RESUMO
Bacterial pneumonia is a common clinical syndrome leading to significant morbidity and mortality worldwide. In the current study, we investigate a novel, multidirectional relationship between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Using an in vivo pneumonia model, we demonstrate that highly sulfated heparan sulfate (HS) oligosaccharides are shed into the airspaces in response to MRSA pneumonia. In vitro, these HS oligosaccharides do not directly alter MRSA growth or gene transcription. However, in the presence of an antimicrobial peptide (cathelicidin), increasing concentrations of HS inhibit the bactericidal activity of cathelicidin against MRSA as well as other nosocomial pneumonia pathogens (Klebsiella pneumoniae and Pseudomonas aeruginosa) in a dose-dependent manner. Surface plasmon resonance shows avid binding between HS and cathelicidin with a dissociation constant of 0.13 µM. These findings highlight a complex relationship in which shedding of airspace HS may hamper host defenses against nosocomial infection via neutralization of antimicrobial peptides. These findings may inform future investigation into novel therapeutic targets designed to restore local innate immune function in patients suffering from primary bacterial pneumonia.NEW & NOTEWORTHY Primary Staphylococcus aureus pneumonia causes pulmonary epithelial heparan sulfate (HS) shedding into the airspace. These highly sulfated HS fragments do not alter bacterial growth or transcription, but directly bind with host antimicrobial peptides and inhibit the bactericidal activity of these cationic polypeptides. These findings highlight a complex local interaction between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of bacterial pneumonia.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Pneumonia Bacteriana , Camundongos , Humanos , Animais , Catelicidinas/farmacologia , Catelicidinas/uso terapêutico , Peptídeos Catiônicos Antimicrobianos , Modelos Animais de Doenças , Pneumonia Bacteriana/tratamento farmacológico , Heparitina Sulfato , Oligossacarídeos/uso terapêutico , AntibacterianosRESUMO
INTRODUCTION: Patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) may require continuous renal replacement therapy (CRRT) as a supportive intervention. While CRRT is effective at achieving solute control and fluid balance, the indiscriminate nature of this procedure raises the possibility that beneficial substances may similarly be removed. Hepcidin, an antimicrobial peptide with pivotal roles in iron homeostasis and pathogen clearance, has biochemical properties amenable to direct removal via CRRT. We hypothesized that serum hepcidin levels would significantly decrease after initiation of CRRT. METHODS: In this prospective, observational trial, we enrolled 13 patients who required CRRT: 11 due to stage 3 AKI, and 2 due to critical illness in the setting of ESKD. Plasma was collected at the time of enrollment, and then plasma and effluent were collected at 10:00 a.m. on the following 3 days. Plasma samples were also collected from healthy controls, and we compared hepcidin concentrations in those with renal disease compared to normal controls, evaluated trends in hepcidin levels over time, and calculated the hepcidin sieving coefficient. RESULTS: Plasma hepcidin levels were significantly higher in patients initiating CRRT than in normal controls (158 ± 60 vs. 17 ± 3 ng/mL respectively, p < 0.001). Hepcidin levels were highest prior to CRRT initiation (158 ± 60 ng/mL), and were significantly lower on day 1 (102 ± 24 ng/mL, p < 0.001) and day 2 (56 ± 14 ng/mL, p < 0.001) before leveling out on day 3 (51 ± 11 ng/mL). The median sieving coefficient was consistent at 0.82-0.83 for each of 3 days. CONCLUSIONS: CRRT initiation is associated with significant decreases in plasma hepcidin levels over the first 2 days of treatment regardless of indication for CRRT, or presence of underlying ESKD. Since reduced hepcidin levels are associated with increased mortality and our data implicate CRRT in hepcidin removal, larger clinical studies evaluating relevant clinical outcomes based on hepcidin trends in this population should be pursued.
Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Humanos , Terapia de Substituição Renal/métodos , Estudos Prospectivos , Hepcidinas , Estudos Retrospectivos , Estado Terminal/terapiaRESUMO
Prior research has focused on host factors as mediators of exaggerated sepsis-associated morbidity and mortality in older adults. This focus on the host, however, has failed to identify therapies that improve sepsis outcomes in the elderly. We hypothesized that the increased susceptibility of the aging population to sepsis is not only a function of the host, but also reflects longevity-associated changes in the virulence of gut pathobionts. We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Further murine and human investigations into these polymicrobial bacterial communities demonstrated that age was associated with only subtle shifts in ecological composition, but an overabundance of genomic virulence factors that have functional consequence on host immune evasion. One Sentence Summary: The severity of sepsis in the aged host is in part mediated by longevity-associated increases in gut microbial virulence.
RESUMO
Prior research has focused on host factors as mediators of exaggerated sepsis-associated morbidity and mortality in older adults. This focus on the host, however, has failed to identify therapies that improve sepsis outcomes in the elderly. We hypothesized that the increased susceptibility of the aging population to sepsis is not only a function of the host but also reflects longevity-associated changes in the virulence of gut pathobionts. We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Further murine and human investigations into these polymicrobial bacterial communities demonstrated that age was associated with only subtle shifts in ecological composition but also an overabundance of genomic virulence factors that have functional consequence on host immune evasion. IMPORTANCE Older adults suffer more frequent and worse outcomes from sepsis, a critical illness secondary to infection. The reasons underlying this unique susceptibility are incompletely understood. Prior work in this area has focused on how the immune response changes with age. The current study, however, focuses instead on alterations in the community of bacteria that humans live with within their gut (i.e., the gut microbiome). The central concept of this paper is that the bacteria in our gut evolve along with the host and "age," making them more efficient at causing sepsis.