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.
Highlights
Viral hepatitis remains a major cause of human morbidity and mortality worldwide and is the leading cause of primary liver cancer and the most common indication for liver transplantation worldwide [1]
Following infection of fgl2+/+ mice with 26106 PFU Lymphocytic Choriomeningitis Virus WE (LCMV WE), plasma levels of Fibrinogen-like protein 2 (FGL2) increased from basal level of 0.860.2 ng/ml reaching a peak of 7.860.5 ng/ml on day 8 pi and remained elevated at all time points studied when compared to uninfected mice (Figure 1)
Expression levels of the Dendritic cells (DC) maturation markers CD80 and MHC class II were assessed on DC which were isolated from spleens and lymph nodes of LCMV-infected fgl2+/+ or fgl22/2mice on day 1 post LCMV WE infection
Summary
Viral hepatitis remains a major cause of human morbidity and mortality worldwide and is the leading cause of primary liver cancer and the most common indication for liver transplantation worldwide [1]. Conventional treatment of patients with chronic HBV reduces hepatitis activity and disease progression, HBV is rarely eliminated and lifelong anti-viral therapy is required [4]. Despite major advances in the development of anti-viral therapy for HCV, 40– 50% of patients chronically infected with HCV remain nonresponsive to treatment and will progress to developing liver cirrhosis or HCC within 15–20 years [5,6,7,8]. Patients who do not respond to current HCV treatment appear to have reduced anti-viral immune responses due to an increased number and activity of Treg cells and their suppressive molecules [9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
