July 2015 | Volume 212, No. 8
Brief Definitive Report
- Basigin is a druggable target for host-oriented antimalarial interventions
Zenonos et al. report the development of a new therapeutic for P. falciparum malaria. A recombinant chimeric antibody targeting basigin—a receptor essential for erythrocyte invasion—inhibited parasite invasion and rapidly cleared an established blood-stage infection in vivo.
- Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells
Clearance of neurotropic infections is challenging because the CNS is relatively intolerant of immunopathological reactions. Herz et al. use a model of persistent viral infection in mice to demonstrate therapeutic antiviral T cells can purge the CNS infection without causing tissue damage resulting from limited recruitment of inflammatory innate immune cells and conversion of microglia into APCs.
- CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
Maintenance of stem cell properties is associated with reduced proliferation but it is unknown whether the transition kinetics through distinct cell cycle phases influences the function of HSCs. Mende et al examine the effects of increasing two cell cycle complexes CCND1–CDK4 and CCNE1–CDK2 on the transition kinetics of human HSCs and their maintenance and functional alterations in vivo.
- Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress
Rissone et al. demonstrate that adenylate kinase AK2, an enzyme mutated in reticular dysgenesis (RD) in humans, prevents oxidative stress during hematopoiesis. Using a zebrafish model, as well as induced pluripotent stem cells derived from an RD patient, they find that AK2 deficiency affects hematopoietic stem and progenitor development with increased oxidative stress. Antioxidant treatment rescues the hematopoietic phenotypes.
- Identification of resolvin D2 receptor mediating resolution of infections and organ protection
Chiang et al. identify GPR18 as a novel receptor for resolvin D2, and show that activation of this receptor in human and mouse phagocytes stimulates phagocytic clearance during bacterial infections and promotes organ protection
- Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells
Kang et al. show that genetic or pharmacological inactivation of the enzyme phospholipase D1 (PLD1) disrupts colitis-associated intestinal tumorigenesis by suppressing the self-renewal capacity of colon cancer stem cells.
- Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
Malle et al. identify a role for nuclear factor inducing κB (NIK) in pancreatic β cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs β cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for β cell failure in obesity.
- Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia
Organ hemorrhage represents a major complication in thrombocytopenia with potential fatal outcome. Hillgruber et al. demonstrate that neutrophil diapedesis through the endothelial barrier is responsible for the bleeding and could represent a therapeutic target in immune-thrombocytopenic patients.
- Blocking neutrophil integrin activation prevents ischemia–reperfusion injury
Yago et al. find that neutrophils expressing a talin1 mutant that perturbs integrin activation fail to undergo chemokine-induced arrest, spreading, and migration, thus preventing ischemia–reperfusion injury.
- CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts
Greenblatt et al. show that deletion of CHMP5 in osteoclasts leads to increased bone resorption coupled with exuberant osteoblast activity, resembling an early onset form of human Paget’s Disease of Bone
- Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease
Koyama et al. show that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes, mediated by donor CD103+CD11b− DCs that migrate from the colon under the influence of CCR7. This antigen presentation imprints gut-homing integrin signatures on donor T cells, leading to their migration to the GI tract where they mediate fulminant disease.
- T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi
Zou et al. identify a Golgi-associated factor, TRAF3-interacting protein 3 (TRAF3IP3), as a crucial mediator of thymocyte development regulating TCR-stimulated ERK signaling in the Golgi.