title: Evidence for spleen dysfunction in malaria-HIV co-infection in a subset of pediatric patients.
abstract: The spleen has an important role in the clearance of malaria parasites, and the role of HIV co-infection on this process is yet to be described. Using a combination of histological and molecular methods, we systematically evaluated parasite load across multiple organs from HIV-positive and HIV-negative cases of an autopsy study of pediatric comatose children with malaria infection (n=103) in Blantyre, Malawi. Quantification of parasite load across organs was done using histology. A subset of cases was further characterized for parasite localization and stage of development using immunohistochemistry-based labeling of parasite and host cells (5 HIV-positive, 10 HIV-negative), and quantitative RT-PCR (qRT-PCR) of asexual and sexual-specific genes (4 HIV-positive, 5 HIV-negative). The results were compared with clinical information including HIV status. The HIV-positive rate was 21% for the group studied (20 of 95) and HIV-positive patients had a significantly shorter duration of time between onset of illness and death, and were significantly older than HIV-negative patients. We found that spleens of HIV-positive cases had significantly higher parasite loads compared with those of HIV-negative cases in each of the three methods we used: (i) standard histology, (ii) immunohistochemistry-based labeling of Plasmodium lactate dehydrogenase (pLDH), and (iii) molecular detection of asexual parasite transcript apical membrane antigen 1 (AMA1). Immunohistochemistry-based labeling of macrophage marker CD163 in a subset of spleens revealed fewer activated macrophages containing engulfed parasites and a greater number of free unphagocytosed parasites in the HIV-positive cases. The mechanism by which HIV infection is associated with more rapid progression to severe cerebral malaria disease is possibly impairment of parasite destruction by splenic macrophages, supported by published in vitro studies showing inefficient phagocytosis of malaria parasites by HIV-infected macrophages.
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Joice
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.|Department of Pathology, The Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Frantzreb
authors.affiliation: Department of Pathology, The Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Alana
authors.initials: A
authors.lastname: Pradham
authors.affiliation: The Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.|Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Seydel
authors.affiliation: College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Steve
authors.initials: S
authors.lastname: Kamiza
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
authors.affiliation: College of Medicine, University of Malawi, Blantyre, Malawi.|Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.|Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.affiliation: The Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.|Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
authors.affiliation: Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.|Department of Pathology, The Brigham and Women's Hospital, Boston, MA, USA.|The Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
mesh_terms: D001344:Autopsy; D002648:Child; D002675:Child, Preschool; D060085:Coinfection; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000469:parasitology*; D006801:Humans; D007150:Immunohistochemistry; D008288:Malaria / Q000150:complications* / Q000469:parasitology*; D008297:Male; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000469:parasitology*