@article{de3e9747f0b44f5aa26dcf72ff47a748,
title = "Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection",
abstract = "Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis.",
author = "Isaacs, {Albert M.} and Morton, {Sarah U.} and Mercedeh Movassagh and Qiang Zhang and Christine Hehnly and Lijun Zhang and Morales, {Diego M.} and Sinnar, {Shamim A.} and Ericson, {Jessica E.} and Edith Mbabazi-Kabachelor and Peter Ssenyonga and Justin Onen and Ronnie Mulondo and Mady Hornig and Warf, {Benjamin C.} and Broach, {James R.} and Townsend, {R. Reid} and Limbrick, {David D.} and Paulson, {Joseph N.} and Schiff, {Steven J.}",
note = "Funding Information: The expert technical assistance of Petra Erdmann-Gilmore, Rose Connors, Yiling Mi, and Alan Davis at the Washington University Proteomics Shared Resource (WU-PSR), where the proteomic experiments were performed, is gratefully acknowledged. We also appreciate the efforts of all staff at the genomics core of the Institute of Personalized Medicine at Penn State University, where the majority of the genomic studies were performed. We are grateful to all our colleagues and collaborators in Uganda who were involved in many stages of this study. We thank our funding agencies who supported this work: The National Institutes of Health Director's Pioneer Award 5DP1HD086071-05 to S.J.S., Hydrocephalus Association 2018 Discovery Science Award to R.R.T., and Vanier Canada Graduate Scholarship 396212 to A.M.I. The WU-PSR is supported in part by the Washington University Institute of Clinical and Translational Sciences ( NCATS UL1 TR000448 ), the Mass Spectrometry Research Resource ( NIGMS P41 GM103422 ; R24GM136766 ), and the Siteman Comprehensive Cancer Center Support Grant ( NCI P30 CA091842 ). None of the organizations listed had any role in the study design, data collection, data analysis, data interpretation, writing, or decision to submit the report for publication. Funding Information: The expert technical assistance of Petra Erdmann-Gilmore, Rose Connors, Yiling Mi, and Alan Davis at the Washington University Proteomics Shared Resource (WU-PSR), where the proteomic experiments were performed, is gratefully acknowledged. We also appreciate the efforts of all staff at the genomics core of the Institute of Personalized Medicine at Penn State University, where the majority of the genomic studies were performed. We are grateful to all our colleagues and collaborators in Uganda who were involved in many stages of this study. We thank our funding agencies who supported this work: The National Institutes of Health Director's Pioneer Award 5DP1HD086071-05 to S.J.S. Hydrocephalus Association 2018 Discovery Science Award to R.R.T. and Vanier Canada Graduate Scholarship 396212 to A.M.I. The WU-PSR is supported in part by the Washington University Institute of Clinical and Translational Sciences (NCATS UL1 TR000448), the Mass Spectrometry Research Resource (NIGMS P41 GM103422; R24GM136766), and the Siteman Comprehensive Cancer Center Support Grant (NCI P30 CA091842). None of the organizations listed had any role in the study design, data collection, data analysis, data interpretation, writing, or decision to submit the report for publication. Study conceptual design and methodology were by S.J.S. J.N.P. D.D.L. R.R.T. J.R.B. A.M.I. M.H. S.U.M. and B.C.W. Formal data analysis and validation were by A.M.I. S.U.M. M.M. Q.Z. C.H. S.J.S. and L.Z. Investigations were performed by A.M.I. C.H. J.O. R.M. E.K. S.J.S. and J.R.B. Resources were provided by D.M.M. E.K. P.S. J.O. R.M. B.C.W. J.R.B. R.R.T. D.D.L. J.N.P. and S.J.S. Data curation was by J.N.P. M.M. C.H. L.Z. and Q.Z. Writing (original draft) was by A.M.I. S.U.M. and J.N.P. Writing (review and editing) were by A.M.I. S.U.M. J.N.P. and S.J.S. with contributions from Q.Z. C.H. L.Z. D.M. S.S. J.E.E. E.M. P.S. J.O. R.M. M.H. and J.R.B. Visualization was by A.M.I. S.J.S. M.M. and J.N.P. Supervision was provided by J.R.B. R.R.T. D.D.L. J.N.P. and S.J.S. Project administration was by C.H. E.K. and S.A.S. Project administration was by A.M.I. S.U.M. C.H. D.M.M. J.R.B. J.N.P. and S.J.S. Acquisition of financial support was by S.J.S. D.D.L. A.M.I. and R.R.T. Final manuscript review and approval was by all authors. Dr. Limbrick receives research funds and/or research equipment for unrelated projects from Medtronic, Inc. and Microbot Medical, Inc. Dr. Limbrick has received philanthropic equipment contributions for humanitarian relief work from Karl Storz, Inc. and Aesculap, Inc. The authors have no personal, financial, or institutional interest in any of the materials or devices described in this article. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = apr,
day = "23",
doi = "10.1016/j.isci.2021.102351",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}