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Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.

Javid A, Zlotnikov N, Pětrošová H, Tang TT, Zhang Y, Bansal AK, Ebady R, Parikh M, Ahmed M, Sun C, Newbigging S, Kim YR, Santana Sosa M, Glogauer M, Moriarty TJ - PLoS ONE (2016)

Bottom Line: Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint.Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs.These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

View Article: PubMed Central - PubMed

Affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada.

ABSTRACT
Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

No MeSH data available.


Related in: MedlinePlus

B. burgdorferi tissue colonization and bacterial DNA copy number in hyperglycemic and normoglycemic mice.(A, C and E) Percentage of tissues/mouse positive for B. burgdorferi flaB DNA in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Percentage of qPCR-positive tissues/mouse in C57BL/6 (A), C3H/HeN (C), and Akita (E) mice are shown. (B, D and F) Median B. burgdorferi flaB copy number/μg total DNA in indicated tissues and in all tissues combined (ALL) in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Shown are individual values and medians (bars) in tissues of C57BL/6 (B), C3H/HeN (D) and Akita (F) mice. Values are plotted on a log scale to facilitate visualization of a large range of values. Dotted lines in each graph indicate the cutoff point (1 flaB copy/μg DNA) below which tissues were considered negative. Statistical analysis: Kruskal-Wallis ANOVA with Dunn’s post-test. For all panels, N = 10–13 mice per experimental group and strain. Fold differences in medians are summarized in Table 2. * indicates p<0.05 vs. normoglycemic controls.
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pone.0158019.g002: B. burgdorferi tissue colonization and bacterial DNA copy number in hyperglycemic and normoglycemic mice.(A, C and E) Percentage of tissues/mouse positive for B. burgdorferi flaB DNA in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Percentage of qPCR-positive tissues/mouse in C57BL/6 (A), C3H/HeN (C), and Akita (E) mice are shown. (B, D and F) Median B. burgdorferi flaB copy number/μg total DNA in indicated tissues and in all tissues combined (ALL) in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Shown are individual values and medians (bars) in tissues of C57BL/6 (B), C3H/HeN (D) and Akita (F) mice. Values are plotted on a log scale to facilitate visualization of a large range of values. Dotted lines in each graph indicate the cutoff point (1 flaB copy/μg DNA) below which tissues were considered negative. Statistical analysis: Kruskal-Wallis ANOVA with Dunn’s post-test. For all panels, N = 10–13 mice per experimental group and strain. Fold differences in medians are summarized in Table 2. * indicates p<0.05 vs. normoglycemic controls.

Mentions: To detect B. burgdorferi DNA in tissues of infected mice and to determine if hyperglycemia altered tissue bacterial burden, samples were harvested from mice at 4 weeks post-infection (after 5–6 weeks of sustained hyperglycemia). The examined tissues were bladder, blood, brain, ear, heart, liver, lung, knee joint (patella) and ventral thoracic skin. Previous studies have reported that B. burgdorferi can be cultivated and detected by quantitative PCR (qPCR) in all of these tissues [2–4,43–46]. Heart, skin, joint, bladder and ear are among the most common targets examined in murine pathogenesis studies, because these tissues often display higher B. burgdorferi burden and are the sites of disease pathology in mice (heart, joint). Tissues such as brain and liver are much less commonly positive for these bacteria, but can still be infrequently colonized. We collected samples from tissues typically targeted by B. burgdorferi (bladder, blood, ear, heart, knee joint and ventral thoracic skin), tissues that exhibit physiological dysfunction in hyperglycemia (liver, brain) [47,48], and tissues where hyperglycemia is associated with impaired immune responses to bacterial infection (lung) [49]. B. burgdorferi DNA copy number was quantified by measuring absolute copy number of bacterial flaB DNA sequence per microgram of extracted DNA by qPCR, as previously described [32,33] (Fig 2). We did not determine viability of B. burgdorferi isolated from individual organs.


Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.

Javid A, Zlotnikov N, Pětrošová H, Tang TT, Zhang Y, Bansal AK, Ebady R, Parikh M, Ahmed M, Sun C, Newbigging S, Kim YR, Santana Sosa M, Glogauer M, Moriarty TJ - PLoS ONE (2016)

B. burgdorferi tissue colonization and bacterial DNA copy number in hyperglycemic and normoglycemic mice.(A, C and E) Percentage of tissues/mouse positive for B. burgdorferi flaB DNA in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Percentage of qPCR-positive tissues/mouse in C57BL/6 (A), C3H/HeN (C), and Akita (E) mice are shown. (B, D and F) Median B. burgdorferi flaB copy number/μg total DNA in indicated tissues and in all tissues combined (ALL) in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Shown are individual values and medians (bars) in tissues of C57BL/6 (B), C3H/HeN (D) and Akita (F) mice. Values are plotted on a log scale to facilitate visualization of a large range of values. Dotted lines in each graph indicate the cutoff point (1 flaB copy/μg DNA) below which tissues were considered negative. Statistical analysis: Kruskal-Wallis ANOVA with Dunn’s post-test. For all panels, N = 10–13 mice per experimental group and strain. Fold differences in medians are summarized in Table 2. * indicates p<0.05 vs. normoglycemic controls.
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pone.0158019.g002: B. burgdorferi tissue colonization and bacterial DNA copy number in hyperglycemic and normoglycemic mice.(A, C and E) Percentage of tissues/mouse positive for B. burgdorferi flaB DNA in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Percentage of qPCR-positive tissues/mouse in C57BL/6 (A), C3H/HeN (C), and Akita (E) mice are shown. (B, D and F) Median B. burgdorferi flaB copy number/μg total DNA in indicated tissues and in all tissues combined (ALL) in infected normoglycemic and hyperglycemic mice at 4 weeks post-infection. Shown are individual values and medians (bars) in tissues of C57BL/6 (B), C3H/HeN (D) and Akita (F) mice. Values are plotted on a log scale to facilitate visualization of a large range of values. Dotted lines in each graph indicate the cutoff point (1 flaB copy/μg DNA) below which tissues were considered negative. Statistical analysis: Kruskal-Wallis ANOVA with Dunn’s post-test. For all panels, N = 10–13 mice per experimental group and strain. Fold differences in medians are summarized in Table 2. * indicates p<0.05 vs. normoglycemic controls.
Mentions: To detect B. burgdorferi DNA in tissues of infected mice and to determine if hyperglycemia altered tissue bacterial burden, samples were harvested from mice at 4 weeks post-infection (after 5–6 weeks of sustained hyperglycemia). The examined tissues were bladder, blood, brain, ear, heart, liver, lung, knee joint (patella) and ventral thoracic skin. Previous studies have reported that B. burgdorferi can be cultivated and detected by quantitative PCR (qPCR) in all of these tissues [2–4,43–46]. Heart, skin, joint, bladder and ear are among the most common targets examined in murine pathogenesis studies, because these tissues often display higher B. burgdorferi burden and are the sites of disease pathology in mice (heart, joint). Tissues such as brain and liver are much less commonly positive for these bacteria, but can still be infrequently colonized. We collected samples from tissues typically targeted by B. burgdorferi (bladder, blood, ear, heart, knee joint and ventral thoracic skin), tissues that exhibit physiological dysfunction in hyperglycemia (liver, brain) [47,48], and tissues where hyperglycemia is associated with impaired immune responses to bacterial infection (lung) [49]. B. burgdorferi DNA copy number was quantified by measuring absolute copy number of bacterial flaB DNA sequence per microgram of extracted DNA by qPCR, as previously described [32,33] (Fig 2). We did not determine viability of B. burgdorferi isolated from individual organs.

Bottom Line: Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint.Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs.These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

View Article: PubMed Central - PubMed

Affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada.

ABSTRACT
Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

No MeSH data available.


Related in: MedlinePlus