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Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease.

ABSTRACT: Chronic granulomatous disease (CGD) is characterized by frequent infections, most of which are curable. Granulibacter bethesdensis is an emerging pathogen in patients with CGD that causes fever and necrotizing lymphadenitis. However, unlike typical CGD organisms, this organism can cause relapse after clinical quiescence. To better define whether infections were newly acquired or recrudesced, we use comparative bacterial genomic hybridization to characterize 11 isolates obtained from 5 patients with CGD from North and Central America. Genomic typing showed that 3 patients had recurrent infection months to years after apparent clinical cure. Two patients were infected with the same strain as previously isolated, and 1 was infected with a genetically distinct strain. This organism is multidrug resistant, and therapy required surgery and combination antimicrobial drugs, including long-term ceftriaxone. G. bethesdensis causes necrotizing lymphadenitis in CGD, which may recur or relapse.

SUBMITTER: Greenberg DE

PROVIDER: S-EPMC3294967 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease.

Greenberg David E DE Shoffner Adam R AR Zelazny Adrian M AM Fenster Michael E ME Zarember Kol A KA Stock Frida F Ding Li L Marshall-Batty Kimberly R KR Wasserman Richard L RL Welch David F DF Kanakabandi Kishore K Sturdevant Dan E DE Virtaneva Kimmo K Porcella Stephen F SF Murray Patrick R PR Malech Harry L HL Holland Steven M SM

Emerging infectious diseases 20100901 9

Chronic granulomatous disease (CGD) is characterized by frequent infections, most of which are curable. Granulibacter bethesdensis is an emerging pathogen in patients with CGD that causes fever and necrotizing lymphadenitis. However, unlike typical CGD organisms, this organism can cause relapse after clinical quiescence. To better define whether infections were newly acquired or recrudesced, we use comparative bacterial genomic hybridization to characterize 11 isolates obtained from 5 patients w ...[more]

PMID: 20735916

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Project description:Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by CGD PMN and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in normal and CGD PMN during incubation with G. bethesdensis and, simultaneously, in G. bethesdensis with normal and CGD PMN. We detected upregulation of anti-apoptotic genes (e.g., XIAP, GADD45B) and downregulation of pro-apoptotic genes (e.g., CASP8, APAF1) in infected PMN. Transcript and protein levels of inflammation and immunity-related genes were also altered. Upon interaction with PMN, G. bethesdensis altered expression of ROS-resistance genes in the presence of normal but not CGD PMN. Bacterial stress response genes, including ClpB, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knock down demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of Granulibacter growth in PMN included upregulation of pyruvate dehydrogenase. Pharmacologic inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to Granulibacter. This study expands knowledge of microbial pathogenesis by Granulibacter in cells from permissive (CGD) and non-permissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen. pathogen time series 0-1-4-24 in CGD subjects and normals : host time series 0-1-4-24 in CGD subjects and normals non-infected and infected with Gb

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Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease.

Publications

Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease.

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