Altered macrophage function is associated with severe Burkholderia pseudomallei infection in a murine model of type 2 diabetes

Hodgson, Kelly; Morris, Jodie L.; Feterl, Marshall; Govan, Brenda; Ketheesan, Natkunam

doi:10.1016/j.micinf.2011.07.008

Cited by 38 publications

(36 citation statements)

References 34 publications

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“…Washed CFSE-labeled BMDC were rested for 1 h at 37°C, and then 10 6 BMDC (40 l) were injected into the left hind footpads of C57BL/6 mice. At designated time points (18,24, or 36 h) postinjection (p.i.) of BMDC, the draining pLN was harvested, macerated, and digested with collagenase (type IV, 400 U/ml; Gibco/Life Technologies Australia Pty, Ltd.) for 30 min at 37°C to release the DC.…”

Section: Methodsmentioning

confidence: 99%

“…Investigations of the functional responses of DC toward B. pseudomallei have shown internalization and killing of intracellular B. pseudomallei by DC occurs in vitro (15)(16)(17)(18)(19). DC maturation was triggered by B. pseudomallei, demonstrated by increased expression of molecules for antigen presentation and costimulation, along with increased cytokine production (15,17).…”

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confidence: 99%

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Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

et al. 2014

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Burkholderia pseudomallei, the etiological agent for melioidosis, is an important cause of community-acquired sepsis in northern Australia and northeast Thailand. Due to the rapid dissemination of disease in acute melioidosis, we hypothesized that dendritic cells (DC) could act as a vehicle for dissemination of B. pseudomallei. Therefore, this study investigated the effect of B. pseudomallei infection on DC migration capacity and whether migration of DC enabled transportation of B. pseudomallei from the site of infection. B. pseudomallei stimulated significantly increased migration of bone marrow-derived DC (BMDC), both in vitro and in vivo, compared to uninfected BMDC. Furthermore, migration of BMDC enabled significantly increased in vitro trafficking of B. pseudomallei and in vivo dissemination of B. pseudomallei to secondary lymphoid organs and lungs of C57BL/6 mice. DC within the footpad infection site of C57BL/6 mice also internalized B. pseudomallei and facilitated dissemination. Although DC have previously been shown to kill intracellular B. pseudomallei in vitro, the findings of this study demonstrate that B. pseudomallei-infected DC facilitate the systemic spread of this pathogen.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

et al. 2014

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“…To this end, several groups have recently begun to exploit host models engineered to mimic the risk factors for melioidosis, such as type 1 and 2 diabetic mice, in an effort to elucidate the attributes of B. pseudomallei virulence in the corresponding predisposed individuals. [10][11][12] Over the last decade, there has been a growing appreciation that Caenorhabditis elegans can serve as a simple surrogate host for modeling bacterial diseases. 13 C. elegans is also deemed a relevant host model for studying acute melioidosis.…”

Section: Introductionmentioning

confidence: 99%

Burkholderia pseudomalleikillsCaenorhabditis elegansthrough virulence mechanisms distinct from intestinal lumen colonization

et al. 2012

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The nematode Caenorhabditis elegans is hypersusceptible to Burkholderia pseudomallei infection. However, the virulence mechanisms underlying rapid lethality of C. elegans upon B. pseudomallei infection remain poorly defined. To probe the host-pathogen interaction, we constructed GFP-tagged B. pseudomallei and followed bacterial accumulation within the C. elegans intestinal lumen. Contrary to slow-killing by most bacterial pathogens, B. pseudomallei caused fairly limited intestinal lumen colonization throughout the period of observation. Using grinder-defective mutant worms that allow the entry of intact bacteria also did not result in full intestinal lumen colonization. In addition, we observed a significant decline in C. elegans defecation and pharyngeal pumping rates upon B. pseudomallei infection. The decline in defecation rates ruled out the contribution of defecation to the limited B. pseudomallei colonization. We also demonstrated that the limited intestinal lumen colonization was not attributed to slowed host feeding as bacterial loads did not change significantly when feeding was stimulated by exogenous serotonin. Both these observations confirm that B. pseudomallei is a poor colonizer of the C. elegans intestine. To explore the possibility of toxin-mediated killing, we examined the transcription of the C. elegans ABC transporter gene, pgp-5, upon B. pseudomallei infection of the ppgp-5::gfp reporter strain. Expression of pgp-5 was highly induced, notably in the pharynx and intestine, compared with Escherichia coli-fed worms, suggesting that the host actively thwarted the pathogenic assaults during infection. Collectively, our findings propose that B. pseudomallei specifically and continuously secretes toxins to overcome C. elegans immune responses.

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“…Macrophages, essential immune system components, are involved in 3 fundamental homeostatic activities: host defense, wound healing, and immune regulation. It is generally accepted that phagocytic functions such as chemotaxis, phagocytosis, and respiratory burst are impaired in the polymorphonuclear (PMN) cells and monocytes/macrophages from diabetic individuals compared to those from healthy individuals (17)(18)(19). Accordingly, we isolated peritoneal macrophages from both hyperglycemic and control mice, infected these cells with the pathogenic bacteria described previously, and measured the bactericidal activity of the macrophages across 2 different time intervals.…”

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confidence: 99%

“…3). Previously, PMN cells from diabetic subjects suffering from melioidosis reportedly exhibited decreased phagocytosis and chemotaxis in response to Burkholderia pseudomallei infection (19) as well as the defective release of processed chromatin known as neutrophil extracellular traps, which together resulted in lower bactericidal activity (20). Similarly, monocytes in diabetic patients suffering from tuberculosis, a condition wherein alveolar macrophages and monocytes are vital for containment, displayed impaired chemotaxis in response to the infection and to alveolar macrophages.…”

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confidence: 99%

Mice with Streptozotocin-Induced Hyperglycemia are Susceptible to Invasive Enteric Bacterial Infection

et al. 2017

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SUMMARY: Diabetes mellitus and diarrhea are becoming increasingly burdensome worldwide, particularly in developing countries such as India. Diabetic patients are susceptible to infection with pathogenic bacteria, particularly those causing invasive enteric infections. In this study, we observed changes in the pathophysiological features of mice with streptozotocin-induced hyperglycemia. In our experiments, both hyperglycemic and control mice were infected with pathogenic enteric bacteria-nontyphoidal Salmonella, Shigella flexneri, or Vibrio parahaemolyticus. Morbidity, mortality, and bacterial load were all higher in the diabetic mice than in the control mice, and the phagocytic and bactericidal activities of peritoneal macrophages isolated from hyperglycemic mice were lower than they were in the controls. We hypothesize that hyperglycemia leads to a downregulation of the innate immune response, which in turn increases vulnerability to enteric bacterial infection.

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Altered macrophage function is associated with severe Burkholderia pseudomallei infection in a murine model of type 2 diabetes

Cited by 38 publications

References 34 publications

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

Burkholderia pseudomalleikillsCaenorhabditis elegansthrough virulence mechanisms distinct from intestinal lumen colonization

Mice with Streptozotocin-Induced Hyperglycemia are Susceptible to Invasive Enteric Bacterial Infection

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