TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine

Jemielity, Stephanie; Wang, Jinyize J.; Chan, Ying Kai; Ahmed, Asim A.; Li, Wenhui; Monahan, Sheena; Bu, Xia; Farzan, Michael; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Choe, Hyeryun

One important question concerning viral PS receptor usage is whether PS receptors are sufficient for productive infection or whether virus-specific receptors are still required. We showed for several pseudoviruses that TIM1-mediated entry depended on the availability of their cellular receptors (Figs. 6B and 8) , indicating that TIM1 functions solely as an attachment factor. For instance, TIM1 was unable to enhance the infection of EBOV and MARV pseudoviruses in the absence of the intracellular filovirus entry factor NPC1 (Fig. 8) . Also, blocking the accessibility of MACV pseudovirus to its receptor hTfR1 lowered MACV TIM1 usage (Fig. 6B) . On the other hand, some viruses were reported to fuse with receptor-free liposomes at low pH [62] [63] [64] , raising the possibility that in a few specific cases PS receptor-mediated internalization may be sufficient for productive infection. Nevertheless, studies using liposomes that are unnaturally enriched with specific lipid components may not accurately represent physiological conditions. PS receptors form a complementary, widely expressed network of receptors that is characterized by functional rather than structural conservation. These particular features of PS receptors likely contribute to their exploitation by viruses as attachment factors. Notably, several PS receptors, including TIM4, are highly expressed on mammalian macrophages and dendritic cells. These cells play critical roles in the initial stages of infection of filoviruses and flaviviruses in particular [55, 56, 65] , and PS receptors may thus play correspondingly important roles in establishing these infections. PS receptors may be more important still for viruses like DENV, WNV, EEEV and CHKV, which are borne by insect vectors. The role of PS as apoptotic marker is conserved in insects [66] , and compared to mammalian cells the membranes of insect cells are generally enriched with PE [67, 68] , which binds several PS receptors. Thus mosquito-delivered virions may especially benefit from PS receptor-mediated enhancement of infection.