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Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.

ABSTRACT: Human skin is commonly colonized and infected by Staphylococcus aureus. Exactly how these organisms are sensed by keratinocytes has not been clearly delineated. Using a combination of metabolic and transcriptomic methodologies, we found that S. aureus infection is sensed as a metabolic stress by the hypoxic keratinocytes. This induces HIF1? signaling, which promotes IL-1? production and stimulates aerobic glycolysis to meet the metabolic requirements of infection. We demonstrate that staphylococci capable of glycolysis, including WT and agr mutants, readily induce HIF1? responses. In contrast, ?pyk glycolytic mutants fail to compete with keratinocytes for their metabolic needs. Suppression of glycolysis using 2-DG blocked keratinocyte production of IL-1? in vitro and significantly exacerbated the S. aureus cutaneous infection in a murine model. Our data suggest that S. aureus impose a metabolic stress on keratinocytes that initiates signaling necessary to promote both glycolysis and the proinflammatory response to infection.

SUBMITTER: Wickersham M

PROVIDER: S-EPMC6799992 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.

Wickersham Matthew M Wachtel Sarah S Wong Fok Lung Tania T Soong Grace G Jacquet Rudy R Richardson Anthony A Parker Dane D Prince Alice A

Cell reports 20170301 11

Human skin is commonly colonized and infected by Staphylococcus aureus. Exactly how these organisms are sensed by keratinocytes has not been clearly delineated. Using a combination of metabolic and transcriptomic methodologies, we found that S. aureus infection is sensed as a metabolic stress by the hypoxic keratinocytes. This induces HIF1α signaling, which promotes IL-1β production and stimulates aerobic glycolysis to meet the metabolic requirements of infection. We demonstrate that staphylococ ...[more]

PMID: 28297676

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Project description:Staphylococcus aureus is an important pathogen that leads to high morbidity and mortality. Although S. aureus produces many factors important for pathogenesis, few have been validated as playing a role in the pathogenesis of S. aureus pneumonia. To gain a better understanding of the genetic elements required for S. aureus pathogenesis in the airway, we performed an unbiased genome-wide transposon sequencing (Tn-seq) screen in a model of acute murine pneumonia. We identified 136 genes important for bacterial survival during infection, with a high proportion involved in metabolic processes. Phenotyping 80 individual deletion mutants through diverse in vitro and in vivo assays demonstrated that metabolism is linked to several processes, which include biofilm formation, growth, and resistance to host stressors. We further validated the importance of 23 mutations in pneumonia. Multivariate and principal-component analyses identified two key metabolic mechanisms enabling infection in the airway, growth (e.g., the ability to replicate and form biofilms) and resistance to host stresses. As deep validation of these hypotheses, we investigated the role of pyruvate carboxylase, which was important across multiple infection models and confirmed a connection between growth and resistance to host cell killing. Pathogenesis is conventionally understood in terms of the host-pathogen interactions that enable a pathogen to neutralize a host's immune response. We demonstrate with the important bacterial pathogen S. aureus that microbial metabolism influences key traits important for in vivo infection, independent from host immunomodulation. IMPORTANCE Staphylococcus aureus is an important bacterial pathogen that causes significant morbidity and mortality, infecting numerous bodily sites, including the respiratory tract. To identify the bacterial requirements for lung infection, we conducted a genome-wide screen in a mouse model of acute pneumonia. We discovered that metabolic genes were overrepresented in those required for lung infection. In contrast to the conventional view of pathogenesis focusing on immunomodulation, we demonstrate through phenotyping of deletion mutants in several functional assays that replicative ability and tolerance against host defenses form two key metabolic dimensions of bacterial infection. These dimensions are independent for most pathways but are coupled in central carbon metabolism and highlight the critical role of bacterial metabolism in survival against host defenses during infection.

Project description:Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were used in vitro and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. In vitro experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6) from severe Escherichia coli sepsis (n = 10) and identified treatment responses over time. Combined analysis of human, in vitro, and mice samples identified 25 metabolites indicative of effective treatment of S. aureus sepsis. Taken together, this study provides a proof of concept of the utility of analyzing metabolite patterns in blood for early differentiation between ineffective and effective antibiotic treatment in acute S. aureus infections.

Dataset Information

Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.

Publications

Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.

Similar Datasets

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