title: Massive destruction of malaria-parasitized red blood cells despite spleen closure.
abstract: It is currently accepted that malaria-parasitized red blood cells (pRBC) are eliminated, like senescent erythrocytes, phagocytically by macrophages in the red pulp of the spleen. Here, however, we show that self-healing Plasmodium chabaudi malaria activates spleen closure in C57BL/6 mice. Confocal laser scanning microscopy revealed that spleen closing was manifested by elimination of entry into the red pulp of 3-microm polystyrol particles, pRBC, and nonparasitized red blood cells but not of bovine serum albumin. This spleen closure did not reflect a reduction in the number of phagocytic cells, as shown by flow cytometry, whereas marginal zone macrophages (MZM) were lost and red pulp macrophages entered the white pulp. Splenic trapping of pBRC was strongly reduced in the absence of MZM and marginal metallophilic macrophages (MMM), as it is in noninfected mice with a disrupted lymphotoxin beta receptor (LTbetaR(-/-)), and it was still significantly reduced when the number of MZM and MMM was diminished, as in tumor necrosis factor alpha-deficient (TNF-alpha(-/-)) mice. Moreover, mice deficient in TNF-alpha, tumor necrosis factor receptor I (TNFRI(-/-)), and LTbetaR exhibited progressive impairment in malaria-induced spleen closing. Treatment of C57BL/6 mice with TNF-alpha induced loss of MZM and spleen closing by about 20%. Our data indicate that TNF/TNFRI signaling is involved in regulating malaria-induced spleen closure, which is maximal during crisis, when parasitemia declines more than 100-fold. Consequently, the vast majority of pRBC cannot be destroyed by the spleen during crisis, suggesting that the known sophisticated sequestration system of Plasmodium parasites did not evolve to avoid splenic clearance.
authors.affiliation: Division of Molecular Parasitology and Centre for Biological and Medical Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krücken
authors.forename: Liv I
authors.initials: LI
authors.lastname: Mehnert
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Dkhil
authors.forename: Manal
authors.initials: M
authors.lastname: El-Khadragy
authors.forename: W Peter M
authors.initials: WP
authors.lastname: Benten
authors.forename: Horst
authors.initials: H
authors.lastname: Mossmann
authors.forename: Frank
authors.initials: F
authors.lastname: Wunderlich
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000469:parasitology*; D053259:Lymphotoxin beta Receptor; D008264:Macrophages / Q000276:immunology; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018512:Parasitemia / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D010587:Phagocytosis; D016788:Plasmodium chabaudi; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000098:blood supply / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
chemical_list: C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha