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Gene expression analysis of children with acute hematogenous osteomyelitis caused by Methicillin-resistant Staphylococcus aureus: correlation with clinical severity of illness.

Gaviria-Agudelo C, Carter K, Tareen N, Pascual V, Copley LA - PLoS ONE (2014)

Bottom Line: Three over-expressed genes, P2RX1, SORT1, and RETN, and two under-expressed genes, LOC641788 and STAT 4, were significantly correlated with severity of illness.This study identified specific genes which correspond to disease severity during the early hospitalization of children with AHO from MRSA.Pattern recognition of this combination of genes could help to identify in the future severe clinical phenotypes before the disease is fully manifest and direct appropriate attention and resources to those children.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics Infectious Disease, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Children's Medical Center, Dallas, Texas, United States of America.

ABSTRACT
Children with acute hematogenous osteomyelitis (AHO) demonstrate a broad spectrum of clinical manifestations, ranging from mild to severe. Several advances have been achieved in the study of host immune response to acute invasive Staphylococcus aureus infections through gene expression analysis. However, previous research has neither attempted to evaluate the response of children with AHO specific to Methicillin-resistant Staphylococcus aureus (MRSA) nor to correlate gene expression with clinical phenotype. Study objective was to correlate gene expression of children with AHO due to MRSA with clinical severity of illness. Whole blood samples were obtained in Tempus tubes from 12 children with osteomyelitis once cultures obtained directly from the site of infection confirmed to be positive for MRSA. Using an Illumina platform and a systems-wide modular analysis, microarray findings from ten of these children were compared to that of nine healthy (age, ethnicity and gender) matched controls and correlated with clinical severity of illness. Children with AHO from MRSA demonstrated over-expression of innate immunity with respect to neutrophil activity, coagulation, inflammatory response, and erythrocyte development. Concurrently, these children demonstrated under-expression of adaptive immunity with respect to lymphocyte activation and activity of T-cell, cytotoxic or NK cell, and B-cell lines. Three over-expressed genes, P2RX1, SORT1, and RETN, and two under-expressed genes, LOC641788 and STAT 4, were significantly correlated with severity of illness. STAT 4 showed the strongest correlation (R2 = -0.83). STAT4 downregulation could potentially explain under-expression of genes related to adaptive immunity in this cohort of patients with AHO. This study identified specific genes which correspond to disease severity during the early hospitalization of children with AHO from MRSA. Pattern recognition of this combination of genes could help to identify in the future severe clinical phenotypes before the disease is fully manifest and direct appropriate attention and resources to those children.

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Related in: MedlinePlus

Gene Expression Biosignature in Whole Blood From Healthy Controls and Patients With MRSA AHO.Complete statistical analysis (Welch t-Test with Benjamini - Hochberg false discovery rate, p<0.05) between the two groups (healthy control group with 9 subjects and MRSA AHO group with 10 subjects) identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls.
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pone-0103523-g003: Gene Expression Biosignature in Whole Blood From Healthy Controls and Patients With MRSA AHO.Complete statistical analysis (Welch t-Test with Benjamini - Hochberg false discovery rate, p<0.05) between the two groups (healthy control group with 9 subjects and MRSA AHO group with 10 subjects) identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls.

Mentions: 12 children with MRSA AHO were enrolled during the study. The clinical data of these children are shown in Table 1. Matched control samples were unavailable for 2 children due to their young age (<2 years) so their samples were excluded from subsequent analysis. Fluorescent hybridization resulted in the identification of 23,023 transcripts within the microarray of the remaining 10 children (Figure 1A). Welch’s t-test with multiple testing correction using the Benjamini and Hochberg False Discovery Rate initially identified 269 transcripts which significantly (p<0.05) distinguished the two groups (Figure 1B). However, a modular interpretation of the gene expression revealed an unusual array of cellular expression and immune response in one of the children within the healthy control group. This child was excluded and the microarray statistical analysis was repeated without this subject (Figure 2). The completed analysis with 9 controls and 10 study patients identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls (Figure 3). The modular framework analysis of these children (Figure 4) demonstrated an up-regulation of innate immunity and downregulation of adaptive immunity. This was illustrated by significant over-expression of modules linked to neutrophil activity (M5.15), the coagulation cascade (M1.1), inflammatory response (M4.2), and erythrocyte development (M2.3). Concurrently, these children displayed an under-expression of modules associated with T-cells (M4.1, M6.15, and M6.19), cytotoxicity/NK cells and lymphocyte activation (M3.6 and M4.15), and B-cells (M4.10).


Gene expression analysis of children with acute hematogenous osteomyelitis caused by Methicillin-resistant Staphylococcus aureus: correlation with clinical severity of illness.

Gaviria-Agudelo C, Carter K, Tareen N, Pascual V, Copley LA - PLoS ONE (2014)

Gene Expression Biosignature in Whole Blood From Healthy Controls and Patients With MRSA AHO.Complete statistical analysis (Welch t-Test with Benjamini - Hochberg false discovery rate, p<0.05) between the two groups (healthy control group with 9 subjects and MRSA AHO group with 10 subjects) identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4116206&req=5

pone-0103523-g003: Gene Expression Biosignature in Whole Blood From Healthy Controls and Patients With MRSA AHO.Complete statistical analysis (Welch t-Test with Benjamini - Hochberg false discovery rate, p<0.05) between the two groups (healthy control group with 9 subjects and MRSA AHO group with 10 subjects) identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls.
Mentions: 12 children with MRSA AHO were enrolled during the study. The clinical data of these children are shown in Table 1. Matched control samples were unavailable for 2 children due to their young age (<2 years) so their samples were excluded from subsequent analysis. Fluorescent hybridization resulted in the identification of 23,023 transcripts within the microarray of the remaining 10 children (Figure 1A). Welch’s t-test with multiple testing correction using the Benjamini and Hochberg False Discovery Rate initially identified 269 transcripts which significantly (p<0.05) distinguished the two groups (Figure 1B). However, a modular interpretation of the gene expression revealed an unusual array of cellular expression and immune response in one of the children within the healthy control group. This child was excluded and the microarray statistical analysis was repeated without this subject (Figure 2). The completed analysis with 9 controls and 10 study patients identified 58 genes (24 over-expressed and 34 under-expressed) which significantly differentiated children with MRSA AHO from the healthy controls (Figure 3). The modular framework analysis of these children (Figure 4) demonstrated an up-regulation of innate immunity and downregulation of adaptive immunity. This was illustrated by significant over-expression of modules linked to neutrophil activity (M5.15), the coagulation cascade (M1.1), inflammatory response (M4.2), and erythrocyte development (M2.3). Concurrently, these children displayed an under-expression of modules associated with T-cells (M4.1, M6.15, and M6.19), cytotoxicity/NK cells and lymphocyte activation (M3.6 and M4.15), and B-cells (M4.10).

Bottom Line: Three over-expressed genes, P2RX1, SORT1, and RETN, and two under-expressed genes, LOC641788 and STAT 4, were significantly correlated with severity of illness.This study identified specific genes which correspond to disease severity during the early hospitalization of children with AHO from MRSA.Pattern recognition of this combination of genes could help to identify in the future severe clinical phenotypes before the disease is fully manifest and direct appropriate attention and resources to those children.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics Infectious Disease, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Children's Medical Center, Dallas, Texas, United States of America.

ABSTRACT
Children with acute hematogenous osteomyelitis (AHO) demonstrate a broad spectrum of clinical manifestations, ranging from mild to severe. Several advances have been achieved in the study of host immune response to acute invasive Staphylococcus aureus infections through gene expression analysis. However, previous research has neither attempted to evaluate the response of children with AHO specific to Methicillin-resistant Staphylococcus aureus (MRSA) nor to correlate gene expression with clinical phenotype. Study objective was to correlate gene expression of children with AHO due to MRSA with clinical severity of illness. Whole blood samples were obtained in Tempus tubes from 12 children with osteomyelitis once cultures obtained directly from the site of infection confirmed to be positive for MRSA. Using an Illumina platform and a systems-wide modular analysis, microarray findings from ten of these children were compared to that of nine healthy (age, ethnicity and gender) matched controls and correlated with clinical severity of illness. Children with AHO from MRSA demonstrated over-expression of innate immunity with respect to neutrophil activity, coagulation, inflammatory response, and erythrocyte development. Concurrently, these children demonstrated under-expression of adaptive immunity with respect to lymphocyte activation and activity of T-cell, cytotoxic or NK cell, and B-cell lines. Three over-expressed genes, P2RX1, SORT1, and RETN, and two under-expressed genes, LOC641788 and STAT 4, were significantly correlated with severity of illness. STAT 4 showed the strongest correlation (R2 = -0.83). STAT4 downregulation could potentially explain under-expression of genes related to adaptive immunity in this cohort of patients with AHO. This study identified specific genes which correspond to disease severity during the early hospitalization of children with AHO from MRSA. Pattern recognition of this combination of genes could help to identify in the future severe clinical phenotypes before the disease is fully manifest and direct appropriate attention and resources to those children.

Show MeSH
Related in: MedlinePlus