期刊
MSYSTEMS
卷 5, 期 4, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/mSystems.00368-20
关键词
group B Streptococcus; TMT; blood-brain barrier; meningitis; multiplexing; proteomics
类别
资金
- NIAID/NIH [R01AI148417, R21AI149090]
- NINDS/NIH [R56 NS051247, R01 NS116716]
- UCSD Microbial Sciences Initiative Graduate Research Fellowship
- UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences [T32 GM007752]
- Rheumatic Diseases Research Investigator Program through an institutional training grant from the National Institute of and Musculoskeletal and Skin Diseases [T32AR064194]
- Rees Stealy Research Foundation/SDSU Heart Institute
- San Diego Chapter ARCS Scholarship
- NIH/NINDS [R01 NS091281-01A1]
- UCSD training grant from the NIH/NIDDK Gastroenterology Training Program [T32 DK007202]
Group B Streptococcus (GBS) remains the leading cause of neonatal meningitis, a disease associated with high rates of adverse neurological sequelae. The in vivo relationship between GBS and brain tissues remains poorly characterized, partly because past studies had focused on microbial rather than host processes. Additionally, the field has not capitalized on systems-level technologies to probe the host-pathogen relationship. Here, we use multiplexed quantitative proteomics to investigate the effect of GBS infection in the murine brain at various levels of tissue complexity, beginning with the whole organ and moving to brain vascular substructures. Infected whole brains showed classical signatures associated with the acutephase response. In isolated brain microvessels, classical blood-brain barrier proteins were unaltered, but interferon signaling and leukocyte recruitment proteins were upregulated. The choroid plexus showed increases in peripheral immune cell proteins. Proteins that increased in abundance in the vasculature during GBS invasion were associated with major histocompatibility complex (MHC) class I antigen processing and endoplasmic reticulum dysfunction, a finding which correlated with altered host protein glycosylation profiles. Globally, there was low concordance between the infection proteome of whole brains and isolated vascular tissues. This report underscores the utility of unbiased, systems-scale analyses of functional tissue substructures for understanding disease. IMPORTANCE Group B Streptococcus (GBS) meningitis remains a major cause of poor health outcomes very early in life. Both the host-pathogen relationship leading to disease and the massive host response to infection contributing to these poor outcomes are orchestrated at the tissue and cell type levels. GBS meningitis is thought to result when bacteria present in the blood circumvent the selectively permeable vascular barriers that feed the brain. Additionally, tissue damage subsequent to bacterial invasion is mediated by inflammation and by immune cells from the periphery crossing the blood-brain barrier. Indeed, the vasculature plays a central role in disease processes occurring during GBS infection of the brain. Here, we employed quantitative proteomic analysis of brain vascular substructures during invasive GBS disease. We used the generated data to map molecular alterations associated with tissue perturbation, finding widespread intracellular dysfunction and punctuating the importance of investigations relegated to tissue type over the whole organ.
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