Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells

Weng, Tsui Ying; Chen, Lien Cheng; Shyu, Huey Wen; Chen, Shun Hua; Wang, Jen Ren; Yu, Chun Keung; Lei, Huan Yao; Yeh, Trai Ming

doi:10.1016/j.antiviral.2005.03.005

Cited by 77 publications

(55 citation statements)

References 21 publications

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“…The serum collected from EV71-infected individuals during the convalescent phase could neutralize EV71 infection in vitro, and the neutralization epitope was mapped to a fragment of VP1 (8,43). Lactoferrin, a protein component of mammalian breast milk, has been shown to bind to VP1 and to block EV71 infection (48). These observations suggest that VP1 plays a pivotal role in the life cycle of EV71.…”

mentioning

confidence: 77%

Annexin II Binds to Capsid Protein VP1 of Enterovirus 71 and Enhances Viral Infectivity

Yang

Chou

et al. 2011

J Virol

160

131

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Enterovirus type 71 (EV71) causes hand, foot, and mouth disease (HFMD), which is mostly self-limited but may be complicated with a severe to fatal neurological syndrome in some children. Understanding the molecular basis of virus-host interactions might help clarify the largely unknown neuropathogenic mechanisms of EV71. In this study, we showed that human annexin II (Anx2) protein could bind to the EV71 virion via the capsid protein VP1. Either pretreatment of EV71 with soluble recombinant Anx2 or pretreatment of host cells with an anti-Anx2 antibody could result in reduced viral attachment to the cell surface and a reduction of the subsequent virus yield in vitro. HepG2 cells, which do not express Anx2, remained permissive to EV71 infection, though the virus yield was lower than that for a cognate lineage expressing Anx2. Stable transfection of plasmids expressing Anx2 protein into HepG2 cells (HepG2-Anx2 cells) could enhance EV71 infectivity, with an increased virus yield, especially at a low infective dose, and the enhanced infectivity could be reversed by pretreating HepG2-Anx2 cells with an anti-Anx2 antibody. The Anx2-interacting domain was mapped by yeast two-hybrid analysis to VP1 amino acids 40 to 100, a region different from the known receptor binding domain on the surface of the picornavirus virion. Our data suggest that binding of EV71 to Anx2 on the cell surface can enhance viral entry and infectivity, especially at a low infective dose.Enterovirus type 71 (EV71) is a member of the Enterovirus genus of the family Picornaviridae and is one of the causative viral agents of hand, foot, and mouth disease (HFMD) (6,7,14,16,41). HFMD is largely a common self-limited childhood illness but may have complications of severe to fatal neurological symptoms in some children (1,5,6,16,21). In the past decade, the frequency of EV71 outbreaks associated with severe neurological illness appeared to have increased in the Pacific region, most notably in China, where large outbreaks have been occurring annually since 2007 (24, 53). While the epidemiological or virological mechanism underlying this regional focus of severe EV71 infection remains largely unknown, the impact of EV71 infection is a global concern, as evidenced by the increase in virological surveillance and studies of EV71 infection in many regions of the world (29,46,53).EV71 is composed of a single-stranded, positive-polarity RNA molecule surrounded by a nonenveloped, pentameric icosahedral capsid (3, 35), which consists of 60 copies of the four structural proteins VP1 to VP4. While there is no animal model for EV71 infection in humans, intraperitoneal injection of EV71 is lethal to suckling mice. Suckling mice born to mothers previously immunized with VP1 subunit vaccines acquire resistance to lethal EV71 challenge (8, 50), and administration of a VP1-based antigen, either protein or DNA, to mice could elicit a neutralizing antibody against EV71 infection in vitro (8,42,44). The serum collected from EV71-infected individuals during the convalescent pha...

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confidence: 77%

Annexin II Binds to Capsid Protein VP1 of Enterovirus 71 and Enhances Viral Infectivity

Yang

Chou

et al. 2011

J Virol

160

131

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“…We postulated that SP40 interacted with heparan sulfate and blocked EV-71 attachment (14). Similarly, bovine and human lactoferrin exhibited antiviral activities against EV-71 when tested in vitro and in vivo, possibly due to direct interaction with heparan sulfate, resulting in interference with EV-71 binding (15,16). In a recent study, heparin and heparan sulfate were reported to exhibit antiviral activities against EV-71 infection (17).…”

mentioning

confidence: 99%

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

Tan

Poh

Sam

et al. 2013

J Virol

169

183

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“…With respect to its antiviral activity, LF acts as an inhibitor for viral entry to target cells but does not repress the intracellular replication of viruses (4). For example, LF prevents viral infection by binding to the envelope proteins E1 and E2 of the hepatitis C virus (5) or the VP1 protein in enterovirus (6). Several reports have also described the immunoregulatory and anti-tumor metastasis activities of LF.…”

Section: Lactoferrin (Lf)mentioning

confidence: 99%

Interaction of Human Lactoferrin with Cell Adhesion Molecules through RGD Motif Elucidated by Lactoferrin-binding Epitopes

Sakamoto

Ito

Mori

et al. 2006

Journal of Biological Chemistry

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Lactoferrin (LF) is an iron-binding secretory protein, which is distributed in the secondary granules of polynuclear lymphocytes as well as in the milk produced by female mammals. Although it has multiple functions, for example antimicrobial, immunomodulatory, antiviral, and anti-tumor metastasis activities, the receptors responsible for these activities are not fully understood. In this study, the binding epitopes for human LF were first isolated from a hexameric random peptide library displayed on T7 phage. Interestingly, two of the four isolated peptides had a representative cell adhesion motif, Arg-Gly-Asp (RGD), implying that human LF interacts with proteins with the RGD motif. We found that human LF bound to the RGD-containing human extracellular matrix proteins, fibronectin and vitronectin. Furthermore, human LF inhibited cell adhesion to these matrix proteins in a concentration-dependent manner but not to the RGD-independent cell adhesion molecule like laminin or collagen. These results indicate that a function of human LF is to block the various interactions between the cell surface and adhesion molecules. This may explain the multifunctionality of LF.

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Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells

Cited by 77 publications

References 21 publications

Annexin II Binds to Capsid Protein VP1 of Enterovirus 71 and Enhances Viral Infectivity

Annexin II Binds to Capsid Protein VP1 of Enterovirus 71 and Enhances Viral Infectivity

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

Interaction of Human Lactoferrin with Cell Adhesion Molecules through RGD Motif Elucidated by Lactoferrin-binding Epitopes

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