Immune-mediated viral clearance from the CNS without collateral damage

Abstract

Reticular dysgenesis (RD) is the most severe form of human severe combined immunodeficiency (SCID). It is associated with mutations in adenylate kinase 2 (AK2), the mitochondrial intermembrane space enzyme that regulates energy metabolism by reversibly catalyzing the reaction of ATP with AMP to generate two molecules of ADP. However, the impact of AK2 mutations on hematopoiesis has not been directly addressed. In this issue, Rissone et al. report that mitochondrial metabolic stress is an underlying cause of defective hematopoietic stem and progenitor cell (HSPC) maintenance and the failure of multilineage hematopoiesis in the absence of AK2.RD is characterized by sensorineural hearing loss and the lack of innate and acquired immune responses. The lymphopenia and neutropenia in RD patients is caused by severe defects in lymphoid and myeloid differentiation. Hematopoietic stem cell transplantation (HSCT) is currently the only therapeutic option, but RD patients often die from infections before HSCT can be performed. Thus, novel therapeutic strategies are required for this severe condition.Rissone et al. modeled AK2 deficiency in zebrafish embryos and induced pluripotent stem cells (iPSCs) derived from RD patients. AK2-deficient zebrafish embryos displayed impaired survival of HSPCs and committed hematopoietic precursors, as well as arrests in lymphoid and myeloid development. Studies using RD patient-derived iPSCs harboring a homozygous AK2 mutation recapitulated myeloid maturation arrest (at the promyelocyte stage) observed in RD patient bone marrow and additionally showed defective erythropoiesis. AK2 deficiency resulted in ADP depletion, thus limiting the substrate availability for ATP production by the mitochondrial ATP synthase. This disturbance in cellular energy homeostasis was coupled with increased generation of reactive oxygen species (ROS). Notably, provision of ectopic antioxidants largely rescued AK2-deficient HSPCs and committed progenitors from apoptosis in the zebrafish embryo and restored lymphoid and myeloid differentiation in both zebrafish and iPSC models of RD. By exploiting the strengths of these complementary experimental systems, the authors show that AK2 deficiency has broader deleterious consequences for hematopoietic differentiation than previously anticipated. Although antioxidants deplete ROS in AK2-deficient cells, they are unlikely to restore normal energy homeostasis. It is therefore somewhat surprising that antioxidant-treated cells lacking AK2 appear to undergo apparently normal energy-demanding differentiation. Nevertheless, this work elegantly illustrates that disease modeling in zebrafish together with studies on patient-derived iPSCs provides a powerful platform to reveal mechanisms underlying human immunodeficiency and identify novel targets for future therapeutic interventions. Although antioxidant treatment alone is unlikely to have long-term beneficial effects in RD, antioxidant administration may alleviate severe lymphopenia and neutropenia in RD patients and allow them t...

Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

“…The acronym TORCH (toxoplasmosis, other [syphilis, varicella, mumps, parvovirus and HIV], rubella, cytomegalovirus, and herpes simplex) was first coined to highlight the commonality of the observed phenotype secondary to transplacental transmission of such microbes ( Shin et al, 1976 ; Fine and Arndt, 1985 ; Donley, 1993 ). Events involved in the control of infections are associated with important immune-mediated collateral damage, with the CNS being more susceptible due to its immune privileged status ( Konradt and Hunter, 2015 ). CNS characteristics of TORCH include microcephaly, white matter disease, cerebral atrophy, and calcifications.…”