Elevated Mitochondrial Reactive Oxygen Species and Cellular Redox Imbalance in Human NADPH-Oxidase-Deficient Phagocytes.

Chronic granulomatous disease (CGD) is caused by mutations in genes that encode the NADPH-oxidase and result in a failure of phagocytic cells to produce reactive oxygen species (ROS) this enzyme system. Patients with CGD are highly susceptible to infections and often suffer from inflammatory disorders; the latter occurs in the absence of infection and correlates with the spontaneous production of inflammatory cytokines. This clinical feature suggests that NADPH-oxidase-derived ROS are not required for, or may even suppress, inflammatory processes.

A Prospective Cohort Study of Common Childhood Infections in South African HIV-exposed Uninfected and HIV-unexposed Infants.

Background: Much evidence of HIV-exposed uninfected (HEU) infant infectious morbidity predates availability of maternal combination antiretroviral therapy and does not control for universal risk factors (preterm birth, low birth weight, suboptimal breastfeeding and poverty).

Methods: This prospective cohort study identified HIV-infected and HIV-uninfected mothers and their newborns from South African community midwife unit. The primary outcome, infectious cause hospitalization or death before 6 months of age, was compared between HEU and HIV-unexposed (HU) infants and classified for type and severity using validated study-specific case definitions.

Long-Term Evolution of during a Chronic Cystic Fibrosis Infection Reveals Shifting Forces of Selection.

is an opportunistic pathogen capable of causing severe disease in patients with cystic fibrosis (CF). Patients may be chronically infected for years, during which the bacterial population evolves in response to unknown forces. Here we analyze the genomic and functional evolution of a infection that was sequentially sampled from a CF patient over 20 years.

Activity of Tobramycin against Cystic Fibrosis Isolates of Burkholderia cepacia Complex Grown as Biofilms.

Pulmonary infection with Burkholderia cepacia complex in cystic fibrosis (CF) patients is associated with more-rapid lung function decline and earlier death than in CF patients without this infection. In this study, we used confocal microscopy to visualize the effects of various concentrations of tobramycin, achievable with systemic and aerosolized drug administration, on mature B. cepacia complex biofilms, both in the presence and absence of CF sputum.

Cystic fibrosis-adapted quorum sensing mutants cause hyperinflammatory responses.

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogen and severe neutrophilic pulmonary inflammation. undergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator gene commonly arise. We sought to define how mutations in alter host-pathogen relationships.

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia.

Burkholderia cenocepacia and other members of the Burkholderia cepacia complex (BCC) are highly multidrug-resistant bacteria that cause severe pulmonary infections in patients with cystic fibrosis. A screen of 2686 compounds derived from marine organisms identified molecules that could synergise with polymyxin B (PMB) to inhibit the growth of B. cenocepacia.

Brain Abscesses Due to Aspergillus nidulans Infection During Induction Chemotherapy for Acute Lymphoblastic Leukemia.

We present the case of a 3-year-old boy who was diagnosed with cerebral abscesses due to Aspergillus nidulans infection on day 28 of induction chemotherapy for acute lymphoblastic leukemia. He responded well to treatment with voriconazole and caspofungin, making a full recovery. There are very few cases of invasive aspergillosis reported in children during induction chemotherapy for acute leukemia and A.

Burkholderia species infections in patients with cystic fibrosis in British Columbia, Canada. 30 years' experience.

Rationale: We have been collecting Burkholderia species bacteria from patients with cystic fibrosis (CF) for the last 30 years. During this time, our understanding of their multispecies taxonomy and infection control has evolved substantially.

Objectives: To evaluate the long-term (30 year) epidemiology and clinical outcome of Burkholderia infection in CF, and fully define the risks associated with infection by each species.

Randomized controlled trial of biofilm antimicrobial susceptibility testing in cystic fibrosis patients.

This study aimed to determine whether antimicrobial susceptibility testing of Pseudomonas aeruginosa grown as a biofilm, rather than planktonically, improves efficacy of antibiotic treatment for pulmonary exacerbations. This was a multicenter randomized, double-blind controlled trial of 14 days of intravenous antibiotic treatment for pulmonary exacerbations chosen based on conventional vs. biofilm antimicrobial susceptibility results in CF patients with chronic P.

In vitro efficacy of high-dose tobramycin against Burkholderia cepacia complex and Stenotrophomonas maltophilia isolates from cystic fibrosis patients.

Burkholderia cepacia complex and Stenotrophomonas maltophilia infections are associated with poor clinical outcomes in persons with cystic fibrosis (CF). The MIC50 based on planktonic growth and the biofilm concentration at which 50% of the isolates tested are inhibited (BIC50) of tobramycin were measured for 180 B. cepacia complex and 101 S.

Swimming motility in a longitudinal collection of clinical isolates of Burkholderia cepacia complex bacteria from people with cystic fibrosis.

Chronic bacterial lung infections in cystic fibrosis (CF) are the leading cause of morbidity and mortality. While a range of bacteria are known to be capable of establishing residence in the CF lung, only a small number have a clearly established link to deteriorating clinical status. The two bacteria with the clearest roles in CF lung disease are Pseudomonas aeruginosa and bacteria belonging to the Burkholderia cepacia complex (BCC).

Single-cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents.

Innate immunity instructs adaptive immunity, and suppression of innate immunity is associated with an increased risk for infection. We showed previously that whole-blood cellular components from a cohort of South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors compared with whole blood from cohorts of Ecuadorian, Belgian, or Canadian children. To begin dissecting the responsible molecular mechanisms, we set out to identify the relevant cellular source of these differences.

Fosmidomycin decreases membrane hopanoids and potentiates the effects of colistin on Burkholderia multivorans clinical isolates.

Burkholderia cepacia complex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria.

Altered innate immune development in HIV-exposed uninfected infants.

Background: Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high.

Methods: A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed.

Investigation of aminoglycoside resistance inducing conditions and a putative AmrAB-OprM efflux system in Burkholderia vietnamiensis.

Background: Burkholderia cepacia complex (BCC) bacteria are highly virulent, typically multidrug-resistant, opportunistic pathogens in cystic fibrosis (CF) patients and other immunocompromised individuals. B. vietnamiensis is more often susceptible to aminoglycosides than other BCC species, and strains acquire aminoglycoside resistance during chronic CF infection and under tobramycin and azithromycin exposure in vitro, apparently from gain of antimicrobial efflux as determined through pump inhibition.

Anti-Biofilm and Immunomodulatory Activities of Peptides That Inhibit Biofilms Formed by Pathogens Isolated from Cystic Fibrosis Patients.

Cystic fibrosis (CF) patients often acquire chronic respiratory tract infections due to Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc) species. In the CF lung, these bacteria grow as multicellular aggregates termed biofilms. Biofilms demonstrate increased (adaptive) resistance to conventional antibiotics, and there are currently no available biofilm-specific therapies.

Pseudomonas aeruginosa enhances production of a non-alginate exopolysaccharide during long-term colonization of the cystic fibrosis lung.

The gram-negative opportunistic pathogen Pseudomonas aeruginosa is the primary cause of chronic respiratory infections in individuals with the heritable disease cystic fibrosis (CF). These infections can last for decades, during which time P. aeruginosa has been proposed to acquire beneficial traits via adaptive evolution.

Pattern recognition receptor-mediated cytokine response in infants across 4 continents.

Background: Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination.

Total protein extraction and 2-D gel electrophoresis methods for Burkholderia species.

The investigation of the intracellular protein levels of bacterial species is of importance to understanding the pathogenic mechanisms of diseases caused by these organisms. Here we describe a procedure for protein extraction from Burkholderia species based on mechanical lysis using glass beads in the presence of ethylenediamine tetraacetic acid and phenylmethylsulfonyl fluoride in phosphate buffered saline. This method can be used for different Burkholderia species, for different growth conditions, and it is likely suitable for the use in proteomic studies of other bacteria.

Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation.

Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration.

Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life.

HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants.

Ontogeny of Toll-like receptor mediated cytokine responses of South African infants throughout the first year of life.

The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date.

Serum susceptibility in clinical isolates of Burkholderia cepacia complex bacteria: development of a growth-based assay for high throughput determination.

Burkholderia cepacia complex (BCC) bacteria can cause devastating chronic infections in people with cystic fibrosis. Of particular concern is "cepacia syndrome," a rapidly progressive and usually fatal decline in health, characterized by a necrotizing bacteremic pneumonia. An important component of defense against bloodstream infections is the bactericidal action of serum.

Metabolic adaptations of Pseudomonas aeruginosa during cystic fibrosis chronic lung infections.

Pseudomonas aeruginosa forms chronic infections in the lungs of cystic fibrosis (CF) patients, and is the leading cause of morbidity and mortality in patients with CF. Understanding how this opportunistic pathogen adapts to the CF lung during chronic infections is important to increase the efficacy of treatment and is likely to increase insight into other long-term infections. Previous studies of P.