Gene Expression Analysis of Children with Acute Hematogenous Osteomyelitis Caused by Methicillin-Resistant Staphylococcus aureus: Correlation with Clinical Severity of Illness

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.

Genomic Heterogeneity of Methicillin Resistant Staphylococcus aureus Associated with Variation in Severity of Illness among Children with Acute Hematogenous Osteomyelitis

“…The pathogenetic mechanisms underlying the variation of clinical manifestations of children with osteomyelitis due to MRSA are incompletely understood. We have previously reported that children with invasive MRSA infections display an over-expression of innate immunity and under-expression of adaptive immunity and that specific genes correlate with severity of illness [ 32 ]. Although host factors are likely to play a role in clinical variability, attention must still be directed to the bacteria in light of the diverse virulence capabilities of MRSA.…”

Assessment of immune status using blood transcriptomics and potential implications for global health

“…[51][52][53]) or 5 on Staphylococcus aureus infection (e.g. [54,55]). Notably considerable interest has also emerged recently over the use of blood transcriptomic platforms for the profiling of in vivo responses to vaccines (e.g.…”

Practice Variation in the Surgical Management of Children With Acute Hematogenous Osteomyelitis

“…Although platelets are not a laboratory measure that is routinely followed for AHO disease monitoring, upregulation of platelets can help distinguish between patients with and without the disease 16. An upregulation of innate immunity, including platelets, has been found in patients with MRSA AHO 17. Furthermore, Panton-Valentine leucocidin–positive Staphylococcus aureus strains have been linked to thrombosis in AHO, which is likely activated by Panton-Valentine leucocidin–damaged neutrophils 18.…”