Intramacrophage survival of uropathogenic Escherichia coli: Differences between diverse clinical isolates and between mouse and human macrophages

Bokil, Nilesh J.; Totsika, Makrina; Carey, Alison J.; Stacey, Katryn J.; Hancock, Viktoria; Saunders, Bernadette M.; Ravasi, Timothy; Ulett, Glen C.; Schembri, Mark A.; Sweet, Matthew J.

doi:10.1016/j.imbio.2011.05.011

Cited by 69 publications

(76 citation statements)

References 45 publications

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“…Importantly, UPEC can also survive within mouse and human macrophages (49). It has been suggested that chronically infected epithelial cells could thus provide a constant source for reinfection of macrophages, which are unable to eliminate the bacteria completely, thus helping the bacteria to spread (49).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement

et al. 2015

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Uropathogenic strains of Escherichia coli (UPEC) are the major cause of bacteremic urinary tract infections. Survival in the bloodstream is associated with different mechanisms that help to resist serum complement-mediated killing. While the phenotypic heterogeneity of bacteria has been shown to influence antibiotic tolerance, the possibility that it makes cells refractory to killing by the immune system has not been experimentally tested. In the present study we sought to determine whether the heterogeneity of bacterial cultures is relevant to bacterial targeting by the serum complement system. We monitored cell divisions in the UPEC strain CFT073 with fluorescent reporter protein. T he immune system has several pathways for recognizing and killing pathogenic bacteria. However, some pathogenic bacteria can maintain infection in mammalian hosts despite inflammation, specific antimicrobial mechanisms, and a robust adaptive immune response and can therefore give rise to persistent infection (1). Uropathogenic Escherichia coli (UPEC) causes recurrent urinary tract infections that can progress from the lower to the upper urinary tract and can lead to the dissemination of bacteria into the bloodstream.The complement system is part of the defense against invading pathogens, with an essential role in both innate and adaptive immunity (2). It is composed of more than 40 plasma and membrane proteins. It can be activated via three distinct routes: the classical (antibody dependent), lectin, and alternative pathways. Activation of complement cascades leads to the formation of the key component C3b on the bacterial surface, which stimulates phagocytosis. Late complement components (C5 to C9 proteins) are also activated via C3b, resulting in the formation of the membrane attack complex (MAC) causing cell lysis (2). The primary source of complement is blood, but complement proteins are also synthesized by a variety of other cell types and tissues (3).Bacterial resistance to serum complement killing depends on the presence or absence of antigenic outer membrane proteins (4). Pathogens often resist recognition and subsequent complement activation owing to their surface capsular polysaccharide, which masks underlying structures and by itself activates complement poorly (5-7). In addition, secretion of the exopolysaccharide colanic acid protects UPEC from complement-mediated killing (8). Modification of lipopolysaccharide (LPS) is also important for complement evasion (9, 10). It has been shown that serum sensitivity depends on the bacterial growth phase; cells are more readily killed by serum during early logarithmic phase (11)(12)(13)(14). However, there are examples showing that exponential-phase cells are more resistant to complement-mediated killing than stationary-phase cells (15,16). That phenomenon is largely explained by the growth-phase-dependent expression of antigens, capsule, and LPS modification (14, 15). Cell size can also be an important determinant of complement-mediated killing, since larger or aggregated cells ...

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Section: Discussionmentioning

confidence: 99%

Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement

et al. 2015

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“…Bacterial infection assays were conducted in HMDMs and CRIg hi/lo macrophages as previously described (55). In brief, in vitro-differentiated HMDMs or flow cytometry-sorted ascites cells were cultured at 2 × 10 5 cells/well in 1 mL antibiotic-free tissue culture media at 37°C overnight prior to infection with E. coli (strain MG1655) at a MOI of 10.…”

Section: Methodsmentioning

confidence: 99%

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

Irvine¹,

Banh²,

Gadd³

et al. 2016

JCI Insight

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“…Bacterial infection assays were conducted with HMDM and PMA-differentiated THP-1 macrophages to assess intracellular bacterial loads as previously described (28). In brief, cells were cultured at 4 ϫ 10 5 cells/well in 1 ml antibiotic-free tissue culture medium at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.

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Intramacrophage survival of uropathogenic Escherichia coli: Differences between diverse clinical isolates and between mouse and human macrophages

Cited by 69 publications

References 45 publications

Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement

Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

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