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Metagenomic sequencing of mpox virus clade Ib lesions

ABSTRACT: Metagenomic sequencing of mpox virus clade Ib lesions

PROVIDER: PRJEB88042 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	ERR14820706.fastq.gz	Fastqsanger.gz
	ERR14820707.fastq.gz	Fastqsanger.gz
	ERR14817849.fastq.gz	Fastqsanger.gz
	ERR14817850.fastq.gz	Fastqsanger.gz

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Primary human intestinal organoids recapitulate enteric infection of monkeypox virus and enable scalable drug discovery

Project description:Monkeypox virus (MPXV) infection-associated intestinal manifestations including diarrhea and proctitis have been frequently reported during mpox outbreaks. The clade IIb MPXV strain has caused the 2022-2023 global outbreak, whereas the Ia and Ib strains are causing the concurrent outbreaks in Africa. Here, we found clinical evidence that MPXV can directly infect human intestine to induce lesions. Intriguingly, primary organoids cultured from human ileum and rectum support productive infections of MPXV clade IIb, Ia and Ib strains. Upon differentiation, we found that enterocytes and goblet cells but not enteroendocrine cells are capable of supporting viral replication. Given that primary intestinal organoids can be rapidly expanded in large scale, we were able to screen a broad-spectrum antiviral drug library. We identified 12 leading candidates of safe-in-human agents including clinically used drugs such as clofarabine. We extensively validated the anti-MPXV activity of clofarabine in human intestinal and skin organoids, and consistently demonstrated the potent antiviral activity against clade Ia, Ib and IIb strains. These findings are important for better understanding the clinical manifestations of mpox. Primary intestinal organoids-based infection models and the established antiviral drug discovery pipeline bear major implications in responding to the current mpox global health emergency, and sustaining epidemic poxvirus preparedness.

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Project description:Mpox, a zoonotic disease caused by the mpox virus (MPXV), has seen a significant shift in its epidemiological status since 2022, evolving from an initial local outbreak to a global epidemic. This recent outbreak of MPXV mainly emerged in several European and American countries and subsequently spread to over 100 countries and regions worldwide. The rapid evolution of MPXV, coupled with increased international interactions, has led to a gradual rise in mpox cases in certain regions of Asia, mostly involving MPXV clade II and its branch strains. In contrast, the more pathogenic and clinically severe MPXV clade Ib has been relatively rare, with no reports in China to date. Here, we analyzed the whole gene sequence of imported MPXV clade Ib variant from the first infection case detected in China. Through whole genome sequencing, we successfully obtained a full-length MPXV genome of 195,405 base pairs (bp). Phylogenetic analysis revealed that the genetic sequence of the MPXV in this case was predominantly clustered with MPXV clade Ib sequences previously reported from multiple African and European countries. Compared with the MPXV clade Ib reference strain DQ011155.1, there are 127 nucleotide alterations and 57 amino acid mutations in the MPXV genome of this case. Given that the MPXV clade Ib has started to appear in China, we must pay more attention to the prevention of and control measures for the spread of mpox.

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