Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes were associated with distinct clinical features including age, sex, severity, and disease stages of COVID-19. SARS-CoV-2 RNAs were found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within viral positive cells. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and developing effective therapeutic strategies for COVID-19.

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Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N-methyladenosine (mA), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive mA mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the mA RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of mA and depletion of SSCs. mA depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA mA modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.