title: 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.
abstract: 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.
authors.affiliation: University of Toronto Transplantation Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khattar
authors.forename: Olga
authors.initials: O
authors.lastname: Luft
authors.forename: Nataliya
authors.initials: N
authors.lastname: Yavorska
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.forename: M James
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Oyedele
authors.initials: O
authors.lastname: Adeyi
authors.forename: Darrin
authors.initials: D
authors.lastname: Gao
authors.forename: Agata
authors.initials: A
authors.lastname: Bartczak
authors.forename: Peter
authors.initials: P
authors.lastname: Urbanellis
authors.forename: Wendy
authors.initials: W
authors.lastname: Shyu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Justin
authors.initials: J
authors.lastname: Manuel
authors.forename: Gary A
authors.initials: GA
authors.lastname: Levy
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
mesh_terms: D056704:Adaptive Immunity; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D018122:B7-1 Antigen; C490637:Fgl2 protein, mouse; D007371:Interferon-gamma; D005340:Fibrinogen; D000410:Alanine Transaminase