Replication in Cells of Hematopoietic Origin Is Necessary for Dengue Virus Dissemination

Alissa M. Pham et al., PLoS Pathog. 2012, 8: e1002668

Speaker: Ya-Ting Chu (朱雅婷)                                            Time: 14:00~15:00, Mar. 6, 2013

Commentator: Dr. Guey-Chuen Perng (彭貴春 老師)        Place: Room 601

Abstract

Dengue virus (DENV) is a single-stranded RNA virus that belongs to the family Flaviviridae. The genome encodes three structural proteins (C, prM, E) and seven non-structural (NS) proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). There are four serotypes, including  DENV-1, -2, -3 and -4. DENV infection causes dengue fever and dengue hemorrhagic fever or dengue shock syndrome. Previous studies indicate that hematopoietic lineage including monocytes and macrophages are primary targets of DENV infection [1]. It remains uncertain whether DENV can replicate in the cells of non-hematopoietic lineage. In this study, the authors used microRNA (miRNA) to exclude DENV infection from hematopoietic cells and observed whether DENV could still replicate in the absence of its primary targets. miRNAs are 18-22 nucleotides non-coding RNA that regulate post-transcriptional silencing of target genes. Previous study indicated that miR142 is one of the most abundant hematopoietic-specific miRNA [2]. Therefore, the authors generated a DENV-2 strain which is incorporated in four target sites at downstream of NS5 coding frame (142t virus). The in vitro results showed that the replication of 142t virus is attenuated by endogenous miR142 both in B cells and bone marrow-derived macrophages using NS5 detection, but not in HEK293s. Furthermore, the authors investigated 142t virus by Ifnar1^-/- / Il28r^-/- mice which are susceptible to DENV. The results showed that NS5 transcripts derived from 142t virus were decreased in CD11b⁺, CD11c⁺, and CD45⁺ cells. In addition, the growth of 142t virus was decreased in CD45^- non-hematopoietic cells. Taken together, these results suggest that hematopoietic cells are primary target and critical for dissemination of the virus to other tissues.

References

1. Blackley S. et al. Primary human splenic macrophages, but not T or B Cells, are the principal target cells for dengue virus infection in vitro. J. Virol. 81, 13325-34 (2007).

2. Brown BD. et al. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat. Med. 12, 585-91 (2006).