Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress

Abstract

Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of 's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasite-induced band 3 tyrosine phosphorylation and inhibit parasite-promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance.

Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria

“…During previous studies of human erythrocyte membranes, we observed that the erythrocytes possess a mechanism that is involved in the expulsion of denatured hemoglobin, requiring the activation of Syk [ 10 , 11 , 12 , 13 , 14 ]. This function could play a role in the process of asexual P. falciparum growth, as malaria parasites exert oxidative stress in erythrocytes, causing denaturation of hemoglobin, the oxidation of band 3, and its subsequent phosphorylation by Syk [ 15 , 16 ]. The protein band 3 (also known as the anion exchanger, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte’s lipid bilayer, and thereby contributes critically to the stability of the red cell membrane [ 13 , 17 ].…”

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

“…The band 3-based bridges formed by multiprotein complexes involving ankyrin and protein 4.1 (junctional complex) anchor the red cell membrane to the skeleton network (Figure 3, left panel) [19,109,110]. Studies in G6PD deficient red cells exposed in vitro to diamide, β-thalassemic erythrocytes or sickle erythrocytes undergoing in vitro deoxygenation, have had documented an over-activation of Syk bypassing the canonical cascade and targeting clustered band 3 [17,18,107,[114][115][116][117]. This favors the release of erythroid microparticles and the macrophage biting during transit of pathologic red cells in spleen microcirculation (Figure 3, right panel).…”

“…This favors the release of erythroid microparticles and the macrophage biting during transit of pathologic red cells in spleen microcirculation (Figure 3, right panel). Indeed, pharmacologic active Syk inhibitors such as imatinib in association with artemisinin have been shown to accelerate the clearance of malaria parasitized red cells by splenic macrophages [17,106,114,116,117]. Up to now, a clinical study on the effects of the combination imatinib-artemisinin treatment in patient with malaria is on-going in Vietnam (NCT#02614404).…”

The Malaria News Beat: “This Just In”

“…Current high-throughput efforts are directed at both the blood and liver stages of the disease, and a recent report by Antonova-Koch et al (4) has struck me and more expert observers as promising. Another development, very surprising, is that there is considerable promise in a drug developed for a hematological malignancy, namely Gleevec, based on a revealed role for Syk kinases in creating the erythrocyte membrane band 3 protein tyrosine phosphorylation induced by the parasite that leads to a destabilization of the membrane-one of the parasite's many tricks (5). And one cannot fail to note that should this very promising new lead pan out, it would be a wonderful case of how basic research (which is how Gleevec was first envisioned) can radiate even beyond the first disease application (chronic myelogenous leukemia).…”

“…Thoru Pederson Editor-in-Chief, The FASEB Journal doi: 10.1096/fj.190301ufm ACKNOWLEDGMENTS I thank Joseph Hoffman (Yale University) for alerting me to Panteleo et al (5).…”