scholarly journals A Murine Model for Infection withBurkholderia cepacia with Sustained Persistence in the Spleen

1999 ◽  
Vol 67 (8) ◽  
pp. 4027-4032 ◽  
Author(s):  
David P. Speert ◽  
Barbara Steen ◽  
Keith Halsey ◽  
Eddie Kwan
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Murine Model ◽  
Burkholderia Cepacia ◽  
Systemic Infection ◽  
Opportunistic Pathogen ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Murine Spleen ◽  
Systemic Infections

ABSTRACT Burkholderia cepacia is an opportunistic pathogen that causes severe systemic infections in patients with chronic granulomatous disease (CGD) or with cystic fibrosis (CF), but its mechanisms of virulence are poorly understood. We developed a murine model of systemic infection in wild-type (WT) and gamma interferon knockout (GKO) BALB/c mice to facilitate dissection of components of pathogenicity and host defense. Both WT and GKO mice were susceptible to chronic splenic infection with B. cepacia, but not withPseudomonas aeruginosa. B. cepacia strains from patients with CGD persisted longer than those from CF patients. C57BL/6 mice were the most susceptible murine strain; bacteria persisted in the spleen for 2 months. DBA/2, BALB/c, and A/J strains of mice were relatively resistant to infection. Certain strains of B. cepacia complex can persist in the murine spleen after systemic infection; this may provide clues to its virulence in compromised hosts, such as those with CGD and CF.

scholarly journals Impaired Host Defense against Sporothrix schenckii in Mice with Chronic Granulomatous Disease

2004 ◽  
Vol 72 (9) ◽  
pp. 5073-5079 ◽  
Author(s):  
Hideko Kajiwara ◽  
Mitsumasa Saito ◽  
Shouichi Ohga ◽  
Takeshi Uenotsuchi ◽  
Shin-ichi Yoshida
Keyword(s):  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Superoxide Anion ◽  
Sporothrix Schenckii ◽  
Systemic Infection ◽  
Immune Defense ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Oxidative Metabolites

ABSTRACT We compared the immune defense of mice with chronic granulomatous disease (CGD mice) with that of wild-type C57BL/6 mice for their response to Sporothrix schenckii. A subcutaneous injection of 5 × 104 CFU S. schenckii strain IFM41598 into CGD mice resulted in systemic infection and death within 84 days. In contrast, injected C57BL/6 mice did not develop systemic infection and were able to survive through 100 days of observation. Differences in host resistance were analyzed in vitro. Neutrophils and macrophages obtained from CGD mice were found to allow greater growth of this organism than did those obtained from C57BL/6 mice. Moreover, macrophages obtained from immunized CGD mice were able to simply inhibit the growth of this fungus whereas macrophages obtained from immunized C57BL/6 mice killed the fungus within 48 h after phagocytosis. These results suggest that (i) the lack of NADPH oxidase function is a risk factor for lethal S. schenckii infection and (ii) superoxide anion and its reactive oxidative metabolites produced by neutrophils and macrophages are involved in fungistatic and fungicidal activities.

scholarly journals Differential Persistence among Genomovars of the Burkholderia cepacia Complex in a Murine Model of Pulmonary Infection

2002 ◽  
Vol 70 (5) ◽  
pp. 2715-2720 ◽  
Author(s):  
Karen K. Chu ◽  
Donald J. Davidson ◽  
T. Keith Halsey ◽  
Jacqueline W. Chung ◽  
David P. Speert
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Outcomes ◽  
Murine Model ◽  
Burkholderia Cepacia ◽  
Pulmonary Infection ◽  
Burkholderia Cepacia Complex ◽  
Clinical Infection ◽  
Minimal Toxicity

ABSTRACT Cystic fibrosis patients infected with strains from different genomovars of the Burkholderia cepacia complex can experience diverse clinical outcomes. To identify genomovar-specific determinants that might be responsible for these differences, we developed a pulmonary model of infection in BALB/c mice. Mice were rendered leukopenic by administration of cyclophosphamide prior to intranasal challenge with 1.6 × 104 bacteria. Five of six genomovar II strains persisted at stable numbers in the lungs until day 16 with minimal toxicity, whereas zero of seven genomovar III strains persisted but resulted in variable toxicity. We have developed a chronic pulmonary model of B. cepacia infection which reveals differences among genomovars in terms of clinical infection outcome.

Burkholderia cepacia. [Descriptions of Fungi and Bacteria].

1994 ◽  
Author(s):  
G. S. Saddler
Keyword(s):  
Cystic Fibrosis ◽  
Lycopersicon Esculentum ◽  
Geographical Distribution ◽  
Allium Cepa ◽  
Leaf Spot ◽  
Burkholderia Cepacia ◽  
Allium Sativum ◽  
Opportunistic Pathogen ◽  
Agaricus Bitorquis ◽  
Cultivated Mushroom

Abstract A description is provided for Burkholderia cepacia. Information is included on the disease caused by the organism, its transmission, geographical distribution, and hosts. HOSTS: Common host is Allium cepa, but can also cause disease in Allium sativum. Also identified as causing disease in Lycopersicon esculentum (63, 3168), a cavity disease of a cultivated mushroom (Agaricus bitorquis) (72, 5605) and a leaf spot on the a number of orchids including Cymbidium spp., Dendrobium sp. and Paphiopedilum spp. (66, 4326). The bacterium can also be found in soil, in clinical material, in disinfectant solutions and as an opportunistic pathogen of man and animals. It is gaining in significance as a major pathogen for sufferers of cystic fibrosis (Isles et al., 1984; McKevitt & Woods, 1984; Thomassen et al., 1985). DISEASE: Onion slippery skin; this is a rot of bulb scales, usually occurring at or near maturity, sometimes in storage. The bacterium does not appear to be strongly invasive, attacking plants that are damaged or weakened. Bacteria are thought to gain entry through the neck or leaf blades as the foliage falls over and the epidermis breaks, at maturity (64, 5550). GEOGRAPHICAL DISTRIBUTION: Worldwide. TRANSMISSION: Appears to be a soilborne wound pathogen.

scholarly journals Retroviral-Mediated Gene Transfer of gp91phox Into Bone Marrow Cells Rescues Defect in Host Defense Against Aspergillus fumigatus in Murine X-Linked Chronic Granulomatous Disease

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Helga Björgvinsdóttir ◽  
Chunjin Ding ◽  
Nancy Pech ◽  
Mary A. Gifford ◽  
Ling Lin Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gene Transfer ◽  
Aspergillus Fumigatus ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Bone Marrow Cells ◽  
Superoxide Production ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Marrow Cells

Abstract The X-linked form of chronic granulomatous disease (X-CGD), an inherited deficiency of the respiratory burst oxidase, results from mutations in the X-linked gene for gp91phox, the larger subunit of the oxidase cytochrome b. The goal of this study was to evaluate the impact of retroviral-mediated gene transfer of gp91phox on host defense against Aspergillus fumigatus in a murine model of X-CGD. Retrovirus vectors constructed using the murine stem cell virus (MSCV) backbone were used for gene transfer of the gp91phox cDNA into murine X-CGD bone marrow cells. Transduced cells were transplanted into lethally irradiated syngeneic X-CGD mice. After hematologic recovery, superoxide production, as monitored by the nitroblue tetrazolium (NBT) test, was detected in up to ≈80% of peripheral blood neutrophils for at least 28 to 35 weeks after transplantation. Neutrophil expression of recombinant gp91phox and superoxide production were significantly less than wild-type neutrophils. However, 9 of 9 mice with ≈50% to 80% NBT+ neutrophils after gene transfer did not develop lung disease after respiratory challenge with 150 to 500 A fumigatus spores, doses that produced disease in 16 of 16 control X-CGD mice. In X-CGD mice transplanted with mixtures of wild-type and X-CGD bone marrow, ≥5% wild-type neutrophils were required for protection against A fumigatus challenge. These data suggest that expression of even low levels of recombinant gp91phox can substantially improve phagocyte function in X-CGD, although correction of very small percentage of phagocytes may not be sufficient for protection against A fumigatus.

Deletion of OLFM4 Rescues Defective Host Defense Against Staphylococcus Aureus, but Not Aspergillus Fumigatus in Murine X-Linked Chronic Granulomatous Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3276-3276
Author(s):  
Wenli Liu ◽  
Janyce A Sugui ◽  
Hongzhen Li ◽  
Kyung J Kwon-Chung ◽  
Griffin P. Rodgers
Keyword(s):  
Staphylococcus Aureus ◽  
Innate Immunity ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Cathepsin G ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Cathepsin C ◽  
Host Innate Immunity ◽  
Deficient Mice

Abstract Abstract 3276 Introduction: Chronic granulomatous disease (CGD) patients have recurrent life-threating bacterial and fungal infections due to the mutation of one of four subunits of the respiratory burst oxidase (NADPH-oxidase). Currently, the overall fatality rate in CGD patients remains high, making it necessary to better understand the basic biological processes governing host defense against bacteria and fungi in CGD. Olfactomedin 4 (OLFM4) is a neutrophil granule protein, which has been recently identified as a negative regulator of host innate immunity against bacteria infection in mice through modulation of neutrophil protease activity. The goal of this study was to evaluate the impact of OLFM4 deletion on host innate immunity against Staphylococcus aureus and Aspergillus fumigatus, two major pathogens encountered in CGD patients, in a murine X-linked CGD model. Results: We created gp91phox-and OLFM4-double deficient mice and investigated the mice defense against S. aureus and A. fumigatus infection. We found that neutrophil intracellular killing and in vivo clearance of S. aureus have been significantly increased in gp91phox- and OLFM4-double deficiency mice compared with CGD mice. The mice survival to S. aureus sepsis in gp91phox- and OLFM4-double deficiency mice has also been significantly prolonged compared with CGD mice. Our study has shown that the CGD mice immune deficiency against S. aureus has been totally corrected by additional loss of OLFM4 gene. To explore the mechanism that OLFM4 deletion rescued the bactericidal activities of CGD neutrophils, we analyzed cathepsin C and its downstream protease (neutrophil elastase and cathepsin G) activities in the mice neutrophils. Cathepsin C activities in OLFM4 deficient as well as double deficient mice neutrophils were significantly higher than those in WT mouse neutrophils. Cathepsin C activities in the neutrophils of CGD were similar to those in WT mice. Accordingly, the elastase and cathepsin G activities in the neutrophils of OLFM4 deficient and double deficient mice were also substantially higher than those in WT mice as well as CGD mice. However, we have not observed enhanced innate immunity against A. fumigatus in OLFM4 deficiency mice compared with wild-type mice using a lung infection model. The lung histopathology showed similar inflammation and fungal burden in the OLFM4 deficiency mice compared with wild-type mice. Correspondingly, mice survival to severe A. fumigatus infection did not show significant difference in gp91phox- and OLFM4-double deficiency mice compared with CGD mice, suggesting that OLFM4 may not play a role in mice host defense against A. fumigatus. Conclusion: 1. The damaged neutrophil bacterial killing and host innate immunity against S. aureus in CGD mice due to oxidative mechanism deficiency could be successfully rescued by deletion of OLFM4. 2. These results showed that the granule protease activities in CGD neutrophils could be substantially enhanced above the level in normal neutrophils by deletion of OLFM4, suggesting that the increased of serine proteinase activities due to OLFM4 deletion is NADPH-independent. 3. OLFM4 may not play a role in mice host defense against pulmonary A. fumigatus infection. 4. OLFM4 might prove to be an important target in CGD patients to augment host defense against bacterial infection. Disclosures: No relevant conflicts of interest to declare.

Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3738-3745 ◽  
Author(s):  
Mary C. Dinauer ◽  
Mary A. Gifford ◽  
Nancy Pech ◽  
Ling Lin Li ◽  
Patricia Emshwiller
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Gene Transfer ◽  
Nadph Oxidase ◽  
Host Defense ◽  
Marrow Transplantation ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Nadph Oxidase Activity

Chronic granulomatous disease (CGD) is an inherited immunodeficiency in which the absence of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in recurrent bacterial and fungal infections. A murine model of X-linked CGD (X-CGD) was used to explore variables influencing reconstitution of host defense following bone marrow transplantation and retroviral-mediated gene transfer. The outcomes of experimental infection with Aspergillus fumigatus, Staphylococcus aureus, orBurkholderia cepacia were compared in wild-type, X-CGD mice, and transplanted X-CGD mice that were chimeric for either wild-type neutrophils or neutrophils with partial correction of NADPH oxidase activity after retroviral-mediated gene transfer. Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils. However, intact protection against bacterial pathogens required relatively greater numbers of oxidant-generating phagocytes compared to protection against A fumigatus. The host response also appeared to be influenced by the relative level of cellular NADPH oxidase activity, particularly forA fumigatus. These results may have implications for developing effective approaches for gene therapy of CGD.

scholarly journals Complete Genome Sequence of Burkholderia cenocepacia K56-2, an Opportunistic Pathogen

2020 ◽  
Vol 9 (43) ◽  
Author(s):  
Inmaculada García-Romero ◽  
Miguel A. Valvano
Keyword(s):  
Cystic Fibrosis ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Burkholderia Cepacia ◽  
Opportunistic Pathogen ◽  
Burkholderia Cenocepacia ◽  
Content Type ◽  
Advance Research

ABSTRACT Burkholderia cenocepacia K56-2, an opportunistic bacterium for people with cystic fibrosis (CF), belongs to the Burkholderia cepacia complex (Bcc) and is consistently used as a model pathogen. We describe here the closed genome sequence for this strain, which will help advance research in B. cenocepacia biology and omics studies.

scholarly journals Scnn1b-Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Kristen J. Brao ◽  
Brendan P. Wille ◽  
Joshua Lieberman ◽  
Robert K. Ernst ◽  
Mark E. Shirtliff ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Immune Cell ◽  
Opportunistic Pathogen ◽  
Sodium Absorption ◽  
Lung Pathology ◽  
Wild Type ◽  
Content Type ◽  
Lung Infections ◽  
Content Modeling

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. P. aeruginosa lung infections are difficult to treat because P. aeruginosa adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of P. aeruginosa, modeling P. aeruginosa infections in CF has been challenging. Here, we characterize Scnn1b-transgenic (Tg) BALB/c mice as P. aeruginosa lung infection models. Scnn1b-Tg mice overexpress the epithelial Na+ channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected Scnn1b-Tg mice and wild-type littermates with the laboratory P. aeruginosa strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. Scnn1b-Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; Scnn1b-Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. Scnn1b-Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected Scnn1b-Tg mice. In contrast, Scnn1b-Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1β (IL-1β), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of Scnn1b-Tg mice as models of early P. aeruginosa colonization in the CF lung.

scholarly journals Burkholderia cepacia Produces a Hemolysin That Is Capable of Inducing Apoptosis and Degranulation of Mammalian Phagocytes

1998 ◽  
Vol 66 (5) ◽  
pp. 2033-2039 ◽  
Author(s):  
Michael L. Hutchison ◽  
Ian R. Poxton ◽  
John R. W. Govan
Keyword(s):  
Cystic Fibrosis ◽  
Burkholderia Cepacia ◽  
Opportunistic Pathogen ◽  
Cathepsin G ◽  
Human Neutrophils ◽  
Purification Method ◽  
Major Threat ◽  
Low Concentrations ◽  
Neutrophil Degranulation ◽  
Surface Active

ABSTRACT Burkholderia cepacia is an opportunistic pathogen that has become a major threat to individuals with cystic fibrosis (CF). In approximately 20% of patients, pulmonary colonization with B. cepacia leads to cepacia syndrome, a fatal fulminating pneumonia sometimes associated with septicemia. It has been reported that culture filtrates of clinically derived strains of B. cepacia are hemolytic. In this study, we have characterized a factor which contributes to this hemolytic activity and is secreted from B. cepacia J2315, a representative of the virulent and highly transmissible strain belonging to the recently described genomovar III grouping. Biochemical data from the described purification method for this hemolysin allows us to hypothesize that the toxin is a lipopeptide. As demonstrated for other lipopeptide toxins, the hemolysin from B. cepacia was surface active and lowered the surface tension of high-pressure liquid chromatography-grade water from 72.96 to 29.8 mN m−1. Similar to reports for other pore-forming cytotoxins, low concentrations of the hemolysin were able to induce nucleosomal degradation consistent with apoptosis in human neutrophils and the mouse-derived macrophage-type cell line J774.2. Exposure of human neutrophils to higher concentrations of toxin resulted in increased activities of the neutrophil degranulation markers cathepsin G and elastase. Based on the results obtained in this study, we suggest a role that allows B. cepacia to thwart the immune response and a model of the events that may contribute to the severe inflammatory response in the lungs of CF patients.

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