Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

Abstract

BK virus (BKV) is a polyomavirus that establishes a lifelong persistence in most humans and is a major impediment to success of kidney grafts. The function of the innate immune system in BKV infection and pathology has not been investigated. Here we examine the role of antimicrobial defensins in BKV infection of Vero cells. Our data show that ␣-defensin human neutrophil protein 1 (HNP1) and human ␣-defensin 5 (HD5) inhibit BKV infection by targeting an early event in the viral lifecycle. HD5 treatment of BKV reduced viral attachment to cells, whereas cellular treatment with HD5 did not. Colocalization studies indicated that HD5 interacts directly with BKV. Ultrastructural analysis revealed HD5-induced aggregation of virions. HD5 also inhibited infection of cells by other related polyomaviruses. This is the first study to demonstrate polyomavirus sensitivity to defensins. We also show a novel mechanism whereby HD5 binds to BKV leading to aggregation of virion particles preventing normal virus binding to the cell surface and uptake into cells.BK virus is a member of the polyomaviridae family. Polyomaviruses are small (40 -50 nm in diameter), non-enveloped, double-stranded DNA viruses that cause tumors in some species outside of their natural host range (1). BKV infects ϳ80 -90% of the human population and establishes a lifelong persistence within epithelial cells of the urinary tract (2, 3). Although BKV infection remains asymptomatic throughout the lifetime of most humans, immunocompromised individuals are susceptible to BKV-induced disease. Reactivation of BKV has been linked to hemorrhagic cystitis in bone marrow transplant recipients and is the etiological agent of polyomavirus-induced nephropathy (PVN), 2 a complication found in 5% of kidney transplant recipients (4, 5). In PVN, BKV induces interstitial nephritis resulting in graft destruction and leads to transplant failure in ϳ50% of diagnosed cases (6, 7). BKV reactivation causes a serious viral infection after renal transplantation and is a significant obstacle to the success of kidney grafts.The factors that contribute to BKV-induced disease are largely unknown. As only a subset of kidney transplant recipients develop PVN, this raises the question of what unique factors are present in these situations for pathogenesis to ensue? The factors that contribute to PVN likely comprise multiple conditions that involve the virus, the host, and the graft. Some risk factors for the development of PVN include male gender, older age, and higher number of HLA mismatches (7, 8). Epidemiological studies suggest that the most significant cofactor leading to PVN is the degree of immunosuppression. The rise in PVN diagnoses is directly correlated to the increased use of the more potent anti-rejection drugs, tacromilus and mycophenolate mofetil (9, 10). Currently, a reduction of immunosuppressive therapy is effectively used to decrease viral replication in PVN patients suggesting that a functional immune system is critical in controlling BKV replication and pathology (11). ...

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

“…HD5 inhibits adenovirus infections by binding to the virus capsid and preventing its subsequent uncoating, an event the virus requires to escape the endosomal compartment and enter the cytosol (37). HD5 and HNP1 also inhibit infection by BK polyoma virus, a cause of interstitial nephritis in immunosuppressed renal transplant recipients, evidently acting by binding to the virions and agglutinating them (38).…”

The Human Alpha Defensin HD5 Neutralizes JC Polyomavirus Infection by Reducing Endoplasmic Reticulum Traffic and Stabilizing the Viral Capsid

“…Alpha defensins have also been shown to block papillomavirus infection by sequestering the virions in their en-docytic vesicles (32). The human alpha defensin HD5 inhibits replication of the JCPyV-related polyomavirus BK by blocking binding to host cells (33).…”

Antimicrobial peptides: mode of action and perspectives of practical application

“…Таким образом, дефензины препятствуют выходу частиц аденовируса из эндосом, вследствие чего вирионы накапливаются в районе лизосом и дезактивируются [71]. Пептиды класса a-дефензинов способны угнетать адсорбцию другого вируса -полиомы, связываясь с гликопротеинами на его поверхности, а так же ингибировать сборку вирусной частицы [72].…”