Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection

Abstract

Human parvovirus B19 (B19) infects human erythroid cells expressing P antigen. However, some cell lines that were positive for P antigen failed to bind B19, whereas some cell lines had an ability to bind B19 despite undetectable expression of P antigen. We here demonstrate that B19 specifically binds with Ku80 autoantigen on the cell surface. IntroductionHuman parvovirus B19 (B19) infects erythroid-lineage cells through P antigen and causes various clinical symptoms such as erythema infectiosum, anemia, polyarthritis, or fetal hydrops in humans. 1,2 The cellular receptor for B19 infection has been regarded as blood group P antigen based on the failure of B19 infection in a patient with an hereditary defect of P antigen. 3 However, the target cells of B19 may be not be exclusively P-antigen-positive erythroidlineage cells, as illustrated by the poor relationship between P antigen expression levels and the efficiency of B19 infection 4 or the failure of B19 binding to globoside. 5 Recently, Weigel-Kelley et al described the role of ␣5␤1 integrin as the cellular coreceptor for B19 infection. 6 The notion that B19 receptor is not solely P antigen may be compatible with clinical findings that B19 has been detected in mononuclear cells of blood or tonsils with acute or prolonged B19 infection. 7,8 Also, following B19 infection, the numbers of peripheral blood lymphocytes may decrease despite undetectable levels of P antigen on their cell surface. 9,10 Finally, autoimmune-like phenomena including antinuclear antibodies, rheumatoid factors, or antiphospholipid antibodies are often associated with B19 infection, 8,11 and the levels of tumor necrosis factor ␣ (TNF-␣) and interferon ␥ (IFN-␥) secreted from macrophages or T cells are elevated during acute or prolonged B19 infection. 12 Clinical studies have shown that B19 DNA can be amplified from joint samples by polymerase chain reaction (PCR), 13,14 and infective B19 was detected in the articular lesions of patients with rheumatoid arthritis. B19 transcripts and B19 protein viral protein 1 (VP1) were also present in T cells, B cells, macrophages, and follicular dendritic cells. 14 The cellular mechanism that may allow B19 binding and its entry into nonerythroid cells has not been elucidated. In the present study, we explored a putative receptor for B19 that was distinct from P antigen. Materials and methods CellsMacrophage cell lines U937, urinary bladder carcinoma cell line T24, colon cancer cell line SW620, renal adenocarcinoma cell line ACHN, and HeLa cells were provided by the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan). Human erythroid cell line KU812Ep6 15 was provided by E. Miyagawa (Institute of Fuji Rebio, Tokyo, Japan). T-cell line H9 was purchased from American Type Culture Collection (Manassas, VA). Bone marrow samples were obtained from the volunteers who gave informed consent for the use of their samples for our study. Informed consent was provided in accordance with the Declar...

Ex Vivo-Generated CD36 + Erythroid Progenitors Are Highly Permissive to Human Parvovirus B19 Replication

“…Cells continuously expressed CD71 (the transferrin receptor) and ␣5␤1 integrin (CD49e, a reported B19V coreceptor) over the entire period of proliferation and differentiation (Table 1). However, the expression of Ku80 (a reported B19V coreceptor) (17) remained undetectable or at an extremely low level. Subsequent experiments were conducted using predominantly day 8 cells, as the cell population at this stage was comprised of relatively pure erythroid progenitors CD36 ؉ erythroid progenitor cells are highly permissive to B19V infection.…”

“…We have previously reported that the necessary cellular receptor for B19V infection is globoside (P antigen) (2), and others have reported coreceptors to be ␣5␤1 integrin (37) and/or autoantigen Ku80 (17). The permissiveness to B19V infection of the cells relies primarily on viral entry.…”

“…Antibodies to CD34 (BD Biosciences, Franklin Lakes, NJ), CD36 (BD Biosciences), GPA (BD Biosciences), and CD71 (BD Biosciences) were used for phenotyping. Antibodies against globoside (Matreya, Pleasant Gap, PA), CD49e (BD Biosciences), and KU80 (Calbiochem, San Diego, CA) were used for the detection of B19V cellular receptors (17,37). Flow cytometry was performed using the Beckman Coulter Cytomics FC 500 flow cytometry system (Beckman Coulter, Fullerton, CA).…”

Childhood Skin Disorders: Genetic Study of the Erythema Infectiosum (Fifth Disease)

“…The capsid consists of 60 structural subunits, 95% of which is the major viral protein VP2 (58 kDa) [15]. The other structural protein, VP1 differs from VP2 only in an N-terminal ''unique region'' composed of 227 additional amino acids, which are mostly located outside the virion and, therefore, accessible to antibody binding [16,17].…”

“…In addition to erythroid precursor cells, which are permissive for viral replication, B19V can infect a number of different cell types, utilizing the globoside or blood group P-antigen as a receptor13 along with α5β1 integrin [14]. After entry, the viral DNA is shuttled to the nucleus with the host-encoded DNA repair protein Ku80 [15] where replication and transcription occur concurrently following initial conversion of the viral DNA to double-stranded DNA [16,17]. Expression is thought to occur utilizing a single viral promoter, with mRNA for the different gene products produced from different splice variants [11,18,19].…”