腸病毒71型主要造成手足口症，也會導致嚴重神經性症狀，然而現今對於腸病毒71型如何侵犯中樞神經仍然未知，小兒麻痺病毒文獻指出小兒麻痺病毒可以感染人類單核球細胞，認為小兒麻痺病毒可經由血液細胞進入中樞神經系統，另有文獻指出巨噬細胞吞噬口蹄疫病毒後也許會轉變為具感染性攜帶者，幫助口蹄疫病毒感染及複製至其他細胞，因此巨噬細胞也許在腸病毒感染內扮演重要角色。在本研究發現兩株腸病毒71型病毒株4643-S及4643-R，在周邊血液單核球感染4643-R後產生腫瘤壞死因子α之量比感染4643-S高，此外對phorbol myristate acetate (PMA)刺激後之THP1細胞的感受性亦不同，利用腸病毒71型吸附試驗則發現4643-S及4643-R對於PMA刺激後THP1細胞膜蛋白黏附能力不同，而且從序列分析知道這兩株病毒分別在VP1、VP3、2C及3A基因序列不同。進一步利用感染性克隆系統研究巨噬細胞對於腸病毒71型感受性之病毒決定因子，分別建構4643-S、4643-R及結構性蛋白為4643-R之S-R-S、結構性蛋白為4643-S之R-S-R的感染性克隆，接著利用以上重組病毒感染單核細胞源巨噬細胞，結果發現腸病毒71型殼體蛋白(capsid)影響腸病毒71型對單核細胞源巨噬細胞的感受性。另外，利用點突變技術建構出VP1 K98E、E145Q及S241L突變之感染性克隆，再用以上突變病毒感染單核細胞源巨噬細胞，結果顯示上述三個單點突變並不影響腸病毒71型感染巨噬細胞，在結構蛋白可能有其他胺基酸變異影響，或者需要多個胺基酸突變後才能影響腸病毒71型感染巨噬細胞。本研究結果顯示腸病毒71型之殼體蛋白在對單核細胞源巨噬細胞之感受性扮演重要之角色，此結果幫助瞭解腸病毒71型感染巨噬細胞分子性決定因子。

Enterovirus 71 (EV71) is a major etiological agent of hand-foot-and-mouth disease (HFMD) which can lead to severe neurological complications. However, the mechanisms of EV71 gain access to and invade the central nervous system (CNS) are poorly understood. Previous reports showed poliovirus can productively infect primary human monocytes and suggested poliovirus entry into the CNS via blood. Another study indicated that phagocytosis of foot-and-mouth disease virus (FMDV) by macrophage may create infectious carriers to facilitate FMDV infection and replication in cells. Hence, macrophage may play an important role in the pathogenesis of enterovirus infection. In our study, we found two EV71 strains 4643-S & 4643-R, which were derived from an EV71 isolate from a fatal case, with different susceptibility for PMA-treated THP1 cells by using infectious center assay. In addition, 4643-R produced higher tumor necrosis factor-α (TNF-α) in infected peripheral blood mononuclear cell (PBMC) than 4643-S. EV71 adsorption assay revealed different binding ability of 4643-S & 4643-R to PMA-treated THP1 cell membrane proteins. Moreover, sequence analysis of these two strains revealed several variations in VP1, VP3, 2C and 3A gene regions. Furthermore, the genetic determinants of EV71 susceptibility for macrophages was investigated by using EV71 infectious clone system. Four infectious clones carried viral 4643-S & 4643-R genome, and S-R-S & R-S-R genes which exchanged the structure genes between 4643-S and 4643-R were established. Monocyte-derived macrophage infected with above recombinant viruses demonstrated that EV71 capsid protein influenced susceptibility of monocyte-derived macrophage for EV71. K98E, E145Q and S241L of VP1 mutant infectious clones were then constructed by site-directed mutagenesis. Monocyte-derived macrophage infected with above mutant viruses showed that those single mutations did not affect EV71 infection to macrophage. Our results indicated sapsid proteins of EV71 played an important role in infection of monocyte-derived macrophage. This study helps in understanding the molecular mechanism of EV71 infection in macrophage.

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