Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated by deregulation of T cell-mediated B-cell activation, which results in glomerulonephritis and renal failure. Disease is treated with immunosuppressants and cytostatic agents that have numerous side effects. Here we examine the use of inhibitors of phosphoinositide 3-kinase (PI3K) gamma, a lipid kinase that regulates inflammation, in the MRL-lpr mouse model of SLE. Treatment reduced glomerulonephritis and prolonged lifespan, suggesting that P13Kgamma may be a useful target in the treatment of chronic inflammation.

Summary Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection.

Summary Plasmodium species, the parasitic agents of malaria, invade erythrocytes to reproduce resulting in erythrocyte loss. However, a greater loss is caused by the elimination of uninfected erythrocytes, sometimes long after infection has been cleared. Using a mouse model, we found that Plasmodium infection induces the generation of anti-self antibodies that bind to the surface of uninfected erythrocytes from infected, but not uninfected, mice. These antibodies recognize phosphatidylserine, which is exposed on the surface of a fraction of uninfected erythrocytes during malaria. We find that phosphatidylserine-exposing erythrocytes are reticulocytes expressing high levels of CD47, a ‘do-not-eat-me’ signal, but the binding of anti-phosphatidylserine antibodies mediates their phagocytosis, contributing to anemia. In human patients with late post-malarial anemia, we found a strong inverse correlation between the levels of anti-phosphatidylserine antibodies and plasma hemoglobin, suggesting a similar role in humans. Inhibition of this pathway may be exploited for treating malarial anemia.

Infectious pathogens contribute to the development of autoimmune disorders, but the mechanisms connecting these processes are incompletely understood. Here we show that Plasmodium DNA induces autoreactive responses against erythrocytes by activating a population of B cells expressing CD11c and the transcription factor T-bet, which become major producers of autoantibodies that promote malarial anaemia. Additionally, we identify parasite DNA-sensing through Toll-like receptor 9 (TLR9) along with inflammatory cytokine receptor IFN-γ receptor (IFN-γR) as essential signals that synergize to promote the development and appearance of these autoreactive T-bet+ B cells. The lack of any of these signals ameliorates malarial anaemia during infection in a mouse model. We also identify both expansion of T-bet+ B cells and production of anti-erythrocyte antibodies in ex vivo cultures of naive human peripheral blood mononuclear cells (PBMC) exposed to P. falciprum infected erythrocyte lysates. We propose that synergistic TLR9/IFN-γR activation of T-bet+ B cells is a mechanism underlying infection-induced autoimmune-like responses.

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.

Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into IA isoforms, activated by Tyr kinases and the IB isoform (PI3Kγ), activated by G protein-coupled receptors. Mutations that affect PI3K are implicated in chronic inflammation, although the differential contribution of each isoform to pathology has not been elucidated. Enhanced activation of class IA-PI3K in T cells extends CD4+ memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both IA- and IB-PI3K isoforms regulate T cell activation, and activated pathogenic CD4+ memory cells are involved in triggering systemic lupus, we examined whether deletion of IB could reduce the pathological consequences of increased IA-PI3K activity. IB-PI3Kγ deficiency did not abolish invasion or lymphoproliferation, but reduced CD4+ memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the IB-PI3Kγ isoform thus decreased survival of pathogenic CD4+ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3Kγ isoform as a target for systemic lupus erythematosus treatment.

Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract) and they display inertia (contraction is delayed relative to antigen removal). By modelling inertia and elasticity, we show that tolerance to slow-growing populations can emerge as a population-scale feature of T cells. This result suggests a theoretical framework to understand immune tolerance that goes beyond the self versus non-self dichotomy. It also accounts for currently unexplained observations, such as the paradoxical tolerance to slow-growing pathogens or the presence of self-reactive T cells in the organism.

Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound IC playing an important role in the clearance of circulating immunecomplexes (IC). This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocyte/macrophages and B cells is strongly reduced in mice infected with Plasmodium yoelii, a rodent malaria model. Monocyte/macrophages from these infected mice present a specific inhibition of complement-mediated internalization of IC caused by the decreased CR1 expression. Accordingly, mice show accumulation of circulating IC and deposition of IC in the kidneys that inversely correlates with the decrease in CR1 surface expression. Our results indicate that malaria induces a significant decrease on surface CR1 expression in the monocyte/macrophage population that results in deficient internalization of IC by monocyte/macrophages. To determine whether this phenomenon is found in human malaria patients, we have analyzed 92 patients infected with either P. falciparum (22) or P. vivax (70), the most prevalent human malaria parasites. The levels of surface CR1 on peripheral monocyte/macrophages and B cells of these patients show a significant decrease compared to uninfected control individuals in the same area. We propose that this decrease in CR1 plays an essential role in impaired IC clearance during malaria.