Probing of a human proteome microarray with a recombinant pathogen protein reveals a novel mechanism by which hookworms suppress B cell receptor signaling
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Na-ASP-2 is an efficacious hookworm vaccine antigen; however, despite elucidation of its crystal structure and studies addressing its immunobiology, the function of Na-ASP-2 has remained elusive. We probed a 9,000 protein human proteome microarray with Na-ASP-2 and showed binding to CD79A, a component of the B cell antigen receptor complex. Na-ASP-2 bound to human B lymphocytes ex vivo and down-regulated the transcription of ~1,000 B cell mRNAs, while only ~100 mRNAs were up-regulated compared to control-treated cells. The expression of a range of molecules was affected by Na-ASP-2, including factors involved in leukocyte transendothelial migration pathways and the B cell signaling receptor pathway. Of note was the down-regulated transcription of lyn and pi3 k, molecules that are known to interact with CD79A and control B cell receptor signaling processes. Together, these results highlight a previously unknown interaction between a hookworm-secreted protein and B cells, which has implications for helminth-driven immunomodulation and vaccine development. Further, the novel use of human protein microarrays to identify host-pathogen interactions, coupled to ex vivo binding studies and subsequent analyses of global gene expression in human host cells, demonstrates a new pipeline by which to explore the molecular basis of infectious diseases.
The Journal of Infectious Diseases
© 2014 The Author(s). Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Journal of Infectious Diseases following peer review. The definitive publisher-authenticated version, Probing of a Human Proteome Microarray With a Recombinant Pathogen Protein Reveals a Novel Mechanism by Which Hookworms Suppress B-Cell Receptor Signaling, Journal of Infectious Diseases, (2015) 211 (3): 416-425, is available online at: 10.1093/infdis/jiu451