Cellular adhesion molecules as targets for bacterial infection

Hauck, Christof R.; Agerer, Franziska; Muenzner, Petra; Schmitter, Tim

doi:10.1016/j.ejcb.2005.08.002

Cited by 93 publications

(73 citation statements)

References 45 publications

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“…Many bacterial pathogens target cell adhesion molecules via integrin receptors to establish an intimate contact with host cells and tissues (reviewed in references 43 and 44). Mutagenesis and biochemical studies found that integrin receptors exhibited variable degrees of affinity to organisms with the analogs or mutants of the RGD motif, depending on the property of the integrin-binding protein (44). Individual residues within the RGD motif in surface proteins of many bacteria (such as Shigella, Leptospira, and Streptococcus species) played a dominant role in binding to integrin receptors (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Major respiratory bacteria, such as NTHi, Streptococcus pneumoniae and Moraxella catarrhalis, are common asymptomatic colonizers of the upper respiratory tract, but under certain circumstances may disseminate and cause infections, such as otitis media, sinusitis, and lower respiratory tract ailments including bronchitis, pneumonia, and acute exacerbations of COPD [29][30][31][32]. These species interact with and adhere to a variety of host cell receptors including ECM components and CEACAM-1, ICAM-1 and PAFR [5,33,34] (Fig. 1).…”

Section: Temporal Host Surface Receptor Upregulation In Different Bodmentioning

confidence: 99%

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Shukla

Walters

et al. 2017

Microbiology

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Host surface receptors provide bacteria with a foothold from which to attach, colonize and, in some cases, invade tissue and elicit human disease. In this review, we discuss several key host receptors and cognate adhesins that function in bacterial pathogenesis. In particular, we examine the elevated expression of host surface receptors such as CEACAM-1, CEACAM-6, ICAM-1 and PAFR in response to specific stimuli. We explore how upregulated receptors, in turn, expose the host to a range of bacterial infections in the respiratory tract. It is apparent that exploitation of receptor induction for bacterial adherence is not unique to one body system, but is also observed in the central nervous, gastrointestinal and urogenital systems. Prokaryotic pathogens which utilize this mechanism for their infectivity include Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and Escherichia coli. A number of approaches have been used, in both in vitro and in vivo experimental models, to inhibit bacterial attachment to temporally expressed host receptors. Some of these novel strategies may advance future targeted interventions for the prevention and treatment of bacterial disease.

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“…Integrins are often targeted by bacterial and viral pathogens, which use them to establish intimate contact with, and often gain entry into, host cells (Hauck et al, 2006;Nemerow and Cheresh, 2002;Stewart and Nemerow, 2007).…”

Section: Integrins That Turn Phagocytic In Pathogenic Conditionsmentioning

confidence: 99%

Integrin-dependent phagocytosis – spreading from microadhesion to new concepts

Dupuy

Caron

2008

Journal of Cell Science

218

184

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By linking actin dynamics to extracellular components, integrins are involved in a wide range of cellular processes that are associated with or require cytoskeletal remodelling and cellshape changes. One such function is integrin-dependent phagocytosis, a process that several integrins are capable of mediating and that allows the binding and clearance of particles. Integrin-dependent phagocytosis is involved in a wide range of physiological processes, from the clearance of microorganisms and apoptotic-cell removal to extracellular-matrix remodelling. Integrin signalling is also exploited by microbial pathogens for entry into host cells. Far from being a particular property of specific integrins and specialised cells, integrin-dependent uptake is emerging as a general, intrinsic ability of most integrins that is associated with their capacity to signal to the actin cytoskeleton. Integrin-mediated phagocytosis can therefore be used as a robust model in which to study integrin regulation and signalling. Journal of Cell Science 1774 distinct receptors can be devoted to particle recognition ('tethering' receptors) and stimulation of particle uptake ('tickling' receptors) (Zullig and Hengartner, 2004). Interestingly, zipper-like phagocytosis can also take place in non-professional phagocytes, either naturally or following transfection of phagocytic receptors (Caron and Hall, 1998;Underhill and Ozinsky, 2002).Similar to cell adhesion and migration, phagocytosis crucially depends on remodelling of the actin cytoskeleton and on membrane dynamics (DeMali and Burridge, 2003;Niedergang and Chavrier, 2004). Moreover, the signalling pathways that underlie these processes have several regulatory proteins in common, including Rho-family proteins Ridley et al., 2003). Interestingly, distinct Rho GTPases regulate actin polymerisation during phagocytosis and actually define several modes of phagocytosis that are phenotypically different. Indeed, during FcγR-dependent (also referred as type I) uptake, activation of Rac1 and Cdc42 is thought to drive the formation of local pseudopods and membrane ruffles that engulf the particles. By contrast, actin polymerisation during integrin-αMβ2-dependent (referred as type II) phagocytosis is regulated by RhoA activity, and particles that are bound to αMβ2 sink into cells without generating major protrusions (see below and Fig. 2) (Allen and Aderem, 1996; Caron and Hall, 1998).On the basis of the criteria defined above for phagocytosis (particle size, zipper-like receptor tickling, and actin-dependent and Rho-GTPase-dependent uptake), we review here the role of integrins in phagocytosis, both in professional phagocytes and also in cells that are not classically considered phagocytic. We highlight the similarities between the signalling basis of integrin function during adhesion and phagocytic uptake. Not only is phagocytosis the predominant function of certain integrins, it should be seen as an intrinsic ability of most integrins. By extension, integrin-mediated phagocytosis can be proposed a...

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Cellular adhesion molecules as targets for bacterial infection

Cited by 93 publications

References 45 publications

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

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

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Integrin-dependent phagocytosis – spreading from microadhesion to new concepts

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