Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection
Albert M. Isaacs,
Sarah U. Morton,
Mercedeh Movassagh,
Qiang Zhang,
Christine Hehnly,
Lijun Zhang,
Diego M. Morales,
Shamim A. Sinnar,
Jessica E. Ericson,
Edith Mbabazi-Kabachelor,
Peter Ssenyonga,
Justin Onen,
Ronnie Mulondo,
Mady Hornig,
Benjamin C. Warf,
James R. Broach,
R. Reid Townsend,
David D. Limbrick, Jr.,
Joseph N. Paulson,
Steven J. Schiff
Affiliations
Albert M. Isaacs
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 1N4, Canada
Sarah U. Morton
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Mercedeh Movassagh
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Qiang Zhang
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Christine Hehnly
Institute for Personalized Medicine, Pennsylvania State University, Hershey, PA 17033, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA 16801, USA
Lijun Zhang
Institute for Personalized Medicine, Pennsylvania State University, Hershey, PA 17033, USA
Diego M. Morales
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA
Shamim A. Sinnar
Center for Neural Engineering, Pennsylvania State University, State College, PA 16801, USA; Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Jessica E. Ericson
Department of Pediatrics, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Edith Mbabazi-Kabachelor
CURE Children's Hospital of Uganda, Mbale, Uganda
Peter Ssenyonga
CURE Children's Hospital of Uganda, Mbale, Uganda
Justin Onen
CURE Children's Hospital of Uganda, Mbale, Uganda
Ronnie Mulondo
CURE Children's Hospital of Uganda, Mbale, Uganda
Mady Hornig
Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
Benjamin C. Warf
Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA
James R. Broach
Institute for Personalized Medicine, Pennsylvania State University, Hershey, PA 17033, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA 16801, USA
R. Reid Townsend
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
David D. Limbrick, Jr.
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA
Joseph N. Paulson
Department of Biostatistics, Product Development, Genentech Inc., South San Francisco, CA 94080, USA
Steven J. Schiff
Center for Neural Engineering, Pennsylvania State University, State College, PA 16801, USA; Center for Infectious Disease Dynamics, Departments of Neurosurgery, Engineering Science and Mechanics, and Physics, The Pennsylvania State University, University Park, PA 16802, USA; Corresponding author: Steven J. Schiff, W311 Millennium Science Complex, The Pennsylvania State University, University Park, PA 16802, USA
Summary: 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.
