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-m 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 ␤ receptor (LT␤R ؊/؊ ), and it was still significantly reduced when the number of MZM and MMM was diminished, as in tumor necrosis factor alpha-deficient (TNF-␣ ؊/؊ ) mice. Moreover, mice deficient in TNF-␣, tumor necrosis factor receptor I (TNFRI ؊/؊ ), and LT␤R exhibited progressive impairment in malaria-induced spleen closing. Treatment of C57BL/6 mice with TNF-␣ 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.

Alterations of Splenic Architecture in Malaria Are Induced Independently of Toll-Like Receptors 2, 4, and 9 or MyD88 and May Affect Antibody Affinity

“…1B). Normal splenic structure returned by day 60, when the parasitemia subsided to subpatent levels (2,3,8,29, 54, 67; data not shown).…”

“…Additionally, malaria-associated splenomegaly has been associated with increased erythropoiesis in mice (41,52,61,68). Malarial splenomegaly is accompanied by transient alterations in the microarchitecture during acute infection (2,9,29,32,54,65,67), which in mouse infections returns to normal several weeks after the acute parasitemia (1,54,67).…”

CD8+ T Lymphocyte-Mediated Loss of Marginal Metallophilic Macrophages following Infection withPlasmodium chabaudi chabaudi AS

“…A recent study reported loss of MZM, but not MMM, following infection with P. chabaudi. The authors concluded that, as a similar loss occurred following administration of TNF, the MZM loss was the result of up-regulation of TNF in the infected mice (16).…”

Loss of Ability To Self-Heal Malaria upon Taurine Transporter Deletion

“…We used a nonclonal line of P. chabaudi (59) exhibiting a restriction length polymorphism pattern very similar, but not identical, to that of Plasmodium chabaudi chabaudi AS (28). Erythrocytic stages of P. chabaudi were passaged weekly in NMRI mice.…”

“…The liver plays a central role in malaria: it is the site where the preerythrocytic stages of the malaria parasites have to develop and multiply (in hepatocytes), but it is also the site where the intraerythrocytic stages of the parasites, which are responsible for disease and death, can be trapped and even destroyed (2,3,28). Predominantly the Kupffer cells, which constitute approximately 80 to 90% of total macrophages, contribute to the trapping capacity of the liver.…”