus aureus USA300 strain by applying independent component analysis (ICA) to 385 RNA sequencing samples. We then combined the modular TRN model with a metabolic model to study the regulation of carbon and amino acid metabolism. Our analysis showed that regulation of central carbon metabolism by CcpA and amino acid biosynthesis by CodY are closely coordinated. In general, S. aureus increases the expression of CodY-regulated genes in the presence of preferred carbon sources such as glucose. This transcriptional coordination was corroborated by metabolic model simulations that also showed increased amino acid biosynthesis in the presence of glucose. Further, we found that CodY and CcpA cooperatively regulate the expression of ribosome hibernation-promoting factor, thus linking metabolic cues with translation. In line with this hypothesis, expression of CodY-regulated genes is tightly correlated with expression of genes encoding ribosomal proteins. Together, we propose a coarse-grained model where expression of S. aureus genes encoding enzymes that control carbon flux and nitrogen flux through the system is coregulated with expression of translation machinery to modularly control protein synthesis. While this work focuses on three key regulators, the full TRN model we present contains 76 total independently modulated sets of genes, each with the potential to uncover other complex regulatory structures and interactions. IMPORTANCE Staphylococcus aureus is a versatile pathogen with an expanding antibiotic resistance profile. The biology underlying its clinical success emerges from an interplay of many systems such as metabolism and gene regulatory networks. This work brings together models for these two systems to establish fundamental principles governing the regulation of S. aureus central metabolism and protein synthesis. Studies of these fundamental biological principles are often confined to model organisms such as Escherichia coli. However, expanding these models to pathogens can provide a framework from which complex and clinically important phenotypes such as virulence and antibiotic resistance can be better understood. Additionally, the expanded gene regulatory network model presented here can deconvolute the biology underlying other important phenotypes in this pathogen.

Project description:Staphylococcus aureus is an important pathogen responsible for nosocomial and community-acquired infections in humans, and methicillin-resistant S. aureus (MRSA) infections have continued to increase despite widespread preventative measures. S. aureus can colonize the female vaginal tract, and reports have suggested an increase in MRSA infections in pregnant and postpartum women as well as outbreaks in newborn nurseries. Currently, little is known about specific factors that promote MRSA vaginal colonization and subsequent infection. To study S. aureus colonization of the female reproductive tract in a mammalian system, we developed a mouse model of S. aureus vaginal carriage and demonstrated that both hospital-associated and community-associated MRSA isolates can colonize the murine vaginal tract. Immunohistochemical analysis revealed an increase in neutrophils in the vaginal lumen during MRSA colonization. Additionally, we observed that a mutant lacking fibrinogen binding adhesins exhibited decreased persistence within the mouse vagina. To further identify novel factors that promote vaginal colonization, we performed RNA sequencing to determine the transcriptome of MRSA growing in vivo during vaginal carriage at 5 h, 1 day, and 3 days postinoculation. Over 25% of the bacterial genes were differentially regulated at all time points during colonization compared to laboratory cultures. The most highly induced genes were those involved in iron acquisition, including the Isd system and siderophore transport systems. Mutants deficient in these pathways did not persist as well during in vivo colonization. These results reveal that fibrinogen binding and the capacity to overcome host nutritional limitation are important determinants of MRSA vaginal colonization.IMPORTANCEStaphylococcus aureus is an opportunistic pathogen able to cause a wide variety of infections in humans. Recent reports have suggested an increasing prevalence of MRSA in pregnant and postpartum women, coinciding with the increased incidence of MRSA infections in neonatal intensive care units (NICUs) and newborn nurseries. Vertical transmission from mothers to infants at delivery is a likely route of MRSA acquisition by the newborn; however, essentially nothing is known about host and bacterial factors that influence MRSA carriage in the vagina. Here, we established a mouse model of vaginal colonization and observed that multiple MRSA strains can persist in the vaginal tract. Additionally, we determined that MRSA interactions with fibrinogen and iron uptake can promote vaginal persistence. This study is the first to identify molecular mechanisms which govern vaginal colonization by MRSA, the critical initial step preceding infection and neonatal transmission.

Dataset Information

Revealing 29 sets of independently modulated genes in Staphylococcus aureus, their regulators, and role in key physiological response.

Publications

Revealing 29 sets of independently modulated genes in <i>Staphylococcus aureus</i>, their regulators, and role in key physiological response.

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