Targeted deletion of FGL2 leads to increased early viral replication and enhanced adaptive immunity in a murine model of acute viral hepatitis caused by LCMV WE

• Published in: PloS one 2013-10, Vol.8 (10), p.e72309
• Main Authors: Khattar, Ramzi, Luft, Olga, Yavorska, Nataliya, Shalev, Itay, Phillips, M James, Adeyi, Oyedele, Gao, Darrin, Bartczak, Agata, Urbanellis, Peter, Shyu, Wendy, Zhang, Jianhua, Manuel, Justin, Levy, Gary A, Selzner, Nazia
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Alanine; Alanine transaminase; Alanine Transaminase - blood; Alanine Transaminase - genetics; Animal models; Animals; Antibodies; Antibodies, Neutralizing - blood; Antigen-presenting cells; Antiviral agents; B cells; B-Lymphocytes - immunology; B-Lymphocytes - virology; B7-1 Antigen - genetics; B7-1 Antigen - immunology; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; CD80 antigen; Clonal deletion; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - virology; Female; Fgl2 protein; Fibrin; Fibrinogen; Fibrinogen - genetics; Fibrinogen - immunology; Foxp3 protein; Gene Deletion; Gene Expression Regulation; Health aspects; Hepatitis; Hepatitis - genetics; Hepatitis - immunology; Hepatitis - pathology; Hepatitis - virology; Host-Pathogen Interactions; Immune clearance; Immune response; Immunity; Infection; Infections; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Laboratories; Liver; Liver cancer; Liver diseases; Lymph nodes; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphocytic choriomeningitis virus - immunology; Major histocompatibility complex; Medical research; Mice; Mice, Knockout; Molecular chains; Mortality; Pathogenesis; Proteins; Regulation; Replication; Signal Transduction; Spleen; Spleen - immunology; Spleen - virology; Studies; T cell receptors; T cells; Viral infections; Viral Load; Virus Replication; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072309

Mounting effective innate and adaptive immune responses are critical for viral clearance and the generation of long lasting immunity. It is known that production of inhibitory factors may result in the inability of the host to clear viruses, resulting in chronic viral persistence. Fibrinogen-like protein 2 (FGL2) has been identified as a novel effector molecule of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells that inhibits immune activity by binding to FCγRIIB expressed primarily on antigen presenting cells (APC). In this study, we show that infection of mice with Lymphocytic Choriomeningitis Virus WE (LCMV WE) leads to increased plasma levels of FGL2, which were detected as early as 2 days post-infection (pi) and persisted until day 50 pi. Mice deficient in FGL2 (fgl2(-/-)) had increased viral titers of LCMV WE in the liver early p.i but cleared the virus by day 12 similar to wild type mice. Dendritic cells (DC) isolated from the spleens of LCMV WE infected fgl2(-/-) had increased expression of the DC maturation markers CD80 and MHC Class II compared to wild type (fgl2(+/+)). Frequencies of CD8(+) and CD4(+) T cells producing IFNγ in response to ex vivo peptide re-stimulation isolated from the spleen and lymph nodes were also increased in LCMV WE infected fgl2(-/-) mice. Increased frequencies of CD8(+) T cells specific for LCMV tetramers GP33 and NP396 were detected within the liver of fgl2(-/-) mice. Plasma from fgl2(-/-) mice contained higher titers of total and neutralizing anti-LCMV antibody. Enhanced anti-viral immunity in fgl2(-/-) mice was associated with increased levels of serum alanine transaminase (ALT), hepatic necrosis and inflammation following LCMV WE infection. These data demonstrate that targeting FGL2 leads to early increased viral replication but enhanced anti-viral adaptive T & B cell responses. Targeting FGL2 may enhance the efficacy of current anti-viral therapies for hepatotropic viruses.