RESUMEN
BACKGROUND: The innate immune system is the first line of defense against microbial pathogens and is essential for maintaining good health. If pathogens breach innate barriers, the likelihood of infection is significantly increased. Many bacterial pathogens pose a threat to human health on account of their ability to evade innate immunity and survive in growth-restricted environments. These pathogens have evolved sophisticated strategies to obtain nutrients as well as manipulate innate immune responses, resulting in disease or chronic infection. SUMMARY: The relationship between bacterial metabolism and innate immunity is complex. Although aspects of bacterial metabolism can be beneficial to the host, particularly those related to the microbiota and barrier integrity, others can be harmful. Several bacterial pathogens harness metabolism to evade immune responses and persist during infection. The study of these adaptive traits provides insight into the roles of microbial metabolism in pathogenesis that extend beyond energy balance. This review considers recent studies on bacterial metabolic pathways that promote infection by circumventing several facets of the innate immune system. We also discuss relationships between innate immunity and antibiotics and highlight future directions for research in this field. KEY MESSAGES: Pathogenic bacteria have a remarkable capacity to harness metabolism to manipulate immune responses and promote pathogenesis. While we are beginning to understand the multifaceted and complex metabolic adaptations that occur during infection, there is still much to uncover with future research.
Asunto(s)
Bacterias , Inmunidad Innata , HumanosRESUMEN
Tissue damage and persistent inflammation are distinctive features of antibiotic-resistant chronic infections. In this issue of Cell Host & Microbe, Tang et al. demonstrate that anti-folate antibiotics trigger the synthesis of a bacterial second messenger, which induces an exuberant immune response and establishes a paradigm for chronic infection.
Asunto(s)
Antibacterianos , Bacterias , Antibacterianos/farmacología , Antibacterianos/uso terapéuticoRESUMEN
A central question concerning natural competence is why orthologs of competence genes are conserved in non-competent bacterial species, suggesting they have a role other than in transformation. Here we show that competence induction in the human pathogen Staphylococcus aureus occurs in response to ROS and host defenses that compromise bacterial respiration during infection. Bacteria cope with reduced respiration by obtaining energy through fermentation instead. Since fermentation is energetically less efficient than respiration, the energy supply must be assured by increasing the glycolytic flux. The induction of natural competence increases the rate of glycolysis in bacteria that are unable to respire via upregulation of DNA- and glucose-uptake systems. A competent-defective mutant showed no such increase in glycolysis, which negatively affects its survival in both mouse and Galleria infection models. Natural competence foster genetic variability and provides S. aureus with additional nutritional and metabolic possibilities, allowing it to proliferate during infection.
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Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Metabolismo de los Hidratos de Carbono , Fermentación , Glucólisis/genética , Ratones , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismoRESUMEN
Scaffold proteins are ubiquitous chaperones that bind proteins and facilitate physical interaction of multi-enzyme complexes. Here we used a biochemical approach to dissect the scaffold activity of the flotillin-homolog protein FloA of the multi-drug-resistant human pathogen Staphylococcus aureus. We show that FloA promotes oligomerization of membrane protein complexes, such as the membrane-associated RNase Rny, which forms part of the RNA-degradation machinery called the degradosome. Cells lacking FloA had reduced Rny function and a consequent increase in the targeted sRNA transcripts that negatively regulate S. aureus toxin expression. Small molecules that altered FloA oligomerization also reduced Rny function and decreased the virulence potential of S. aureus in vitro, as well as in vivo, using invertebrate and murine infection models. Our results suggest that flotillin assists in the assembly of protein complexes involved in S. aureus virulence, and could thus be an attractive target for the development of new antimicrobial therapies.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas de la Membrana/metabolismo , Staphylococcus aureus/patogenicidad , Virulencia , Animales , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana Múltiple , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Femenino , Microdominios de Membrana/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacología , Fosforilcolina/uso terapéutico , Multimerización de Proteína/efectos de los fármacos , ARN Bacteriano/genética , ARN Bacteriano/aislamiento & purificación , ARN Bacteriano/metabolismo , ARN Ribosómico 5S/genética , ARN Ribosómico 5S/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/mortalidad , Infecciones Estafilocócicas/patología , Staphylococcus aureus/metabolismo , Tasa de Supervivencia , Técnicas del Sistema de Dos Híbridos , Virulencia/efectos de los fármacos , Virulencia/genéticaRESUMEN
Klebsiella pneumoniae is an opportunistic pathogen important in hospital-acquired infections, which are complicated by the rise of drug-resistant strains and the capacity of cells to adhere to surfaces and form biofilms. In this work, we carried out an analysis of the genes in the K. pneumoniae yfiRNB operon, previously implicated in biofilm formation. The results indicated that in addition to the previously reported effect on type 3 fimbriae expression, this operon also affected biofilm formation due to changes in cellulose as part of the extracellular matrix. Deletion of yfiR resulted in enhanced biofilm formation and an altered colony phenotype indicative of cellulose overproduction when grown on solid indicator media. Extraction of polysaccharides and treatment with cellulase were consistent with the presence of cellulose in biofilms. The enhanced cellulose production did not, however, correlate with virulence as assessed using a Caenorhabditis elegans assay. In addition, cells bearing mutations in genes of the yfiRNB operon varied with respect to the WT control in terms of susceptibility to the antibiotics amikacin, ciprofloxacin, imipenem and meropenem. These results indicated that the yfiRNB operon is implicated in the production of exopolysaccharides that alter cell surface characteristics and the capacity to form biofilms--a phenotype that does not necessarily correlate with properties related with survival, such as resistance to antibiotics.