Impaired Function of Antibodies to Pneumococcal Surface Protein A but Not to Capsular Polysaccharide in Mexican American Adults with Type 2 Diabetes Mellitus

Mathews, Christine; Brown, Eric L.; Martinez, Perla J.; Bagaria, Upasana; Nahm, Moon H.; Burton, Robert L.; Fisher‐Hoch, Susan P.; McCormick, Joseph B.; Mirza, Sharper

doi:10.1128/cvi.00268-12

Cited by 20 publications

(14 citation statements)

References 48 publications

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“…There are data supporting alterations in complement receptors or complement function in DM or hyperglycemia. In diabetics there appears to be a lower percentage of CR3-positive monocytes, and in a separate study anti-PspA antibodies to S. pneumonia displayed reduced capacity for C3 deposition that was proportional to glucose control 16;17 Hyperglycemia has been associated with induction of structural changes on C3 that inhibit C3-mediated effector functions to S. aureus . 40 We are beginning to assess if there are defects in the complement components in serum and monocytes that explain the reduced association of M. tuberculosis , but we cannot exclude abnormalities in other heat-labile components of the immune system, such as cytokines.…”

Section: Discussionmentioning

confidence: 97%

“…Several studies have shown reduced phagocytosis of neutrophils to extracellular pathogens, including Streptococcus pneumonia , Staphylococcus aureus , Escherichia coli , S. epidermidis and Candida spp. 17;37–39 In contrast, there are few studies with monocytes, but all show reduction in phagocytosis to different pathogens (opsonized Eschelichia coli , Candida albicans and Listeria monocytogenes ) 10;15;23 Whether the underlying defect for phagocytosis is in type 1 or type 2 DM, or in PMN versus monocytes is unclear, with alterations attributed to serum factors, the phagocyte, or both, depending on the study. Our findings suggest that reduced M. tuberculosis association may be related to altered complement in serum or complement receptors in monocytes.…”

Section: Discussionmentioning

confidence: 99%

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Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Gómez¹,

Twahirwa²,

Schlesinger³

et al. 2013

Tuberculosis

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The re-emerging importance of type 2 diabetes mellitus (DM) to tuberculosis (TB) control is of growing concern, but the basis for this relationship is poorly understood. Given the importance of mononuclear phagocytes for TB control and the reported alterations in monocytes of DM patients, we evaluated whether the initial interaction between both was affected in diabetics. M. tuberculosis-naïve individuals with and without DM were group matched by age and gender and the efficiency of M. tuberculosis association (attachment and ingestion) with their monocytes was assessed in the presence of autologous serum. The association of M. tuberculosis with monocytes was significantly lower in diabetics (19.2±6.1) than non-diabetics (27.5±7.9; p=0.02). Multivariate analysis controlling for host sociodemographics, DM characteristics and serum lipids indicated that male gender (p=0.04) and poorly-controlled DM (high HbA1c and hyperglycemia; p=0.01) were significantly associated with the lower interaction of M. tuberculosis with monocytes. Serum heat-inactivation reduced the association of M. tuberculosis to similar levels in both study groups (p=0.69) suggesting alterations in the complement pathway of DM patients. These findings suggest an altered route of entry of the pathogen in DM patients that may influence the downstream activation of signaling pathways in the monocyte and the survival of mycobacteria.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Gómez¹,

Twahirwa²,

Schlesinger³

et al. 2013

Tuberculosis

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show abstract

“…Therefore, the absence of glucose in the nasopharynx of colonized adults may help to explain why colonization does not typically result in an overt inflammatory state. Additionally, increases in glucose concentration within the nasopharynx-for example, as a result of virusinduced inflammation or even uncontrolled diabetes-may further explain why individuals with these conditions are vulnerable to IPD (62,64,65). Thus, catabolite repression is possibly a key event in initiating a pathogenic program of S. pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Neuraminidase A-Exposed Galactose Promotes Streptococcus pneumoniae Biofilm Formation during Colonization

et al. 2016

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f Streptococcus pneumoniae is an opportunistic pathogen that colonizes the nasopharynx. Herein we show that carbon availability is distinct between the nasopharynx and bloodstream of adult humans: glucose is absent from the nasopharynx, whereas galactose is abundant. We demonstrate that pneumococcal neuraminidase A (NanA), which cleaves terminal sialic acid residues from host glycoproteins, exposed galactose on the surface of septal epithelial cells, thereby increasing its availability during colonization. We observed that S. pneumoniae mutants deficient in NanA and ␤-galactosidase A (BgaA) failed to form biofilms in vivo despite normal biofilm-forming abilities in vitro. Subsequently, we observed that glucose, sucrose, and fructose were inhibitory for biofilm formation, whereas galactose, lactose, and low concentrations of sialic acid were permissive. Together these findings suggested that the genes involved in biofilm formation were under some form of carbon catabolite repression (CCR), a regulatory network in which genes involved in the uptake and metabolism of less-preferred sugars are silenced during growth with preferred sugars. Supporting this notion, we observed that a mutant deficient in pyruvate oxidase, which converts pyruvate to acetyl-phosphate under non-CCR-inducing growth conditions, was unable to form biofilms. Subsequent comparative transcriptome sequencing (RNA-seq) analyses of planktonic and biofilm-grown pneumococci showed that metabolic pathways involving the conversion of pyruvate to acetyl-phosphate and subsequently leading to fatty acid biosynthesis were consistently upregulated during diverse biofilm growth conditions. We conclude that carbon availability in the nasopharynx impacts pneumococcal biofilm formation in vivo. Additionally, biofilm formation involves metabolic pathways not previously appreciated to play an important role.

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“…Hyperglycemia has been suggested to cause structural changes in C3b that lead to reduced phagocytosis of E. coli [37] in DM2 patients and antibodies show significantly higher glycation when compared to non-DM2 controls but the impact of these findings on function is unclear [38], [39]. Among Hispanics, those with DM2 had lower antibody titers and reduced opsonophagocytosis of S. pneumoniae [40].…”

Section: Discussionmentioning

confidence: 99%

Phagocytosis via Complement or Fc-Gamma Receptors Is Compromised in Monocytes from Type 2 Diabetes Patients with Chronic Hyperglycemia

et al. 2014

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Type 2 diabetes patients (DM2) have a higher risk of tuberculosis (TB) that may be attributed to functional defects in their mononuclear phagocytes given the critical role of these cells in Mycobacterium tuberculosis containment. Our previous findings suggest that monocytes from DM2 have reduced association with serum-opsonized M. tuberculosis. To determine if this alteration is due to defects in phagocytosis via complement or Fc-gamma receptors (FcγRs), in this study we evaluated the uptake of sheep red blood cells coated with IgG or complement, respectively, by monocytes from individuals with and without DM2. We found that chronic hyperglycemia was significantly associated with reduced phagocytosis via either receptor by univariable and multivariable analyses. This defect was independent of host serum opsonins and flow cytometry data indicated this was not attributed to reduced expression of these phagocytic receptors on DM2 monocytes. The positive correlation between both pathways (R = 0.64; p = 0.003) indicate that monocytes from individuals with chronic hyperglycemia have a defect in the two predominant phagocytic pathways of these cells. Given that phagocytosis is linked to activation of effector mechanisms for bacterial killing, it is likely that this defect is one factor contributing to the higher susceptibility of DM2 patients to pathogens like M. tuberculosis.

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Impaired Function of Antibodies to Pneumococcal Surface Protein A but Not to Capsular Polysaccharide in Mexican American Adults with Type 2 Diabetes Mellitus

Cited by 20 publications

References 48 publications

Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control

Neuraminidase A-Exposed Galactose Promotes Streptococcus pneumoniae Biofilm Formation during Colonization

Phagocytosis via Complement or Fc-Gamma Receptors Is Compromised in Monocytes from Type 2 Diabetes Patients with Chronic Hyperglycemia

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