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Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro-Inflammatory Responses during Sepsis  [PDF]
Maria Pino-Yanes,Almudena Corrales,Milena Casula,Jesús Blanco,Arturo Muriel,Elena Espinosa,Miguel García-Bello,Antoni Torres,Miguel Ferrer,Elizabeth Zavala,Jesús Villar,Carlos Flores
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013759
Abstract: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients.
Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis
Rungnapa Pankla, Surachat Buddhisa, Matthew Berry, Derek M Blankenship, Gregory J Bancroft, Jacques Banchereau, Ganjana Lertmemongkolchai, Damien Chaussabel
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-11-r127
Abstract: We have used microarray technology to generate genome-wide transcriptional profiles (>48,000 transcripts) from the whole blood of patients with septicemic melioidosis (n = 32), patients with sepsis caused by other pathogens (n = 31), and uninfected controls (n = 29). Unsupervised analyses demonstrated the existence of a whole blood transcriptional signature distinguishing patients with sepsis from control subjects. The majority of changes observed were common to both septicemic melioidosis and sepsis caused by other infections, including genes related to inflammation, interferon-related genes, neutrophils, cytotoxic cells, and T-cells. Finally, class prediction analysis identified a 37 transcript candidate diagnostic signature that distinguished melioidosis from sepsis caused by other organisms with 100% accuracy in a training set. This finding was confirmed in 2 independent validation sets, which gave high prediction accuracies of 78% and 80%, respectively. This signature was significantly enriched in genes coding for products involved in the MHC class II antigen processing and presentation pathway.Blood transcriptional patterns distinguish patients with septicemic melioidosis from patients with sepsis caused by other pathogens. Once confirmed in a large scale trial this diagnostic signature might constitute the basis of a differential diagnostic assay.Melioidosis is an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei. The disease is endemic in northern Australia, Southeast Asia, and northeast Thailand, where it is a common cause of community-acquired sepsis [1,2]. Cases of melioidosis have also been reported from other regions around the world [3]. In Thailand, the incidence rate of melioidosis was estimated as 4.4 cases per 100,000 individuals, but melioidosis cases are under-reported due to a lack of adequate laboratory testing [1,4]. The disease is the leading cause of community-acquired septicemia in northeast Thailand [5]. The
Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India  [cached]
Pandey Vivek,Rao Sripathi,Rao Sugandhi,Acharya Kiran
Indian Journal of Orthopaedics , 2010,
Abstract: Melioidosis, an infection due to gram negative Burkholderia pseudomallei, is an important cause of sepsis in east Asia especially Thailand and northern Australia. It usually causes abscesses in lung, liver, spleen, skeletal muscle and parotids especially in patients with diabetes, chronic renal failure and thalassemia. Musculoskeletal melioidosis is not common in India even though sporadic cases have been reported mostly involving soft tissues. During a two-year-period, we had five patients with musculoskeletal melioidosis. All patients presented with multifocal osteomyelitis, recurrent osteomyelitis or septic arthritis. One patient died early because of septicemia and multi-organ failure. All patients were diagnosed on the basis of positive pus culture. All patients were treated by surgical debridement followed by a combination of antibiotics; (ceftazidime, amoxy-clavulanic acid, co-trimoxazole and doxycycline) for six months except for one who died due to fulminant septicemia. All other patients recovered completely with no recurrences. With increasing awareness and better diagnostic facilities, probably musculoskeletal melioidosis will be increasingly diagnosed in future.
Host Responses to Melioidosis and Tuberculosis Are Both Dominated by Interferon-Mediated Signaling  [PDF]
Gavin C. K. W. Koh, M. Fernanda Schreiber, Ruben Bautista, Rapeephan R. Maude, Susanna Dunachie, Direk Limmathurotsakul, Nicholas P. J. Day, Gordon Dougan, Sharon J. Peacock
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054961
Abstract: Melioidosis (Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Northeast Thailand and northern Australia. B. pseudomallei is a soil saprophyte endemic to Southeast Asia and northern Australia. The clinical presentation of melioidosis may mimic tuberculosis (both cause chronic suppurative lesions unresponsive to conventional antibiotics and both commonly affect the lungs). The two diseases have overlapping risk profiles (e.g., diabetes, corticosteroid use), and both B. pseudomallei and Mycobacterium tuberculosis are intracellular pathogens. There are however important differences: the majority of melioidosis cases are acute, not chronic, and present with severe sepsis and a mortality rate that approaches 50% despite appropriate antimicrobial therapy. By contrast, tuberculosis is characteristically a chronic illness with mortality <2% with appropriate antimicrobial chemotherapy. We examined the gene expression profiles of total peripheral leukocytes in two cohorts of patients, one with acute melioidosis (30 patients and 30 controls) and another with tuberculosis (20 patients and 24 controls). Interferon-mediated responses dominate the host response to both infections, and both type 1 and type 2 interferon responses are important. An 86-gene signature previously thought to be specific for tuberculosis is also found in melioidosis. We conclude that the host responses to melioidosis and to tuberculosis are similar: both are dominated by interferon-signalling pathways and this similarity means gene expression signatures from whole blood do not distinguish between these two diseases.
Sinonasal Melioidosis in a Returned Traveller Presenting with Nasal Cellulitis and Sinusitis  [PDF]
Rebecca Sin Mei Lim,Sam Flatman,Markus C. Dahm
Case Reports in Otolaryngology , 2013, DOI: 10.1155/2013/920352
Abstract: We illustrate a case involving a 51-year-old man who presented to a tertiary hospital with sepsis secondary to an abscess of the nasal vestibule and pustular eruptions of the nasal mucosa. Associated cellulitis extended across the face to the eye, and mucosal thickening of the sinuses was seen on computed tomography. The patient underwent incision and drainage and endoscopic sinus surgery. Blood cultures and swabs were positive for a gram-negative bacillus, Burkholderia pseudomallei. He had multiple risk factors including travel to an endemic area. The patient received extended antibiotic therapy in keeping with published national guidelines. Melioidosis is caused by Burkholderia pseudomallei, found in the soil in Northern Australia and Asia. It is transmitted via cutaneous or inhaled routes, leading to pneumonia, skin or soft tissue abscesses, and genitourinary infections. Risk factors include diabetes, chronic lung disease, and alcohol abuse. It can exist as a latent, active, or reactivated infection. A high mortality rate has been identified in patients with sepsis. Melioidosis is endemic in tropical Northern Australia and northeastern Thailand where it is the most common cause of severe community-acquired sepsis. There is one other report of melioidosis in the literature involving orbital cellulitis and sinusitis. 1. Melioidosis of the Nose 1.1. Case A 51-year-old Caucasian man presented to a tertiary hospital in Melbourne, Australia, with 7 days of headache, myalgia, fevers, and sweats. There was cellulitis affecting the right side face with purulent discharge from a tender right nostril. He had poorly controlled type 2 diabetes requiring insulin and chronic hepatitis B. He was a 25-pack-year smoker, drank >6 standard drinks of alcohol per day, and occasionally snorted cocaine. He also travelled multiple times to Vietnam and worked as a cabinet maker. He was septic (temperature 39°C, heart rate 110?bpm and blood pressure 90/70?mmHg) with cellulitis extending from the nose across the right cheek and up to the right eye, including a preseptal orbital cellulitis. Visual acuity and eye movements were normal. The right nasal vestibule was tender and swollen with purulent discharge originating from it and the nasal septum. Biochemistry revealed an elevated C-reactive protein of 222.7 ( ) and a normal white cell count of ( ), neutrophils ( ), and lymphocytes ( ). Computed tomography (CT) revealed right sinus mucosal thickening and preseptal tissue swelling overlying the right orbit extending over the zygoma and the nose, with no intracranial collection,
Overexpression of the Endothelial Protein C Receptor Is Detrimental during Pneumonia-Derived Gram-negative Sepsis (Melioidosis)  [PDF]
Liesbeth M. Kager ,Marcel Schouten,W. Joost Wiersinga,J. Daan de Boer,Lionel C. W. Lattenist,Joris J. T. H. Roelofs,Joost C. M. Meijers,Marcel Levi,Arjen M. Dondorp,Charles T. Esmon,Cornelis van 't Veer,Tom van der Poll
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002306
Abstract: Background The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia. Methodology/Principal Findings Soluble EPCR was measured in plasma of patients with septic culture-proven melioidosis and healthy controls. Experimental melioidosis was induced by intranasal inoculation of B. pseudomallei in wild-type (WT) mice and mice with either EPCR-overexpression (Tie2-EPCR) or EPCR-deficiency (EPCR?/?). Mice were sacrificed after 24, 48 or 72 hours. Organs and plasma were harvested to measure colony forming units, cellular influxes, cytokine levels and coagulation parameters. Plasma EPCR-levels were higher in melioidosis patients than in healthy controls and associated with an increased mortality. Tie2-EPCR mice demonstrated enhanced bacterial growth and dissemination to distant organs during experimental melioidosis, accompanied by increased lung damage, neutrophil influx and cytokine production, and attenuated coagulation activation. EPCR?/? mice had an unremarkable response to B. pseudomallei infection as compared to WT mice, except for a difference in coagulation activation in plasma. Conclusion/Significance Increased EPCR-levels correlate with accelerated mortality in patients with melioidosis. In mice, transgenic overexpression of EPCR aggravates outcome during Gram-negative pneumonia-derived sepsis caused by B. pseudomallei, while endogenous EPCR does not impact on the host response. These results add to a better understanding of the regulation of coagulation during severe (pneumo)sepsis.
Melioidosis presenting as genitourinary infection in two men with diabetes  [cached]
Viswaroop B,Balaji V,Mathai E,Kekre N
Journal of Postgraduate Medicine , 2007,
Abstract: Melioidosis is an infectious disease caused by Burkholderia pseudomallei . It occurs predominantly in tropical regions. The manifestations are protean which include pneumonia, visceral abscesses, septic arthritis, osteomyelitis, acute suppurative and chronic granulomatous lesions with involvement of almost all organ systems. Fulminant sepsis is much more common and is associated with high mortality. Hence prompt recognition and early treatment is warranted. We report unusual presentations of urinary tract melioidosis in two diabetic men.
Toll-Like Receptor 2 Impairs Host Defense in Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)  [PDF]
W. Joost Wiersinga ,Catharina W Wieland,Mark C Dessing,Narisara Chantratita,Allen C Cheng,Direk Limmathurotsakul,Wirongrong Chierakul,Masja Leendertse,Sandrine Florquin,Alex F de Vos,Nicholas White,Arjen M Dondorp,Nicholas P Day,Sharon J Peacock,Tom van der Poll
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040248
Abstract: Background Toll-like receptors (TLRs) are essential in host defense against pathogens by virtue of their capacity to detect microbes and initiate the immune response. TLR2 is seen as the most important receptor for gram-positive bacteria, while TLR4 is regarded as the gram-negative TLR. Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia. We aimed to characterize the expression and function of TLRs in septic melioidosis. Methods and Findings Patient studies: 34 patients with melioidosis demonstrated increased expression of CD14, TLR1, TLR2, and TLR4 on the cell surfaces of monocytes and granulocytes, and increased CD14, TLR1, TLR2, TLR4, LY96 (also known as MD-2), TLR5, and TLR10 mRNA levels in purified monocytes and granulocytes when compared with healthy controls. In vitro experiments: Whole-blood and alveolar macrophages obtained from TLR2 and TLR4 knockout (KO) mice were less responsive to B. pseudomallei in vitro, whereas in the reverse experiment, transfection of HEK293 cells with either TLR2 or TLR4 rendered these cells responsive to this bacterium. In addition, the lipopolysaccharide (LPS) of B. pseudomallei signals through TLR2 and not through TLR4. Mouse studies: Surprisingly, TLR4 KO mice were indistinguishable from wild-type mice with respect to bacterial outgrowth and survival in experimentally induced melioidosis. In contrast, TLR2 KO mice displayed a markedly improved host defenses as reflected by a strong survival advantage together with decreased bacterial loads, reduced lung inflammation, and less distant-organ injury. Conclusions Patients with melioidosis displayed an up-regulation of multiple TLRs in peripheral blood monocytes and granulocytes. Although both TLR2 and TLR4 contribute to cellular responsiveness to B. pseudomallei in vitro, TLR2 detects the LPS of B. pseudomallei, and only TLR2 impacts on the immune response of the intact host in vivo. Inhibition of TLR2 may be a novel treatment strategy in melioidosis.
A Thrombomodulin Mutation that Impairs Active Protein C Generation Is Detrimental in Severe Pneumonia-Derived Gram-Negative Sepsis (Melioidosis)  [PDF]
Liesbeth M. Kager ,W. Joost Wiersinga,Joris J. T. H. Roelofs,Onno J. de Boer,Hartmut Weiler,Cornelis van 't Veer,Tom van der Poll
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002819
Abstract: Background During severe (pneumo)sepsis inflammatory and coagulation pathways become activated as part of the host immune response. Thrombomodulin (TM) is involved in a range of host defense mechanisms during infection and plays a pivotal role in activation of protein C (PC) into active protein C (APC). APC has both anticoagulant and anti-inflammatory properties. In this study we investigated the effects of impaired TM-mediated APC generation during melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia caused by Burkholderia (B.) pseudomallei. Methodology/Principal Findings (WT) mice and mice with an impaired capacity to activate protein C due to a point mutation in their Thbd gene (TMpro/pro mice) were intranasally infected with B. pseudomallei and sacrificed after 24, 48 or 72 hours for analyses. Additionally, survival studies were performed. When compared to WT mice, TMpro/pro mice displayed a worse survival upon infection with B. pseudomallei, accompanied by increased coagulation activation, enhanced lung neutrophil influx and bronchoalveolar inflammation at late time points, together with increased hepatocellular injury. The TMpro/pro mutation had limited if any impact on bacterial growth and dissemination. Conclusion/Significance TM-mediated protein C activation contributes to protective immunity after infection with B. pseudomallei. These results add to a better understanding of the regulation of the inflammatory and procoagulant response during severe Gram-negative (pneumo)sepsis.
Urokinase receptor is necessary for bacterial defense against Gram-negative sepsis (melioidosis) by facilitating phagoctytosis
W Joost Wiersinga, JWR Hovius, GJW Windt, JCM Meijers, JJ Roelofs, A Dondorp, M Levi, NP Day, SJ Peacock, T Poll
Critical Care , 2009, DOI: 10.1186/cc8057
Abstract: Using a translational approach we conducted a patient study in patients with culture-confirmed sepsis caused by B. pseudomallei, in vitro experiments using wild-type (WT) and uPAR knockout (KO) cells, and mouse studies using WT and uPAR KO mice inoculated with B. pseudomallei.uPAR mRNA and surface expression was increased in patients with septic melioidosis in/on both peripheral blood monocytes and granulocytes as well as in the pulmonary compartment during experimental pneumonia-derived melioidosis in mice. uPAR-deficient mice intranasally infected with B. pseudomallei showed an enhanced growth and dissemination of B. pseudomallei when compared with WT mice, corresponding with increased pulmonary and hepatic inflammation. uPAR KO mice demonstrated significantly reduced neutrophil migration towards the pulmonary compartment after inoculation with B. pseudomallei. Further in vitro experiments showed that uPAR-deficient macrophages and granulocytes display a markedly impaired phagocytosis of B. pseudomallei. Additional studies showed that uPAR deficiency did not influence hemostatic and fibrinolytic responses during severe melioidosis.These data suggest that uPAR is crucially involved in the host defense against sepsis caused by B. pseudomallei by facilitating the migration of neutrophils towards the primary site of infection and subsequently facilitating the phagocytosis of B. pseudomallei.
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