Role of Bradykinin in Microbial Infection: Enhancement of Septicemia by Microbial Proteases and Kinin

Maeda, Hiroshi; Akaike, Takaaki; Sakata, Yoshifumi; Maruo, Keishi

doi:10.1007/978-3-0348-7397-0_13

Cited by 25 publications

(19 citation statements)

References 12 publications

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“…In some bacterial and viral infections, bradykinin enhances vascular permeability to facilitate pathogen spread [26,27]. However, there are very few studies linking the KKS and C .…”

Section: Introductionmentioning

confidence: 99%

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

et al. 2016

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The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.

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“…In some bacterial and viral infections, bradykinin enhances vascular permeability to facilitate pathogen spread [26,27]. However, there are very few studies linking the KKS and C .…”

Section: Introductionmentioning

confidence: 99%

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

et al. 2016

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“…7 To date, however, there is no evidence that captopril increases T cruzi parasitosis in humans. Captopril increases bacteremia in Pseudomonas aeruginosainfected mice 8 and elevated bradykinin is associated with bacteremia and mortality in Vibrio vulnificus-infected mice. 9 Finally, prolonged captopril therapy for 6 months in a mouse model of Coxsackie viral myocarditis reduced myocardial fibrosis; however, mortality was increased for unknown reasons.…”

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confidence: 99%

Captopril Ameliorates Myocarditis in Acute Experimental Chagas Disease

León¹,

Wang²,

Engman³

2003

Circulation

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Background— Captopril, an angiotensin-converting enzyme inhibitor, is commonly prescribed to patients with Chagas heart disease (CHD). There are few human studies and no animal studies on the effects of captopril in CHD. We investigated the effects of captopril on myocarditis and the host immune response to Trypanosoma cruzi in an experimental model of acute CHD. Methods and Results— A/J mice infected with Brazil strain of T cruzi developed acute myocarditis by day 21 after infection, consisting of severe focal inflammation, necrosis, fibrosis, and T cruzi pseudocysts. Administration of captopril (5 mg/L in the water) significantly reduced necrosis and fibrosis in infected mice. Increasing the captopril dose also led to a decrease in inflammation. Captopril did not affect overall mortality but did delay death while having no effect on parasitemia or cardiac parasite load. Treatment did not affect humoral immunity against T cruzi or cardiac myosin (autoimmunity) but did decrease delayed-type hypersensitivity responses against both antigens. Interestingly, increasing the dose of captopril induced mortality in infected mice in a dose-dependent manner. Mortality was apparently not due to T cruzi because neither parasitemia nor cardiac parasitosis was affected. The combination of captopril and infection may have impaired renal function because these mice had increased water consumption, decreased body mass, and increased serum BUN/creatinine ratio. Conclusions— Captopril ameliorates the myocarditis associated with acute T cruzi infection.

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“…Bradykinin generated as a result of bacterial infections induces pain, edema, vasodilation, hypotension, and shock (16,20). Bradykinins have also been shown to enhance the invasiveness of V. vulnificus by facilitating the transvascular translocation of the bacterium (17,19,21). The extent of peptide processing by PGI-LysAP is likely related to the amount of enzyme present, the duration of contact with the enzyme, the temperature and pH of the reaction, and other physiological conditions; therefore, the digestion products detected in this study may represent only a small sampling of those actually produced in an infected individual.…”

Section: Resultsmentioning

confidence: 99%

“…The source, mass, and sequence of each peptide are listed in Table 1. These substrates were selected because all, except the BK, have a lysyl residue at or near the amino termini, and the kinin peptides mediate signal transduction pathways that enhance bacterial invasiveness (17)(18)(19)21). Bradykinin was chosen to serve as a lysine-negative control.…”

Section: Measurement Of Lysap Activitymentioning

confidence: 99%

Specificity of a Vibrio vulnificus Aminopeptidase toward Kinins and Other Peptidyl Substrates

Richards

Núñez

2006

J Bacteriol

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Recently, phosphoglucose isomerase with a lysyl aminopeptidase (PGI-LysAP) activity was identified in Vibrio vulnificus. In this paper, we demonstrate the proteolytic cleavage of human-derived peptides by PGILysAP of V. vulnificus using three approaches: (i) a quantitative fluorescent ninhydrin assay for free lysine, (ii) matrix-assisted laser desorption ionization-two-stage time of flight mass spectrometry (MALDI-TOF-TOF), and (iii) Tricine gel electrophoresis. PGI-LysAP hydrolyzed bradykinin, Lys-bradykinin, Lys-(des-Arg 9 )-bradykinin, neurokinin A, Met-Lys-bradykinin, histatin 8, and a myosin light chain fragment. We detected the proteolytic release of free L-lysine from peptide digests using a rapid, simple, sensitive, and quantitative fluorescent ninhydrin assay, and results were confirmed by MALDI-TOF-TOF. The use of the fluorescent ninhydrin assay to quantitatively detect free lysine hydrolyzed from peptides is the first application of its kind and serves as a paradigm for future studies. The visualization of peptide hydrolysis was accomplished by Tricine gel electrophoresis. Proteolytic processing of kinins alters their affinities toward specific cellular receptors and initiates signal transduction mechanisms responsible for inflammation, vasodilation, and enhanced vascular permeability. By applying novel approaches to determine the proteolytic potential of bacterial enzymes, we demonstrate that PGI-LysAP has broad exopeptidase activity which may enhance V. vulnificus invasiveness by altering peptides involved in signal transduction pathways.Vibrio vulnificus is a naturally occurring marine bacterium indigenous to temperate and tropical estuarine environments. It has two routes of transmission: wound infections and the ingestion of contaminated seafood, especially raw oysters. During summer months, nearly 100% of the oysters harvested from the Gulf of Mexico contain V. vulnificus (9). Liver cirrhosis, hemochromatosis, diabetes, kidney disease, and immune disorders predispose individuals to V. vulnificus infection via the food-borne route (4, 24); however, even seemingly healthy individuals are susceptible to V. vulnificus through wound infections (24). Symptoms include fever, chills, hypotension, and the development of secondary bullous skin lesions. Septicemia is common, and death can occur within 24 h after contact with the pathogen (8, 24). Mortality rates for V. vulnificus infections are approximately 60% in the United States (15) but are somewhat higher in Asian countries (14,25).Over the past two decades, numerous virulence factors have been identified in V. vulnificus based on cell culture and animal models; however, the validity of these models in assessing virulence has come into question (7). A case in point involves V. vulnificus protease, a well-characterized metalloprotease (23). In the mouse model, injection of this protease causes skin necrosis; however, knockout of the gene in V. vulnificus does not attenuate the symptoms in Vibrio-infected laboratory animals (34).Recently, we isolated a...

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Role of Bradykinin in Microbial Infection: Enhancement of Septicemia by Microbial Proteases and Kinin

Cited by 25 publications

References 12 publications

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

Captopril Ameliorates Myocarditis in Acute Experimental Chagas Disease

Specificity of a Vibrio vulnificus Aminopeptidase toward Kinins and Other Peptidyl Substrates

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