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Role of LFA-1 integrin in the control of a lymphocytic choriomeningitis virus (LCMV) infection.

ABSTRACT: Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8⁺ T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8⁺ T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8⁺ T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection.

SUBMITTER: Perro M

PROVIDER: S-EPMC7714442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The experimental data indicate that during a persistent infection, lymphocytic choriomeningitis virus (LCMV) may both directly or indirectly modulate the regulatory cellular processes and alter the cellular functions that are not critical for the survival, but are needed for the homeostasis in the organism. Two-dimensional differential in-gel electrophoresis (2D-DIGE) and MALDI-TOF MS/MS analyses were used to determine the cellular proteome response of HeLa cell line to persistent LCMV infection. Quantitative analysis revealed 24 differentially abundant proteins, half of which were up-regulated and the rest down-regulated. Functional categorization showed that LCMV-responsive proteins were mainly involved in metabolism, stress and defense responses. Among identified proteins, significant changes were found for peroxiredoxins, family of antioxidant enzymes. Decreased amount of these antioxidant proteins was accompanied with the elevation of ROS content in infected cells.

2019-11-15 | PXD005205 | Pride

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Project description:Mammalian arenaviruses are rodent-borne zoonotic viruses, some of which can cause fatal hemorrhagic diseases in humans. The first discovered arenavirus, lymphocytic choriomeningitis virus (LCMV), has a worldwide distribution and can be fatal for transplant recipients. However, no FDA-approved drugs or vaccines are currently available. In this study, using a quantitative proteomic analysis, we identified a variety of host factors that could be needed for LCMV infection, among which we found that protein disulfide isomerase A4 (PDIA4), a downstream factor of endoplasmic reticulum stress (ERS), is important for LCMV infection. Biochemical analysis revealed that LCMV glycoprotein was the main viral component accounting for PDIA4 upregulation. The inhibition of ATF6-mediated ERS could prevent the upregulation of PDIA4 that was stimulated by LCMV infection. We further found that PDIA4 can affect the LCMV viral RNA synthesis processes and release. In summary, we conclude that PDIA4 could be a new target for antiviral drugs against LCMV.

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