Initially thought of as primarily a respiratory infection, SARS-CoV-2 is now implicated in substantial central nervous system (CNS) pathology [1][2][3] . CNS symptoms include ischemic strokes, hemorrhages, seizures, encephalopathy, encephalitis/meningitis, anosmia, postinfectious syndromes and neurovasculopathy, collectively described in up to 85% of intensive care unit patients [4][5][6][7] . Several reports appear to meet established criteria for infectious encephalitis 8 . SARS-CoV-2 can utilize angiotensin-converting enzyme 2 (ACE2) as a receptor, although other receptors have been proposed 9,10 . Recent studies on single-cell RNA sequencing (scRNA-seq) datasets indicated low levels of ACE2 expression in brain cells; however, expression is relatively high in some neurovascular unit (NVU) components, particularly in brain pericytes [11][12][13][14] . Autopsy series have suggested the potential for SARS-CoV-2 to spread throughout the brain, especially within vascular and immune cells. They note ischemic brain lesions accompanied by widespread activation of astrocytes and cell death 1,15 . The potential for a SARS-CoV-2 elicited neurovasculopathy supports the development of new models to study tropism and pathology.Brain pericytes are derived from neural crest stem cells (NCSCs) and are uniquely positioned in the NVU, physically linking endothelial and astrocytic cells 16 . Embedded within the basement membrane, pericytes connect, coordinate and regulate signals from neighboring cells to generate responses critical for CNS function in both healthy and disease states, including blood-brain barrier permeability, neuroinflammation, neuronal differentiation and neurogenesis in the adult brain [17][18][19] . Results SARS-CoV-2 productively infects PLCs.We found that green fluorescent protein (GFP) + PLCs generated in vitro from human pluripotent stem cell (hPSC)-derived NCSCs expressed the standard pericyte markers NG2 and PDGFR-β (Fig. 1a,b) 20 . We detected appreciable ACE2 messenger RNA and protein in PLCs cultured two-dimensionally compared with cultured human neural precursors (Extended Data Fig. 1a-d) 14,21 . To assess SARS-CoV-2 PLC tropism, we exposed PLCs to authentic SARS-CoV-2 at a multiplicity of infection (MOI) of 0.5, then collected the supernatant and cells daily (Fig. 1c). We found that the percentage of SARS-CoV-2 nucleocapsid protein + cells and viral RNA as measured by quantitative PCR with reverse transcription (RT-qPCR) increased daily up to 72 h postinfection, from 0 to 65% SARS-CoV-2 nucleocapsid protein + , with viral RNA load increasing up to approximately 1,000-fold (Fig. 1d,e). Plaque assay from the PLC supernatants on Vero E6 cells showed approximately 100-fold increased infectious virus production at 24 h postinfection with increased viral RNA as well as viral titers compared to baseline, suggesting viral production by PLCs (Fig. 1f-h) 22 . Furthermore, we found that ACE2 receptor-blocking antibody partially prevented SARS-CoV-2 infection of PLCs (Extended Data Fig. 2a-e) 23 .PCCO generat...
Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrowresident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.
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