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

Abstract

Deletion of the taurine transporter gene (taut) results in lowered levels of taurine, the most abundant amino acid in mammals. Here, we show that taut ؊/؊ mice have lost their ability to self-heal blood-stage infections with Plasmodium chabaudi malaria. All taut ؊/؊ mice succumb to infections during crisis, while about 90% of the control taut ؉/؉ mice survive. The latter retain unchanged taurine levels even at peak parasitemia. Deletion of taut, however, results in the lowering of circulating taurine levels from 540 to 264 mol/liter, and infections cause additional lowering to 192 mol/liter. Peak parasitemia levels in taut ؊/؊ mice are approximately 60% higher than those in taut ؉/؉ mice, an elevation that is associated with increased systemic tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) levels, as well as with liver injuries. The latter manifest as increased systemic ammonia levels, a perturbed capacity to entrap injected particles, and increased expression of genes encoding TNF-␣, IL-1␤, IL-6, inducible nitric oxide synthase (iNOS), NF-B, and vitamin D receptor (VDR). Autopsy reveals multiorgan failure as the cause of death for malaria-infected taut ؊/؊ mice. Our data indicate that taut-controlled taurine homeostasis is essential for resistance to P. chabaudi malaria. Taurine deficiency due to taut deletion, however, impairs the eryptosis of P. chabaudi-parasitized erythrocytes and expedites increases in systemic TNF-␣, IL-1␤, and ammonia levels, presumably contributing to multiorgan failure in P. chabaudi-infected taut ؊/؊ mice.

Cutting Edge: Inhibition of IL-6 Trans-Signaling Protects from Malaria-Induced Lethality in Mice

“…1B). P. chabaudi-induced lethality is known to result from multiple organ failure that varies in individual mice (18). Control IL-6Ra FL mice exhibited a continuous increase in circulating sIL-6Ra during the precrisis phase, from 16 to 190 ng/ml on day 8 p.i., whereas sIL-6Ra was absent in IL-6Ra KO mice (Fig.…”

“…Challenge was i.p. with 10 6 erythrocytes parasitized with virulent P. chabaudi, as detailed previously (18,19).…”

Physiology and Pathophysiology of Eryptosis

“…Eryptosis is triggered following infection with mycoplasma [28] or, as pointed out above, by the malaria pathogen Plasmodium [20,[29][30][31][32][33][34]. Intraerythrocytic plasmodia induce oxidative stress which in turn activates the Ca 2+ -permeable cation channels leading to Ca 2+ entry and eryptosis.…”

Untitled

“…Taurine homeostatis which occurs in the liver appears to be essential in this mammal for resistance to malaria. It is claimed that because of their ketogenic diet rich in meat and rich in taurine, cats and dogs are efficiently protected against malaria [7]. Taurine has anti-oxidant properties [8].…”