Integrin αvβ1 promotes infection by human metapneumovirus

Cseke, G.; Maginnis, Melissa S.; Cox, Reagan G.; Tollefson, Sharon J.; Podsiad, Amy B.; Wright, David W.; Dermody, Terence S.; Williams, John V.

doi:10.1073/pnas.0801433106

Cited by 94 publications

(104 citation statements)

References 61 publications

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“…Recently, Cseke et al (2009) provided evidence that integrin ␣v␤1 is a functional receptor for hMPV F protein (23). Consistent with this, the F proteins of all known hMPV strains contain a putative integrinbinding motif ( 329 RGD 331 ).…”

Section: H Uman Metapneumovirus (Hmpv) Is a Member Of The Genusmentioning

confidence: 62%

“…Previously, it has been shown that hMPV engages ␣v␤1 integrin to mediate virus infection, suggesting that integrins might serve as functional receptors for hMPV (23). However, it is not known whether integrins are involved in hMPV F protein-mediated cell-cell fusion.…”

Section: Resultsmentioning

confidence: 99%

“…Integrin binding is mediated by a specific interaction between integrin receptors and the RGD tripeptide motif in viral glycoproteins or capsid proteins. Cseke et al (2009) first showed that ␣v␤1 integrin is able to promote hMPV infection, suggesting that ␣v␤1 integrin may function as a receptor for hMPV (23). Subsequently, the same group showed that multiple integrins can mediate hMPV binding and entry through interaction with the RGD domain in hMPV F protein (24).…”

Section: Discussionmentioning

confidence: 98%

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Roles of the Putative Integrin-Binding Motif of the Human Metapneumovirus Fusion (F) Protein in Cell-Cell Fusion, Viral Infectivity, and Pathogenesis

Wei

Zhang

Cai

et al. 2014

J Virol

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Human metapneumovirus (hMPV) is a relatively recently identified paramyxovirus that causes acute upper and lower respiratory tract infection. Entry of hMPV is unusual among the paramyxoviruses, in that fusion is accomplished by the fusion (F) protein without the attachment glycoprotein (G protein). It has been suggested that hMPV F protein utilizes integrin ␣v␤1 as a cellular receptor. Consistent with this, the F proteins of all known hMPV strains possess an integrin-binding motif ( 329 RGD 331 ). The role of this motif in viral entry, infectivity, and pathogenesis is poorly understood. Here, we show that ␣5␤1 and ␣v integrins are essential for cell-cell fusion and hMPV infection. Mutational analysis found that residues R329 and G330 in the 329 RGD 331 motif are essential for cell-cell fusion, whereas mutations at D331 did not significantly impact fusion activity. Furthermore, fusion-defective RGD mutations were either lethal to the virus or resulted in recombinant hMPVs that had defects in viral replication in cell culture. In cotton rats, recombinant hMPV with the R329K mutation in the F protein (rhMPV-R329K) and rhMPV-D331A exhibited significant defects in viral replication in nasal turbinates and lungs. Importantly, inoculation of cotton rats with these mutants triggered a high level of neutralizing antibodies and protected against hMPV challenge. Taken together, our data indicate that (i) ␣5␤1 and ␣v integrins are essential for cell-cell fusion and viral replication, (ii) the first two residues in the RGD motif are essential for fusion activity, and (iii) inhibition of the interaction of the integrin-RGD motif may serve as a new target to rationally attenuate hMPV for the development of live attenuated vaccines. IMPORTANCEHuman metapneumovirus (hMPV) is one of the major causative agents of acute respiratory disease in humans. Currently, there is no vaccine or antiviral drug for hMPV. hMPV enters host cells via a unique mechanism, in that viral fusion (F) protein mediates both attachment and fusion activity. Recently, it was suggested that hMPV F protein utilizes integrins as receptors for entry via a poorly understood mechanism. Here, we show that ␣5␤1 and ␣v integrins are essential for hMPV infectivity and F proteinmediated cell-cell fusion and that the integrin-binding motif in the F protein plays a crucial role in these functions. Our results also identify the integrin-binding motif to be a new, attenuating target for the development of a live vaccine for hMPV. These findings not only will facilitate the development of antiviral drugs targeting viral entry steps but also will lead to the development new live attenuated vaccine candidates for hMPV.

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Section: H Uman Metapneumovirus (Hmpv) Is a Member Of The Genusmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Roles of the Putative Integrin-Binding Motif of the Human Metapneumovirus Fusion (F) Protein in Cell-Cell Fusion, Viral Infectivity, and Pathogenesis

Wei

Zhang

Cai

et al. 2014

J Virol

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“…In addition to serving as a receptor for several RGD-containing matrix proteins (Hynes, 2002;Takada et al, 2007), V1 serves as a receptor or co-receptor for several viruses, including adenovirus (Davison et al, 2001;Li et al, 2001), foot-and-mouth disease virus (Jackson et al, 2002), parechovirus (Triantafilou et al, 2000) and metapneumovirus (Cseke et al, 2009). Although many integrins function as both adhesion and signaling receptors (Hynes, 2002;Takada et al, 2007), the role of V1 in cell signaling remains to be fully explored.…”

Section: Research Articlementioning

confidence: 99%

Integrin αV is necessary for gastrulation movements that regulate vertebrate body asymmetry

et al. 2010

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Integrin αV can form heterodimers with several β subunits to mediate cell-cell and cell-extracellular matrix interactions. During zebrafish gastrulation, αV is expressed maternally and zygotically. Here, we used a morpholino-mediated αV knockdown strategy to study αV function. Although αV morphants displayed vascular defects, they also exhibited left-right body asymmetry defects affecting multiple visceral organs. This was preceded by mislocalization of dorsal forerunner cells (DFCs) and malformation of the Kupffer's vesicle (KV) laterality organ. These defects were rescued with morpholino-resistant αV mRNA. Like αV, integrin β1b was expressed in DFCs, and β1b knockdown largely recapitulated the laterality phenotype of αV morphants. When tracked in real-time, individual DFCs of both morphants showed defects in DFC migration, preventing them from organizing into a KV of normal shape and size. Thus, we propose that αVβ1b mediates cellular interactions that are necessary for DFC clustering and movements necessary for Kupffer's vesicle formation, uncovering an early contribution of integrins to the regulation of vertebrate laterality.

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“…15 Little is known about the pathogenesis of HMPV, but an integrin alpha v beta 1 receptor has been identified that facilitates infection of the epithelial cells of the respiratory tract. 16 The most common reasons for hospitalization in children are bronchiolitis and pneumonia. Although HMPV has been associated with upper respiratory tract infections (rhinopharyngitis, laryngitis, croup), severe lower respiratory tract infection has been reported.…”

Section: Discussionmentioning

confidence: 99%