Human Complement Receptor Type 1/CD35 Is an Epstein-Barr Virus Receptor

Ogembo, Javier Gordon; Kannan, Lakshmi; Ghiran, Ionita; Nicholson‐Weller, Anne; Finberg, Robert W.; Tsokos, George C.; Fingeroth, Joyce D.

doi:10.1016/j.celrep.2013.01.023

Cited by 119 publications

(105 citation statements)

References 58 publications

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“…However, Ogembo et al demonstrated that EBV infection could occur via CD35 and HLA-DR in CD21-deficient cells [17], and these molecules have been thought to be the receptor for EBV in THP-1 cells and primary human monocytes. We confirmed the expression of CD35 and HLA-DR and the absence of CD21 in THP-1 cells using flow cytometry; the surface expression levels of CD35 and HLA-DR that we detected in THP-1 cells were equivalent to, or higher than those of previous reports [18,19].…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

et al. 2017

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Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1β (IL-1β) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1β production, while EBV infection of B-cell or T-cell lines did not induce IL-1β production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1β production, and that AIM2, acting as an inflammasome, is involved in this response.

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

et al. 2017

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“…Until recently, the molecular mechanisms of EBV infection of B lymphocytes were better understood than the mechanisms of epithelial cell infection (4). EBV attachment to the B-cell membrane is mediated by interactions between EBV glycoprotein 350 (gp350) and complement receptor type 2 (CR2 or CD21) (5) or CD35 (6). EBV gp42 binding to HLA class II triggers EBV fusion with B cells in the presence of EBV glycoprotein B (gB) and gH/gL (7,8).…”

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confidence: 99%

Nonmuscle myosin heavy chain IIA mediates Epstein–Barr virus infection of nasopharyngeal epithelial cells

Xiong

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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EBV causes B lymphomas and undifferentiated nasopharyngeal carcinoma (NPC). Although the mechanisms by which EBV infects B lymphocytes have been extensively studied, investigation of the mechanisms by which EBV infects nasopharyngeal epithelial cells (NPECs) has only recently been enabled by the successful growth of B lymphoma Mo-MLV insertion region 1 homolog (BMI1)-immortalized NPECs in vitro and the discovery that neuropilin 1 expression positively affects EBV glycoprotein B (gB)-mediated infection and tyrosine kinase activations in enhancing EBV infection of BMI1-immortalized NPECs. We have now found that even though EBV infected NPECs grown as a monolayer at extremely low efficiency (<3%), close to 30% of NPECs grown as sphere-like cells (SLCs) were infected by EBV. We also identified nonmuscle myosin heavy chain IIA (NMHC-IIA) as another NPEC protein important for efficient EBV infection. EBV gH/gL specifically interacted with NMHC-IIA both in vitro and in vivo. NMHC-IIA densely aggregated on the surface of NPEC SLCs and colocalized with EBV. EBV infection of NPEC SLCs was significantly reduced by NMHC-IIA siRNA knock-down. NMHC-IIA antisera also efficiently blocked EBV infection. These data indicate that NMHC-IIA is an important factor for EBV NPEC infection. Epstein-Barr virusBV is a nearly ubiquitous human γ-herpesvirus that causes B-cell lymphomas and nasopharyngeal carcinoma (NPC), indicative of tropism for both cell types (1-3). Until recently, the molecular mechanisms of EBV infection of B lymphocytes were better understood than the mechanisms of epithelial cell infection (4). EBV attachment to the B-cell membrane is mediated by interactions between EBV glycoprotein 350 (gp350) and complement receptor type 2 (CR2 or CD21) (5) or CD35 (6). EBV gp42 binding to HLA class II triggers EBV fusion with B cells in the presence of EBV glycoprotein B (gB) and gH/gL (7,8). For epithelial cells, gH/gL and gB are important for EBV infection (4, 9, 10). Epithelial cells lack HLA class II expression; thus, gp42 cannot trigger EBV and cell fusion. Instead, gp42 inversely suppresses the infection (11), and an antibody against gp350 can enhance infections of CD21/CD35-negative epithelial cells (12). The gH/gL heterodimer is required for virus entry (4) and may be involved in binding (13), as well as fusion of EBV (14-17). However, the crystal structure of EBV gH/gL does not show any known fusion domain (18). It is now thought that gH/gL regulates the fusion function of gB (19). Binding of gH/gL to a subset of αv integrins (e.g., αvβ 5 , αvβ 6 , or αvβ 8 ) provides the initial trigger for gB-mediated fusion (16,20,21). However, E1D1(gH/gL) antibody or CL59(gH) antibody, with a different epitope, can impair epithelial cell infection (20,22). Thus, multiple gH/gL domains are critical to EBV infection, and gH/gL may interact with proteins in addition to integrins. Direct interaction of EBV gB amino acids 23-431 with neuropilin 1 (NRP1) and its associated tyrosine kinases is critical for EBV infection of nasopharyngeal ep...

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“…Cellular entry is initiated by EBV gp350 glycoprotein binding to the virus host cell receptors (CR2/CD21 [6] or CR1/CD35 [7]). gp350 is thought to be a major target of neutralizing antibodies (8)(9)(10), and vaccine development efforts are focused on generating gp350-specific neutralizing antibodies (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro. The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

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Human Complement Receptor Type 1/CD35 Is an Epstein-Barr Virus Receptor

Cited by 119 publications

References 58 publications

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

Nonmuscle myosin heavy chain IIA mediates Epstein–Barr virus infection of nasopharyngeal epithelial cells

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

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