Comparative proteomics of cerebrospinal fluid reveals a predictive model for differential diagnosis of pneumococcal, meningococcal, and enteroviral meningitis, and novel putative therapeutic targets

Abstract

Submitted by sandra infurna ([email protected]) on 2016-03-10T14:47:14Z No. of bitstreams: 1 alex_chapeaurouge_etal_IOC_2015.pdf: 343462 bytes, checksum: deaf5a5bf883dc052b8cdda7882ad5b1 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-03-10T15:07:20Z (GMT) No. of bitstreams: 1 alex_chapeaurouge_etal_IOC_2015.pdf: 343462 bytes, checksum: deaf5a5bf883dc052b8cdda7882ad5b1 (MD5)Made available in DSpace on 2016-03-10T15:07:20Z (GMT). No. of bitstreams: 1 alex_chapeaurouge_etal_IOC_2015.pdf: 343462 bytes, checksum: deaf5a5bf883dc052b8cdda7882ad5b1 (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou (CPqRR). Grupo de Pesquisa em Genômica e Biologia Computacional. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou (CPqRR). Grupo de Pesquisa em Genômica e Biologia Computacional. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxinologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou (CPqRR). Grupo de Pesquisa em Genômica e Biologia Computacional. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxinologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou (CPqRR). Grupo de Pesquisa em Genômica e Biologia Computacional. Belo Horizonte, MG, Brasil.FHEMIG. Hospital de Crianças João Paulo II. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou (CPqRR). Grupo de Pesquisa Informática de Biosistemas. Belo Horizonte, MG, Brasil.Background: Meningitis is the inflammation of the meninges in response to infection or chemical agents. While aseptic meningitis, most frequently caused by enteroviruses, is usually benign with a self-limiting course, bacterial meningitis remains associated with high morbidity and mortality rates, despite advances in antimicrobial therapy and intensive care. Fast and accurate differential diagnosis is crucial for assertive choice of the appropriate therapeutic approach for each form of meningitis. Methods: We used 2D-PAGE and mass spectrometry to identify the cerebrospinal fluid proteome specifically related to the host response to pneumococcal, meningococcal, and enteroviral meningitis. The disease-specific proteome signatures were inspected by pathway analysis. Results: Unique cerebrospinal fluid proteome signatures were found to the three aetiological forms of meningitis investigated, and a qualitative predictive model with four protein markers was developed for the differential diagnosis of these diseases. Nevertheless, pathway analysis of the disease-specific proteomes unveiled that Kallikrein-kinin system may play a crucial role in the pathophysiological mechanisms leading to brain damage in bacterial meningitis. Proteins taking part in this cellular process are proposed as putative targets to novel adjunctive therapies. Conclusions: Comparative proteomics of cerebrospinal fluid disclosed candidate biomarkers, which were combined in a qualitative and sequential predictive model with potential to improve the differential diagnosis of pneumococcal, meningococcal and enteroviral meningitis. Moreover, we present the first evidence of the possible implication of Kallikrein-kinin system in the pathophysiology of bacterial meningitis