αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

Abstract

We report that ␣v␤3 integrin strongly affects the innate immune response in epithelial cells. ␣v␤3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by ␣v␤3 integrin. The boosting was exerted specifically by ␣v␤3 integrin but not by ␣v␤6 or ␣v␤8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response. The Toll-like receptors (TLRs) constitute the first line of defense against invading pathogens (1). They include TLR1, TLR2, and TLR4 to TLR6, which are localized at the plasma membrane, and TLR3, TLR7, and TLR9, which are localized at endosomal membranes (1). TLR2 can be expressed as a homodimer or as a heterodimer with TLR1 or TLR6. The plasma membrane TLRs recognize pathogen-associated molecular patterns (PAMPs) present on the surfaces of bacteria (e.g., lipopolysaccharide [LPS], flagellin) or of viruses (e.g., virion envelope glycoproteins). The endosomal TLRs recognize viral or bacterial DNA or RNA.Integrins are cell surface glycoproteins involved in cell-cell and cell-matrix interactions. They are composed of an ␣ and a ␤ subunit (2-4). They serve as receptors for several viruses, including some herpesviruses (5-10). Our laboratory investigated the role played by integrins in herpes simplex virus (HSV) entry and found that ␣v␤6 and ␣v␤8 integrins serve as interchangeable receptors for HSV entry into epithelial and neuronal cells (11). They bind the envelope glycoproteins gH and gL (gH/gL), a heterodimeric component of the fusion machinery, with high affinity (11). Their interaction with gH/gL promotes virion endocytosis and the displacement of gL from gH, most likely as part of the process of gH activation (12). An additional integrin involved in HSV entry is ␣v␤3, which serves two functions. It binds gH/gL at low affinity and routes HSV to lipid rafts and an acidic endosomal pathway of entry and thus serves as a routing factor (13). Importantly, it contributes to the innate immune response through a concerted action with TLR2 (14-16). In epithelial cell lines, including keratinocytic and neuronal cells, interferon alpha (IFN-␣) and IFN-␤, interleukin 2, and interleukin 10 are upregulated, and NF-B is activated in response to HSV or to LPS (14). This response is strongly impaired in the absence of TLR2 or upon ␤3-integrin depletion. The HSV PAMP is gH/gL, which simultaneously binds ␣v␤3 integrin and TLR2 and thus cross-links the two receptors (14). The basis of the concerted ␣v␤3 integrin-TLR2 response rests in boosting by ␣v␤3 integrin of MYD88-dependent TLR2 signaling (16).Here, we asked whether the concerted integrin-TLR response is a broader phenomenon that involves epithelial integrins other than ␣v␤3 (e.g., ␣v␤6 and ␣v␤8) or additional TLRs. To address this question, 293T cells and t...

First Impressions—the Potential of Altering Initial Host-Virus Interactions for Rational Design of Herpesvirus Vaccine Vectors

“…In support of an important role for the gH-integrin interaction it was shown that siRNA knockdown of αvβ3 prevents HSV entry (69). Consistent with these results, work from the Campadelli-Fiume laboratory has demonstrated an important role for integrins in HSV infection (8, 10, 35, 72–74). They have proposed that these integrins serve as co-receptors.…”

“…For equine herpesvirus 1(EHV-1), another alphaherpesvirus, it has been shown that binding of gH to α4β1 integrin induces calcium signaling and that abrogation of this pathway redirects entry to the endocytic pathway (38). Multiple groups have shown that gH-integrin complex formation requires the presence of other fusion complex members, such as gD and gB to function (10, 71), implying that either gD receptor binding, or fusion complex formation is important for subsequent gH-integrin complex formation.…”

αvβ3 Integrin Is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26

“…Recently, Casiraghi et al reported that ␣v␤3 integrin strongly affects the innate immune response in epithelial cells. They showed that ␣v␤3 integrin greatly increased the immune response elicited by herpes simplex virus, which had previously been shown to bind ␣v␤3 integrin (42). This implies that HAdV26 interaction with ␣v␤3 integrin might also influence the innate immune response in infected cells, and therefore, it would be interesting to investigate it in more detail.…”

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

“…Moreover, internalized integrins cosignal with these receptors from endosomes toward the extracellular signal-regulated kinase (ERK) and AKT pathways, to synergistically drive cell proliferation and survival [ 91 , 92 ]. Some integrins mediate phagocytosis of (complement-opsonized) pathogens, such as herpes simplex virus and Listeria monocytogenes [ 99 , 100 ]. Following internalization, these integrins can induce the recruitment of microtubule-associated protein 1A/1B light chains 3B (LC3) to form autophagosomes, which fuse with lysosomes to degrade the pathogens [ 94 , 95 ].…”