Involvement of Cytoskeletal Components in BK Virus Infectious Entry

Abstract

Posttransplant reactivation of BK virus (BKV) in the renal allograft progresses to polyomavirus-associated nephropathy in 1% to 8% of kidney recipients. Graft dysfunction and loss in 30% to 45% of polyomavirusassociated nephropathy-affected patients are secondary to extensive tubular epithelial cell injury induced by the lytic replication of BKV. The early events in productive BKV infection are not thoroughly understood. We have previously shown that BKV enters cells by caveola-mediated endocytosis. In this report we examine the role of microfilaments and microtubules during early viral infection. Our results show that BKV infection of Vero cells is sensitive to nocodazole-induced disassembly of the microtubule network for the initial 8 hours following virus binding. In contrast, suppression of microtubule turnover with the stabilizing agent paclitaxel has no effect on BKV infectivity. Selective disassembly of the actin filaments with latrunculin A does not impede BKV infection, while inhibition of microfilament dynamics with jasplakinolide results in reduced numbers of viral antigen-positive cells. These data demonstrate that BKV, like other polyomaviruses, relies on an intact microtubule network during early infection. BKV, however, does not share the requirement with the closely related JC virus for an intact actin cytoskeleton during intracellular transport.First discovered in 1970, BK virus (BKV) has recently drawn renewed interest as the causative agent of an infectious complication termed polyomavirus-associated nephropathy in renal transplant recipients (16, 52). Asymptomatic BKV infection is ubiquitous, occurring in 70% to 90% of healthy adults worldwide (41). Surgical injury and potent immunosuppressive therapy following renal transplantation lead to BKV reactivation and progression to polyomavirus-associated nephropathy in 1% to 10% of kidney recipients (24, 51). The clinical concern stems from the extensive virally induced damage to the kidney, which in turn results in severe allograft dysfunction and ultimate graft loss in 45% to 60% of polyomavirus-associated nephropathy-affected patients (32,52).BKV belongs to the family Polyomaviridae, which are small, nonenveloped, double-stranded DNA viruses. Other well-studied polyomaviruses include simian virus 40 (SV40), mouse polyomavirus (PyV), and JC virus (JCV). Despite established differences in receptor specificity (3-5, 9, 13, 14, 27, 28, 47, 48), mode of internalization (1,12,17,33,36,37,39,40,43), and intracellular trafficking mechanisms (2,19,36,37), all the members of the polyomavirus family must deliver their genome to the nucleus of the host cell in order to execute a productive viral life cycle. The nucleus is the site of viral gene transcription, viral DNA replication, and progeny assembly (45).Efforts in our laboratory are focused on understanding the early events during BKV infection, namely host cell entry and subsequent intracellular trafficking to the nucleus. We and others have previously demonstrated that BKV enters cells through a cave...

A new model for hemoglobin ingestion and transport by the human malaria parasite Plasmodium falciparum

“…12). Similar effects were observed in endocytic virion entry into host cells (Eash and Atwood, 2005;Gilbert et al, 2003). JAS markedly inhibited virion infection, whereas actin destabilizers did not.…”

BK Virus Infection in Transplant Recipients: An Overview and Update

“…The mechanisms of endocytosis and intra-cellular trafficking utilized by BKV have not been investigated in detail. However, it has been established that the route from cell membrane to the nucleus includes the endoplasmic reticulum and microtubules (12,13). There may also be participation of the Golgi apparatus, and other cytoskeletal elements such as actin, and microfilaments, as has been shown for other members of the polyomavirus family.…”

Role of Membrane Rafts in Viral Infection

“…The role of membrane rafts in entry of nonenveloped viruses has been investigated for simian virus 40 (SV40; Papovaviridae) [4][5][6][7][8][9][10][11][12], BK virus (Papovaviridae) [13][14][15], JC virus (Papovaviridae) [16], bovine papillomavirus (Papovaviridae) [17], human papillomavirus (HPV; Papovaviridae) [18][19][20][21][22][23][24][25][26], rotavirus (Reoviridae) [27][28][29], echovirus type 1 [30] and 11 (Picornaviridae) [31][32][33][34][35], enterovirus (Picornaviridae) [31], rhinovirus (Picornaviridae) [36], Coxsackievirus A9 and B4 (CAV; Picornaviridae) [37][38][39], and species C human adenovirus (HAdV; Adenoviridae) [40,41].…”

“…Although SV40 receptor MHC-I is not localized in membrane rafts, MHC-1 induces association of viral particles with caveola [4][5][6][7][8], or GM1 ganglioside, which is enriched in membrane rafts and known to be one of receptors for SV40 and murine polyoma virus [10,11]. Other polyomaviruses, including BK virus and JC virus, have been reported to utilize caveola-mediated endocytosis in virus entry [13][14][15][16]47]. BK virus, which is a causative agent of an infectious complication termed polyomavirusassociated nephropathy in renal transplant recipients, enters cells by slow caveola-mediated endocytosis dependent on pH in Vero cells and human renal proximal tubular epithelial cells [13][14][15].…”

“…Other polyomaviruses, including BK virus and JC virus, have been reported to utilize caveola-mediated endocytosis in virus entry [13][14][15][16]47]. BK virus, which is a causative agent of an infectious complication termed polyomavirusassociated nephropathy in renal transplant recipients, enters cells by slow caveola-mediated endocytosis dependent on pH in Vero cells and human renal proximal tubular epithelial cells [13][14][15]. JC virus and bovine papillomavirus are transported to early endosomes and caveolae by clathrindependent endocytosis and then carried by the slow caveoladependent pathway [16,17] [48].…”