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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

Bacterial uptake and survival following co-incubation with neutrophils isolated from hyperglycemic and normoglycemic mice.Bone marrow (A-B and E-F) or peritoneally-recruited (C-D and G-J) neutrophils were isolated from B. burgdorferi-infected and mock-infected C57BL/6 (A, C, E, G) and C3H/HeN (B, D, F, H-J) mice at 4 weeks post-infection (5–6 weeks of sustained hyperglycemia), and coincubated with complement-opsonized E. coli (A-D) or B. burgdorferi (E-J). E. coli survival (A-D) and B. burgdorferi uptake by neutrophils (E-H) were measured by comparing numbers of E. coli CFUs and intact B. burgdorferi following neutrophil co-incubation with values for complement-opsonized input bacteria. (I-J) B. burgdorferi killing was measured by LIVE-DEAD staining. Panel I shows sample images for bacteria incubated in the absence (no PMN) and presence (+PMN) of neutrophils. Panel J shows quantification of B. burgdorferi killing. Summary values: mean ±SEM. N = 4–6 mice/group. Experimental groups: No neutrophil (PMN) control: opsonized bacteria incubated in absence of neutrophils, normoglycemic mock-infected (Vh), hyperglycemic mock-infected (STZ), normoglycemic B. burgdorferi-infected (Vh+Bb), hyperglycemic B. burgdorferi-infected (STZ+Bb). Statistical analysis: Two-way ANOVA with Holm-Sidak post-tests. * indicates p<0.05 vs. Vehicle; # indicates p<0.05 vs. normoglycemic B. burgdorferi-infected (Vh+Bb) mice; † indicates p<0.05 vs. hyperglycemic mock-infected mice (STZ); & indicates p<0.05 vs no PMN control (panel J only).
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pone.0158019.g005: Bacterial uptake and survival following co-incubation with neutrophils isolated from hyperglycemic and normoglycemic mice.Bone marrow (A-B and E-F) or peritoneally-recruited (C-D and G-J) neutrophils were isolated from B. burgdorferi-infected and mock-infected C57BL/6 (A, C, E, G) and C3H/HeN (B, D, F, H-J) mice at 4 weeks post-infection (5–6 weeks of sustained hyperglycemia), and coincubated with complement-opsonized E. coli (A-D) or B. burgdorferi (E-J). E. coli survival (A-D) and B. burgdorferi uptake by neutrophils (E-H) were measured by comparing numbers of E. coli CFUs and intact B. burgdorferi following neutrophil co-incubation with values for complement-opsonized input bacteria. (I-J) B. burgdorferi killing was measured by LIVE-DEAD staining. Panel I shows sample images for bacteria incubated in the absence (no PMN) and presence (+PMN) of neutrophils. Panel J shows quantification of B. burgdorferi killing. Summary values: mean ±SEM. N = 4–6 mice/group. Experimental groups: No neutrophil (PMN) control: opsonized bacteria incubated in absence of neutrophils, normoglycemic mock-infected (Vh), hyperglycemic mock-infected (STZ), normoglycemic B. burgdorferi-infected (Vh+Bb), hyperglycemic B. burgdorferi-infected (STZ+Bb). Statistical analysis: Two-way ANOVA with Holm-Sidak post-tests. * indicates p<0.05 vs. Vehicle; # indicates p<0.05 vs. normoglycemic B. burgdorferi-infected (Vh+Bb) mice; † indicates p<0.05 vs. hyperglycemic mock-infected mice (STZ); & indicates p<0.05 vs no PMN control (panel J only).

Mentions: We next examined the ability of neutrophils harvested from C57BL/6 (Fig 5A, 5C, 5E and 5G) and C3H/HeN (Fig 5B, 5D, 5F and 5H–5J) mice after 4 weeks of B. burgdorferi infection (5–6 weeks of sustained hyperglycemia) to control uptake and survival of B. burgdorferi opsonized with pre-immune serum (Fig 5E–5J). Pre-immune serum was used to investigate the effects of hyperglycemia on neutrophil function independent of its effects on adaptive immune responses, and to maintain consistency with the methods of a previous study measuring effects of hyperglycemia on neutrophil killing of E. coli [18]. Opsonization in this context therefore refers to exposure of bacteria to serum complement proteins [52].


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)

Bacterial uptake and survival following co-incubation with neutrophils isolated from hyperglycemic and normoglycemic mice.Bone marrow (A-B and E-F) or peritoneally-recruited (C-D and G-J) neutrophils were isolated from B. burgdorferi-infected and mock-infected C57BL/6 (A, C, E, G) and C3H/HeN (B, D, F, H-J) mice at 4 weeks post-infection (5–6 weeks of sustained hyperglycemia), and coincubated with complement-opsonized E. coli (A-D) or B. burgdorferi (E-J). E. coli survival (A-D) and B. burgdorferi uptake by neutrophils (E-H) were measured by comparing numbers of E. coli CFUs and intact B. burgdorferi following neutrophil co-incubation with values for complement-opsonized input bacteria. (I-J) B. burgdorferi killing was measured by LIVE-DEAD staining. Panel I shows sample images for bacteria incubated in the absence (no PMN) and presence (+PMN) of neutrophils. Panel J shows quantification of B. burgdorferi killing. Summary values: mean ±SEM. N = 4–6 mice/group. Experimental groups: No neutrophil (PMN) control: opsonized bacteria incubated in absence of neutrophils, normoglycemic mock-infected (Vh), hyperglycemic mock-infected (STZ), normoglycemic B. burgdorferi-infected (Vh+Bb), hyperglycemic B. burgdorferi-infected (STZ+Bb). Statistical analysis: Two-way ANOVA with Holm-Sidak post-tests. * indicates p<0.05 vs. Vehicle; # indicates p<0.05 vs. normoglycemic B. burgdorferi-infected (Vh+Bb) mice; † indicates p<0.05 vs. hyperglycemic mock-infected mice (STZ); & indicates p<0.05 vs no PMN control (panel J only).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4920391&req=5

pone.0158019.g005: Bacterial uptake and survival following co-incubation with neutrophils isolated from hyperglycemic and normoglycemic mice.Bone marrow (A-B and E-F) or peritoneally-recruited (C-D and G-J) neutrophils were isolated from B. burgdorferi-infected and mock-infected C57BL/6 (A, C, E, G) and C3H/HeN (B, D, F, H-J) mice at 4 weeks post-infection (5–6 weeks of sustained hyperglycemia), and coincubated with complement-opsonized E. coli (A-D) or B. burgdorferi (E-J). E. coli survival (A-D) and B. burgdorferi uptake by neutrophils (E-H) were measured by comparing numbers of E. coli CFUs and intact B. burgdorferi following neutrophil co-incubation with values for complement-opsonized input bacteria. (I-J) B. burgdorferi killing was measured by LIVE-DEAD staining. Panel I shows sample images for bacteria incubated in the absence (no PMN) and presence (+PMN) of neutrophils. Panel J shows quantification of B. burgdorferi killing. Summary values: mean ±SEM. N = 4–6 mice/group. Experimental groups: No neutrophil (PMN) control: opsonized bacteria incubated in absence of neutrophils, normoglycemic mock-infected (Vh), hyperglycemic mock-infected (STZ), normoglycemic B. burgdorferi-infected (Vh+Bb), hyperglycemic B. burgdorferi-infected (STZ+Bb). Statistical analysis: Two-way ANOVA with Holm-Sidak post-tests. * indicates p<0.05 vs. Vehicle; # indicates p<0.05 vs. normoglycemic B. burgdorferi-infected (Vh+Bb) mice; † indicates p<0.05 vs. hyperglycemic mock-infected mice (STZ); & indicates p<0.05 vs no PMN control (panel J only).
Mentions: We next examined the ability of neutrophils harvested from C57BL/6 (Fig 5A, 5C, 5E and 5G) and C3H/HeN (Fig 5B, 5D, 5F and 5H–5J) mice after 4 weeks of B. burgdorferi infection (5–6 weeks of sustained hyperglycemia) to control uptake and survival of B. burgdorferi opsonized with pre-immune serum (Fig 5E–5J). Pre-immune serum was used to investigate the effects of hyperglycemia on neutrophil function independent of its effects on adaptive immune responses, and to maintain consistency with the methods of a previous study measuring effects of hyperglycemia on neutrophil killing of E. coli [18]. Opsonization in this context therefore refers to exposure of bacteria to serum complement proteins [52].

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