The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune-neurological syndrome has generated worldwide concern. Zika virus is a flavivirus like dengue, yellow fever and West Nile viruses. We present the 3.8Å resolution structure of mature Zika virus determined by cryo-electron microscopy. The structure of Zika virus is similar to other known flavivirus structures except for the ~10 amino acids that surround the Asn154 glycosylation site found in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses and suggests that changes in this region influence virus transmission and disease.

The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease.animal model | phlebovirus | pathology | reduction of platelets | macrophage infection S evere fever with thrombocytopenia syndrome (SFTS) is a recently identified emerging viral infectious disease in China that is caused by a novel phlebovirus in the family Bunyaviridae, SFTS virus (SFTSV) (1). Clinical features of SFTS patients include abrupt high fever, thrombocytopenia, leukocytopenia, and gastrointestinal symptoms. Laboratory tests commonly show elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), lactate dehydrogenase, creatine kinase, creatine kinase MB fraction, as well as elongated activated partial-thromboplastin time (1). These abnormally changed laboratory parameters are indicative of the pathological lesions that occur in multiple organs and altered homeostasis of the coagulation systems of SFTS patients. Pathological studies of SFTS are absent because patient tissues are rarely donated after death in rural areas of China. Therefore, the causes of illness and death, as well as pathological changes within organs, remain unclear. To systematically investigate the pathogenic mechanisms of SFTS and understand key symptoms, such as thrombocytopenia, infectious animal models for SFTSV are urgently needed. ResultsEstablishment of a SFTSV Pathogenic Mouse Model. In our initial study, to identify an infectious animal model that could mimic most clinical features during SFTSV infection, the susceptibilities of three commonly used laboratory rodent strains for phlebovirus (2-4), C57/BL6 mice, BalB/C mice, and Syrian hamsters, were examined. The SFTSV strain HB29 was inoculated at 10 5 TCID 50 (50% tissue culture infective dose) per mouse or 5 × 10 5 TCID 50 per hamster through four different routes of infection, including intravenous, intramuscular, intraperitoneal, and intracerebral...

Human Dicer (hDicer) is a multi-domain protein belonging to the RNase III family. It plays pivotal roles in small RNA biogenesis during the RNA interference (RNAi) pathway by processing a diverse range of double-stranded RNA (dsRNA) precursors to generate ∼22 nt microRNA (miRNA) or small interfering RNA (siRNA) products for sequence-directed gene silencing. In this work, we solved the cryoelectron microscopy (cryo-EM) structure of hDicer in complex with its cofactor protein TRBP and revealed the precise spatial arrangement of hDicer's multiple domains. We further solved structures of the hDicer-TRBP complex bound with pre-let-7 RNA in two distinct conformations. In combination with biochemical analysis, these structures reveal a property of the hDicer-TRBP complex to promote the stability of pre-miRNA's stem duplex in a pre-dicing state. These results provide insights into the mechanism of RNA processing by hDicer and illustrate the regulatory role of hDicer's N-terminal helicase domain.

COVID‐19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID‐19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID‐19‐infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue‐specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN‐I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID‐19‐infected patients experiencing milder disease symptoms showed robust T‐cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS‐CoV‐2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID‐19.