Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria.
Immunohistochemical techniques have been used to investigate specific patterns of potentially reversible cellular injury, DNA damage, and apoptosis in the brainstems of Vietnamese patients who died of severe Plasmodium falciparum malaria. The degree and pattern of neuronal and glial stress responses were compared between patients with cerebral and non-cerebral malaria (CM), and appropriate non-malaria infected controls. The following markers were examined: (i) heat shock protein 70 (HSP70), for reversible injury; (ii) heme oxygenase-1, for oxidative stress; (iii & iv) two DNA-repair proteins, poly(ADP) ribose polymerase (PARP) and DNA-dependent protein kinase catalytic subunit; (v) poly(ADP) ribose, an end-product of PARP activity; and (vi) caspase-3-active, for apoptosis. Stress responses were found in a range of cell types as reflected by the widespread expression of HSP70. Oxidative stress predominated in the vicinity of vessels and haemorrhages. Some degree of DNA damage was found in the majority of malaria patients, but the distribution and frequency of the damage was much less than that observed in controls with irreversible neuronal injury. Similarly, caspase-3-active expression, as a measure of apoptosis, was no higher in the majority of malaria patients than the negative control cases, although 40% of CM cases expressed caspase-3-active in a small number of neurones of the pontine nuclei or within swollen axons of the pontocerebellar and corticospinal tracts. In conclusion, cells within the brainstem of all patients who died from severe malaria showed staining patterns indicative of considerable stress response and reversible neuronal injury. There was no evidence for a specific pattern of widespread irreversible cell damage in those patients with cerebral malaria.
Medana
I M
IM
Nuffield Department of Clinical Laboratory Sciences, The John Radcliffe Hospital, Oxford University, UK. isabelle.medana@ndc.sox.ac.uk
Mai
N T
NT
Day
N P
NP
Hien
T T
TT
Bethell
D
D
Phu
N H
NH
Farrar
J
J
White
N J
NJ
Turner
G D
GD
D000328:Adult; D017209:Apoptosis; D001933:Brain Stem / Q000201:enzymology / Q000469:parasitology / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002423:Cause of Death; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis; D051547:Heme Oxygenase-1; D006801:Humans; D016779:Malaria, Cerebral / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009457:Neuroglia / Q000473:pathology; D009687:Nuclear Proteins; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D014744:Vietnam
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011064:Poly Adenosine Diphosphate Ribose; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases