Low Serum Fetuin-A as a Biomarker to Predict Pneumococcal Necrotizing Pneumonia and Hemolytic Uremic Syndrome in Children

Chiu, Cheng-Hsun; Hsu, Mei‐Hua; Liao, Wan-Chun; Chien, Kun-Yi; Lee, Hao-Yuan; Chiu, Cheng-Hsun

doi:10.1097/md.0000000000003221

Cited by 15 publications

(10 citation statements)

References 33 publications

(47 reference statements)

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“… 8 hFet is also extensively studied for its potential relevance as a metabolic biomarker. 9 , 10 Increased levels of hFet have been linked to higher risk of cardiovascular disease (CVD) and incident type 2 diabetes (T2DM). 11 , 12 However, there are several obstacles preventing the use of hFet as a biomarker for those and any other diseases.…”

Section: Introductionmentioning

confidence: 99%

Similar Albeit Not the Same: In-Depth Analysis of Proteoforms of Human Serum, Bovine Serum, and Recombinant Human Fetuin

2018

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Fetuin, also known as alpha-2-Heremans Schmid glycoprotein (AHSG), belongs to some of the most abundant glycoproteins secreted into the bloodstream. In blood, fetuins exhibit functions as carriers of metals and small molecules. Bovine fetuin, which harbors 3 N-glycosylation sites and a suggested half dozen O-glycosylation sites, has been used often as a model glycoprotein to test novel analytical workflows in glycoproteomics. Here we characterize and compare fetuin in depth, using protein from three different biological sources: human serum, bovine serum, and recombinant human fetuin expressed in HEK-293 cells, with the aim to elucidate similarities and differences between these proteins and the post-translational modifications they harbor. Combining data from high-resolution native mass spectrometry and glycopeptide centric LC-MS analysis, we qualitatively and quantitatively gather information on fetuin protein maturation, N-glycosylation, O-glycosylation, and phosphorylation. We provide direct experimental evidence that both the human serum and part of the recombinant proteins are processed into two chains (A and B) connected by a single interchain disulfide bridge, whereas bovine fetuin remains a single-chain protein. Although two N-glycosylation sites, one O-glycosylation site, and a phosphorylation site are conserved from bovine to human, the stoichiometry of the modifications and the specific glycoforms they harbor are quite distinct. Comparing serum and recombinant human fetuin, we observe that the serum protein harbors a much simpler proteoform profile, indicating that the recombinant protein is not ideally engineered to mimic human serum fetuin. Comparing the proteoform profile and post-translational modifications of human and bovine serum fetuin, we observe that, although the gene structures of these two proteins are alike, they represent quite distinct proteins when their glycoproteoform profile is also taken into consideration.

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Section: Introductionmentioning

confidence: 99%

Similar Albeit Not the Same: In-Depth Analysis of Proteoforms of Human Serum, Bovine Serum, and Recombinant Human Fetuin

2018

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“…Due to weak immunity in children, pathogenic microorganisms can enter blood through lungs and cause septicemia and septic shock. A broad spectrum antibiotic therapy with powerful activity must be given to patients in early stage to strive for time for the upper sequential treatment ( 7 ). For severe infantile lobar pneumonia, step-down therapy has shown to be more effective than conventional and experimental antibiotic therapy ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

Principles of antibiotic application in children with lobar pneumonia: Step-up or step-down

Feng

Yang

et al. 2017

Experimental and Therapeutic Medicine

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In order to provide a scientific basis for rational use of antibiotics, we studied and compared the therapeutic effects of step-down and step-up antibiotic treatment schemes in children with lobar pneumonia. Eighty cases of children with lobar pneumonia were enrolled in this study and were randomly divided into two groups: The observation group and the control group, with 40 cases in each group. In the observation group, there were 23 cases with mild and 17 cases with severe lobar pneumonia, and in the control group, 25 were mild and 15 were severe cases. Patients in the control group were treated with antibiotics using step-up therapy method, while patients in the observation group were treated using step-down antibiotic therapy. Our results showed no significant differences in white blood cell (WBC) reduction rate, the course of antibiotic treatment, disappearance time of pulmonary rales and total efficiency in children with mild lobar pneumonia in the observation group after 72 h of treatment. The level of high-sensitivity C-reactive protein (hs-CRP) and procalcitonin (PCT) in the observation group were significantly lower. After 72 h of treatment of children with severe lobar pneumonia in the observation group, the rate of WBC reduction accelerated significantly. Compared to the patients in the control group, the course of antibiotic treatment and disappearance time of pulmonary rales were shortened significantly, while the total efficiency of treatment was improved considerably in the observation group. Also in the observation group, hs-CRP and PCT levels were significantly lower than that in the control group. In severe cases, step-down therapy showed a better result in relieving the inflammatory reactions. The disappearance time of pulmonary rales and the effective rate of treatment was significantly higher than those of step-up therapy. It was obvious that for children with severe lobar pneumonia, step-down therapy produced better results in relieving the inflammatory reaction.

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“…NanA, NanB and NanC can cleave serum sialoglycoproteins, including fetuin-A, low levels of which were associated with invasive pneumococcal disease and HUS [50]. Notably, immunization with all three recombinant neuraminidases was shown to modestly increase survival of mice challenged intravenously with different S. pneumoniae strains [51].…”

Section: Introductionmentioning

confidence: 99%

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

et al. 2018

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Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.

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Low Serum Fetuin-A as a Biomarker to Predict Pneumococcal Necrotizing Pneumonia and Hemolytic Uremic Syndrome in Children

Cited by 15 publications

References 33 publications

Similar Albeit Not the Same: In-Depth Analysis of Proteoforms of Human Serum, Bovine Serum, and Recombinant Human Fetuin

Similar Albeit Not the Same: In-Depth Analysis of Proteoforms of Human Serum, Bovine Serum, and Recombinant Human Fetuin

Principles of antibiotic application in children with lobar pneumonia: Step-up or step-down

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

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