Vaccinia Virus-Induced Cell Motility Requires F11L-Mediated Inhibition of RhoA Signaling

Valderrama, Ferran; Cordeiro, João V.; Schleich, Sibylle; Frischknecht, Friedrich; Way, Michael

doi:10.1126/science.1122411

Cited by 107 publications

(168 citation statements)

References 21 publications

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“…This blockade of directional migration could not be explained by either a general disturbance of cellular locomotion or an altered expression of chemokine receptors, as undirected migration and surface expression of the chemokine receptors CXCR4 and CCR7 were barely affected by infection with VV. Infection with the WR strain even slightly enhanced cell motility of infected DC, which corresponds to recently published data showing that WR, but not MVA, is capable of inducing motility and undirected migration in infected cells [43]. In this context, it is also important to mention that the VV strains WR and MVA are not known to encode for so-called viral chemokine-binding-proteins (vCKBP) [26,44,45], which could otherwise explain these results with the viral clearance of chemokines by means of chemokine sequestration.…”

Section: Discussionsupporting

confidence: 89%

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signalregulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-a. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and noninfected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigenpresenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.See accompanying commentary: http://dx

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Section: Discussionsupporting

confidence: 89%

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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“…Although Rac1 is the key GTPase promoting infection by WR MVs, the impact of D/N Cdc42 and Cdc42 siRNA suggests that Cdc42 may also be important. That expression of the constitutively active RhoA inhibited infection confirmed previous data on WR virus (12). This inhibitory effect provided a possible explanation for the effect of Toxin B, which only gave partial inhibition of infection; the toxin may have simultaneously increased infection by inactivating RhoA, and decreased it by inhibiting Cdc42 and Rac1.…”

supporting

confidence: 84%

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Mercer

Knébel

Schmidt

et al. 2010

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

150

159

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To enter host cells, vaccinia virus, a prototype poxvirus, can induce transient macropinocytosis followed by endocytic internalization and penetration through the limiting membrane of pinosomes by membrane fusion. Although mature virions (MVs) of the Western reserve (WR) strain do this in HeLa cells by activating transient plasma membrane blebbing, MVs from the International Health Department-J strain were found to induce rapid formation (and lengthening) of filopodia. When the signaling pathways underlying these responses were compared, differences were observed at the level of Rho GTPases. Key to the filopodial formation was the virus-induced activation of Cdc42, and for the blebbing response the activation of Rac1. In addition, unlike WR, International Health Department-J MVs did not rely on genistein-sensitive tyrosine kinase and PI(3)K activities. Only WR MVs had membrane fusion activity at low pH. Inhibitor profiling showed that MVs from both strains entered cells by macropinocytosis and that this was induced by virion-exposed phosphatidylserine. Both MVs relied on the activation of epidermal growth factor receptor, on serine/ threonine kinases, protein kinase C, and p21-activated kinase 1. The results showed that different strains of the same virus can elicit dramatically different responses in host cells during entry, and that different macropinocytic mechanisms are possible in the same cell line through subtle differences in the activating ligand.epidermal growth factor receptor | endocytosis | poxvirus | Rho GTPases | virus entry

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“…The first is predicted to express a 96 aa long polypeptide that is 100% homologous to vaccinia Copenhagen in the antigenic region we identified (37,69,70). It is not known whether this truncated form is transcribed or translated.…”

Section: Discussionmentioning

confidence: 98%

“…It is not known whether this truncated form is transcribed or translated. Full-length F11L (348 aa) is expressed early (71), effects cell motility via RhoA, and is required for productive infection of primate cells (69). MVA F11L expression can be addressed by testing F11L-specific clones with MVA preparations.…”

Section: Discussionmentioning

confidence: 99%

Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

Jing¹,

Chong

Byrd³

et al. 2007

The Journal of Immunology

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Vaccination with replication-competent vaccinia protects against heterologous orthopoxvirus challenge. CD4 T cells have essential roles helping functionally important Ab and CD8 antiviral responses, and contribute to the durability of vaccinia-specific memory. Little is known about the specificity, diversity, or dominance hierarchy of orthopoxvirus-specific CD4 T cell responses. We interrogated vaccinia-reactive CD4 in vitro T cell lines with vaccinia protein fragments expressed from an unbiased genomic library, and also with a panel of membrane proteins. CD4 T cells from three primary vaccinees reacted with 44 separate antigenic regions in 35 vaccinia proteins, recognizing 8 to 20 proteins per person. The integrated responses to the Ags that we defined accounted for 49 to 81% of the CD4 reactivity to whole vaccinia Ag. Individual dominant Ags drove up to 30% of the total response. The gene F11L-encoded protein was immunodominant in two of three subjects and is fragmented in a replication-incompetent vaccine candidate. The presence of protein in virions was strongly associated with CD4 antigenicity. These findings are consistent with models in which exogenous Ag drives CD4 immunodominance, and provides tools to investigate the relationship between Ab and CD4 T cell specificity for complex pathogens.

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Vaccinia Virus-Induced Cell Motility Requires F11L-Mediated Inhibition of RhoA Signaling

Cited by 107 publications

References 21 publications

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

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