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Staphylococcus aureus has evolved mechanisms to cope with low iron (Fe) availability in host tissues. S. aureus uses the ferric uptake transcriptional regulator (Fur) to sense titers of cytosolic Fe. Upon Fe depletion, apo-Fur relieves transcriptional repression of genes utilized for Fe uptake. We demonstrate that an S. aureus Δfur mutant has decreased expression of acnA, which codes for the Fe-dependent enzyme aconitase. Decreased acnA expression prevented the Δfur mutant from growing with amino acids as sole carbon and energy sources. Suppressor analysis determined that a mutation in isrR, which produces a regulatory RNA, permitted growth by decreasing isrR transcription. The decreased AcnA activity of the Δfur mutant was partially relieved by an ΔisrR mutation. Directed mutation of bases predicted to facilitate the interaction between the acnA transcript and IsrR, decreased the ability of IsrR to control acnA expression in vivo and IsrR bound to the acnA transcript in vitro. IsrR also bound to the transcripts coding the alternate TCA cycle proteins sdhC, mqo, citZ, and citM. Whole cell metal analyses suggest that IsrR promotes Fe uptake and increases intracellular Fe not ligated by macromolecules. Lastly, we determined that Fur and IsrR promote infection using murine skin and acute pneumonia models.
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Type III interferon signaling contributes to the pathogenesis of the important human pathogen Staphylococcus aureus in the airway. Little is known of the cellular factors important in this response. Using Ifnl2-green fluorescent protein reporter mice combined with flow cytometry and cellular depletion strategies, we demonstrate that the alveolar macrophage is the primary producer of interferon lambda (IFN-λ) in response to S. aureus in the airway. Bone marrow chimeras showed reduced bacterial burden in IFN-λ receptor (IFNLR1)-deficient recipient mice, indicative that non-hematopoietic cells were important for pathogenesis, in addition to significant reductions in pulmonary inflammation. These observations were confirmed through the use of an airway epithelial-specific IFNLR knockout mouse. Our data suggest that upon entry to the airway, S. aureus activates alveolar macrophages to produce type III IFN that is subsequently sensed by the airway epithelium. Future steps will determine how signaling from the epithelium then exerts its influence on bacterial clearance. These results highlight the important, yet sometimes detrimental, role of type III IFN signaling during infection and the impact the airway epithelium plays during host-pathogen interactions.IMPORTANCEThe contribution of type III interferon signaling to the control of bacterial infections is largely unknown. We have previously demonstrated that it contributes to the pathogenesis of acute Staphylococcus aureus respiratory infection. In this report, we document the importance of two cell types that underpin this pathogenesis. We demonstrate that the alveolar macrophage is the cell that is responsible for the production of type III interferon and that this molecule is sensed by airway epithelial cells, which impacts both bacterial clearance and induction of inflammation. This work sheds light on the first two aspects of this important pathogenic cascade.
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Interferones , Macrófagos Alveolares , Ratones Noqueados , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/genética , Ratones , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/inmunología , Infecciones Estafilocócicas/microbiología , Interferones/metabolismo , Interferones/genética , Interferones/inmunología , Ratones Endogámicos C57BL , Interacciones Huésped-Patógeno , Transducción de Señal , Mucosa Respiratoria/microbiología , Interferón lambda , Receptores de Interferón/genética , Receptores de Interferón/metabolismo , VirulenciaRESUMEN
The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.
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Proteínas Bacterianas , Regulación Bacteriana de la Expresión Génica , Peróxido de Hidrógeno , Estrés Oxidativo , Percepción de Quorum , Staphylococcus aureus , Transactivadores , Staphylococcus aureus/genética , Staphylococcus aureus/fisiología , Staphylococcus aureus/metabolismo , Percepción de Quorum/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Animales , Transactivadores/metabolismo , Transactivadores/genética , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Ratones , Infecciones Estafilocócicas/microbiología , Viabilidad Microbiana , Especies Reactivas de Oxígeno/metabolismo , Eliminación de GenRESUMEN
The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δagr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.
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Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis.
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Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Ratones , Staphylococcus aureus/genética , Vía de Pentosa Fosfato/genética , Peróxido de Hidrógeno/metabolismo , Virulencia , Escherichia coli , BiopelículasRESUMEN
To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections.
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Cobre , Staphylococcus aureus , Animales , Ratones , Staphylococcus aureus/metabolismo , Vía de Pentosa Fosfato , Ribosa-Fosfato Pirofosfoquinasa/genética , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Fosforribosil Pirofosfato/metabolismo , AdeninaRESUMEN
The pathogenic bacterium Staphylococcus aureus is the most common pathogen isolated in skin-and-soft-tissue infections (SSTIs) in the United States. Most S. aureus SSTIs are caused by the epidemic clone USA300 in the USA. These infections can be serious; in 2019, SSTIs with S. aureus were associated with an all-cause, age-standardized mortality rate of 0.5 globally. Clinical presentations of S. aureus SSTIs vary from superficial infections with local symptoms to monomicrobial necrotizing fasciitis, which can cause systemic manifestations and may lead to serious complications or death. In order to cause skin infections, S. aureus employs a host of virulence factors including cytolytic proteins, superantigenic factors, cell wall-anchored proteins, and molecules used for immune evasion. The immune response to S. aureus SSTIs involves initial responders such as keratinocytes and neutrophils, which are supported by dendritic cells and T-lymphocytes later during infection. Treatment for S. aureus SSTIs is usually oral therapy, with parenteral therapy reserved for severe presentations; it ranges from cephalosporins and penicillin agents such as oxacillin, which is generally used for methicillin-sensitive S. aureus (MSSA), to vancomycin for methicillin-resistant S. aureus (MRSA). Treatment challenges include adverse effects, risk for Clostridioides difficile infection, and potential for antibiotic resistance.
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Acinetobacter baumannii is an opportunistic pathogen that has recently emerged as a global threat associated with high morbidity, mortality, and antibiotic resistance. We determined the role of type I interferon (IFN) signaling in A. baumannii infection. We report that A. baumannii can induce a type I IFN response that is dependent upon TLR4-TRIF-IRF3 and phagocytosis of the bacterium. Phase variants of A. baumannii that have a reduced capsule, lead to enhanced TLR4-dependent type I IFN induction. This was also observed in a capsule-deficient strain. However, we did not observe a role for this pathway in vivo. The enhanced signaling could be accounted for by increased phagocytosis in capsule-deficient strains that also lead to enhanced host cell-mediated killing. The increased cytokine response in the absence of the capsule was not exclusive to type I IFN signaling. Several cytokines, including the proinflammatory IL-6, were increased in cells stimulated with the capsule-deficient strain, also observed in vivo. After 4 h in our acute pneumonia model, the burden of a capsule-null strain was significantly reduced, yet we observed increases in innate immune cells and inflammatory markers compared to wild-type A. baumannii. This study underscores the role of phase variation in the modulation of host immune responses and indicates that the capsule of A. baumannii plays an important role in protection against host cell killing and evasion from activation of the innate immune response.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Infecciones por Acinetobacter/microbiología , Citocinas , Humanos , Inmunidad Innata , Fagocitosis , Receptor Toll-Like 4RESUMEN
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.
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Interacciones Huésped-Patógeno , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/genética , Enfermedad Aguda , Animales , Biopelículas/crecimiento & desarrollo , Elementos Transponibles de ADN/genética , Modelos Animales de Enfermedad , Regulación Bacteriana de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Neumonía Bacteriana/microbiología , Análisis de Secuencia de ADN , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidad , Estrés Fisiológico/genética , Virulencia , Factores de Virulencia/metabolismoRESUMEN
Neutrophils are immune cells classically defined as pro-inflammatory effector cells. However, current accumulated evidence indicates that neutrophils have more versatile immune-modulating properties. During acute lung infection with Streptococcus pneumoniae in mice, interleukin-10 (IL-10) production is required to temper an excessive lung injury and to improve survival, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during S. pneumoniae infection remain unknown. Here we show that neutrophils are the main myeloid cells that produce IL-10 in the lungs during the first 48 h of infection. Importantly, in vitro assays with bone-marrow derived neutrophils confirmed that IL-10 can be induced by these cells by the direct recognition of pneumococcal antigens. In vivo, we identified the recruitment of two neutrophil subpopulations in the lungs following infection, which exhibited clear morphological differences and a distinctive profile of IL-10 production at 48 h post-infection. Furthermore, adoptive transfer of neutrophils from WT mice into IL-10 knockout mice (Il10-/- ) fully restored IL-10 production in the lungs and reduced lung histopathology. These results suggest that IL-10 production by neutrophils induced by S. pneumoniae limits lung injury and is important to mediate an effective immune response required for host survival.
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Interleucina-10/metabolismo , Pulmón/patología , Neutrófilos/metabolismo , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/fisiología , Traslado Adoptivo , Animales , Antiinflamatorios , Células Cultivadas , Inmunidad Celular , Interleucina-10/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración NeutrófilaRESUMEN
Interferons (IFNs) are a broad class of cytokines that have multifaceted roles. Type I IFNs have variable effects when it comes to host susceptibility to bacterial infections, that is, the resulting outcomes can be either protective or deleterious. The mechanisms identified to date have been wide and varied between pathogens. In this review, we discuss recent literature that provides new insights into the mechanisms of how type I IFN signaling exerts its effects on the outcome of infection from the host's point of view.
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Infecciones Bacterianas/inmunología , Interferón Tipo I/inmunología , Animales , Bacterias/genética , Infecciones Bacterianas/genética , Infecciones Bacterianas/microbiología , Fenómenos Fisiológicos Bacterianos , Susceptibilidad a Enfermedades , Humanos , Interferón Tipo I/genéticaRESUMEN
To cause infection, Staphylococcus aureus must withstand damage caused by host immune defenses. However, the mechanisms by which staphylococcal DNA is damaged and repaired during infection are poorly understood. Using a panel of transposon mutants, we identified the rexBA operon as being important for the survival of Staphylococcus aureus in whole human blood. Mutants lacking rexB were also attenuated for virulence in murine models of both systemic and skin infections. We then demonstrated that RexAB is a member of the AddAB family of helicase/nuclease complexes responsible for initiating the repair of DNA double-strand breaks. Using a fluorescent reporter system, we were able to show that neutrophils cause staphylococcal DNA double-strand breaks through reactive oxygen species (ROS) generated by the respiratory burst, which are repaired by RexAB, leading to the induction of the mutagenic SOS response. We found that RexAB homologues in Enterococcus faecalis and Streptococcus gordonii also promoted the survival of these pathogens in human blood, suggesting that DNA double-strand break repair is required for Gram-positive bacteria to survive in host tissues. Together, these data demonstrate that DNA is a target of host immune cells, leading to double-strand breaks, and that the repair of this damage by an AddAB-family enzyme enables the survival of Gram-positive pathogens during infection.IMPORTANCE To cause infection, bacteria must survive attack by the host immune system. For many bacteria, including the major human pathogen Staphylococcus aureus, the greatest threat is posed by neutrophils. These immune cells ingest the invading organisms and try to kill them with a cocktail of chemicals that includes reactive oxygen species (ROS). The ability of S. aureus to survive this attack is crucial for the progression of infection. However, it was not clear how the ROS damaged S. aureus and how the bacterium repaired this damage. In this work, we show that ROS cause breaks in the staphylococcal DNA, which must be repaired by a two-protein complex known as RexAB; otherwise, the bacterium is killed, and it cannot sustain infection. This provides information on the type of damage that neutrophils cause S. aureus and the mechanism by which this damage is repaired, enabling infection.
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Reparación del ADN , Exodesoxirribonucleasas/metabolismo , Interacciones Huésped-Patógeno , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Roturas del ADN de Doble Cadena , Exodesoxirribonucleasas/genética , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Especies Reactivas de Oxígeno/metabolismo , Estallido RespiratorioRESUMEN
Infectious diseases are a leading cause of death worldwide with over 8 million fatalities accounted for in 2016. Solicitation of host immune defenses by vaccination is the treatment of choice to prevent these infections. It has long been thought that vaccine immunity was solely mediated by the adaptive immune system. However, over the past decade, numerous studies have shown that innate immune cells can also retain memory of these encounters. This process, called innate immune memory, is mediated by metabolic and epigenetic changes that make cells either hyperresponsive (trained immunity) or hyporesponsive (tolerance) to subsequent challenges. In this review, we discuss the concepts of trained immunity and tolerance in the context of host-pathogen interactions.
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Inmunidad Adaptativa/inmunología , Interacciones Huésped-Patógeno/inmunología , Tolerancia Inmunológica , Inmunidad Innata/inmunología , Memoria Inmunológica , Epigénesis Genética/inmunología , Humanos , Vacunas/administración & dosificación , Vacunas/inmunologíaRESUMEN
Staphylococcus aureus is a leading cause of bacterial pneumonia, and we have shown previously that type I interferon (IFN) contributes to the pathogenesis of this disease. In this study, we screened 75 S. aureus strains for their ability to induce type I and III IFN. Both cytokine pathways were differentially stimulated by various S. aureus strains independently of their isolation sites or methicillin resistance profiles. These induction patterns persisted over time, and type I and III IFN generation differentially correlated with tumor necrosis factor alpha production. Investigation of one isolate, strain 126, showed a significant defect in type I IFN induction that persisted over several time points. The lack of induction was not due to differential phagocytosis, subcellular location, or changes in endosomal acidification. A correlation between reduced type I IFN induction levels and decreased autolysis and lysostaphin sensitivity was found between strains. Strain 126 had a decreased rate of autolysis and increased resistance to lysostaphin degradation and host cell-mediated killing. This strain displayed decreased virulence in a murine model of acute pneumonia compared to USA300 (current epidemic strain and commonly used in research) and had reduced capacity to induce multiple cytokines. We observed this isolate to be a vancomycin-intermediate S. aureus (VISA) strain, and reduced Ifnb was observed with a defined mutation in walK that induces a VISA phenotype. Overall, this study demonstrates the heterogeneity of IFN induction by S. aureus and uncovered an interesting property of a VISA strain in its inability to induce type I IFN production.
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Citocinas/inmunología , Interferón Tipo I/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/patogenicidad , Animales , Antibacterianos/farmacología , Carga Bacteriana , Proteínas Bacterianas/genética , Células Cultivadas , Farmacorresistencia Bacteriana/genética , Lisostafina/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Mutación , Neumonía Estafilocócica/inmunología , Neumonía Estafilocócica/microbiología , Transducción de Señal , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Vancomicina/farmacología , VirulenciaAsunto(s)
Interacciones Huésped-Patógeno , Interferones/metabolismo , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/fisiología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Proteolisis , Infecciones por Pseudomonas/inmunología , Mucosa Respiratoria/inmunologíaRESUMEN
Staphylococcus aureus is a leading cause of pneumonia. We show here that the ClpXP protease involved in protein turnover is important for pathogenesis in a murine model of acute pneumonia. Staphylococcus aureus lacking this protease is attenuated in vivo, being rapidly cleared from the airway and leading to decreased immune cell influx and inflammation. Characterization of defined mutations in vitro identified defects in intracellular survival and protection against neutrophil killing. Our results further expand on what is known about ClpXP in the pathogenesis of S. aureus to include the respiratory tract.
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Proteínas Bacterianas/metabolismo , Endopeptidasa Clp/metabolismo , Neumonía Estafilocócica/microbiología , Staphylococcus aureus/patogenicidad , Animales , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Endopeptidasa Clp/genética , Femenino , Interacciones Huésped-Patógeno , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Viabilidad Microbiana , Mutación , Neutrófilos/inmunología , Neumonía Estafilocócica/inmunología , Neumonía Estafilocócica/patología , Staphylococcus aureus/enzimología , Staphylococcus aureus/genéticaRESUMEN
Acinetobacter baumannii (A. baumannii) is an extremely versatile multidrug-resistant pathogen with a very high mortality rate; therefore, it has become crucial to understand the host response during its infection. Given the importance of mice for modeling infection and their role in preclinical drug development, equal emphasis should be placed on the use of both sexes. Through our studies using a murine model of acute pneumonia with A. baumannii, we observed that female mice were more susceptible to infection. Likewise, treatment of male mice with estradiol increased their susceptibility to infection. Analysis of the airway compartment revealed enhanced inflammation and reduced neutrophil and alveolar macrophage numbers compared with male mice. Depletion of either neutrophils or alveolar macrophages was important for bacterial clearance; however, depletion of alveolar macrophages further exacerbated female susceptibility because of severe alterations in metabolic homeostasis. Our data highlight the importance of using both sexes when assessing host immune pathways.
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Infecciones por Acinetobacter/inmunología , Susceptibilidad a Enfermedades/inmunología , Neumonía Bacteriana/inmunología , Caracteres Sexuales , Acinetobacter baumannii/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Macrófagos Alveolares/inmunología , Masculino , RatonesRESUMEN
The unexpected discovery of a novel family of antiviral mediators, type III IFNs or IFN-λs, challenged the widely accepted primacy of type I IFNs in antiviral immunity, and it is now well recognized that the IFN-λ-based antiviral system plays a major role in antiviral protection of epithelial barriers. The recent characterization of previously unknown IFN-λ-mediated activities has prompted further reassessment of the role of type I IFNs in innate and adaptive immune and inflammatory responses. Since type I and type III IFNs are co-produced in response to a variety of stimuli, it is likely that many physiological processes are simultaneously and coordinately regulated by these cytokines in pathological conditions, and likely at steady state, as baseline expression of both IFN types is maintained by microbiota. In this review, we discuss emerging differences in the production and signaling of type I and type III IFNs, and summarize results of recent studies describing the involvement of type III IFNs in anti-bacterial and anti-fungal, as well as antiviral, defenses.
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Infecciones Bacterianas/inmunología , Interferón Tipo I/metabolismo , Interferones/metabolismo , Microbiota/inmunología , Micosis/inmunología , Virosis/inmunología , Animales , Humanos , Inmunidad , Inflamación , Transducción de Señal , Interferón lambdaRESUMEN
Bacteria compete with each other for local supremacy in biologic and environmental niches. In humans, who host an array of commensal bacteria, the presence of one species or strain can sometimes prevent colonization by another, a phenomenon known as "bacterial interference." We describe how, in the 1960s, infants (and later adults) were actively inoculated with a relatively benign strain of Staphylococcus aureus, 502A, to prevent colonization with an epidemic S. aureus strain, 80/81. This introduced bacterial interference as a clinical approach to disease prevention, but little was known about the mechanisms of interference at that time. Since then, much has been learned about how bacteria interact with each other and the host to establish carriage, compete for niches and shift from harmless commensal to invasive pathogen. We provide an overview of these findings and summarize recent studies in which the genome and function of 502A were compared with those of the current epidemic strain, USA300, providing insight into differences in their invasiveness and immunogenicity. Although staphylococcal vaccines have been developed, none has yet been approved for clinical use. Further studies of staphylococcal strains and the molecular characteristics that lead to exclusion of specific bacteria from some niches may provide an alternative path to disease prevention.
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Antibiosis , Portador Sano/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Infecciones Estafilocócicas/prevención & control , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Epidemias , Interacciones Huésped-Patógeno , Humanos , Meticilina/farmacología , Ratones , Infecciones Estafilocócicas/tratamiento farmacológico , Simbiosis , Virulencia , Factores de VirulenciaRESUMEN
Acinetobacter baumannii is an emerging opportunistic pathogen that has risen to become a serious global threat, prevalent in health care settings and the community, which results in high morbidity and mortality rates. Its alarming expansion of antibiotic resistance is one of the most problematic traits of A. baumannii and as so, this bacterium has been classified as a serious threat and high priority target by the CDC. The most common types of infections induced by this pathogen include pneumonia (both hospital and community acquired), bacteremia, skin and soft tissue, urinary tract infections, endocarditis, and meningitis. Nosocomial pneumonia is the most prevalent of these. This review summarizes the current state of the signaling and innate immune components activated in response to A. baumannii infection in the airway.