LCMV-mediated hepatitis in rhesus macaques: WE but not ARM strain activates hepatocytes and induces liver regeneration

Abstract

Lymphocytic chorimeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), causative agent of Lassa hemorrhagic fever (LHF), belong to the Old World group of the family Arenaviridae. Both viruses have extensive strain diversity and significant variations in lethality and pathogenicity for man and experimental animals. We have shown that the LHF-like infection of rhesus macaques with the WE strain of LCMV affects liver functions, induces hepatocyte proliferation, and causes a rise in IL-6 and soluble TNF receptors (sTNFR) concomitant with a rise in viremia. The levels of IL-6 and sTNFR can serve as an additional diagnostic tool for liver involvement in pathogenesis of arenavirus infection. Mucosal inoculation of rhesus macaques with LCMV-WE can result in attenuated infection with a transient viremia and liver enzyme abnormalities. The ARM strain of LCMV shares 88% amino acid homology with WE. In contrast to LCMV-WE, ARM strain does not induce manifested disease in monkeys, does not affect liver functions, and does not induce hepatocyte proliferation. Previously we demonstrated that LCMV-ARM infection protected rhesus macaques challenged with LCMV-WE. Here we have shown that the protected animals have no signs of hepatitis and hepatocyte proliferation.

Pathogenic Old World Arenaviruses Inhibit TLR2/Mal-Dependent Proinflammatory Cytokines In Vitro

“…We previously showed for the first time that the replication of the OW pathogenic arenaviruses LASV and LCMV-WE, but not nonpathogenic MOPV and LCMV-Arm, was associated with the inhibition of proinflammatory cytokine/chemokine responses in vitro and in vivo (35,36,38). The detection of proinflammatory cytokines in LF patients and in experimentally infected nonhuman primates showed no evidence for a "cytokine storm" observed previously for cases of filovirus-induced hemorrhagic fever (HF) (46).…”

“…An LF-like disease in immunocompromised transplant patients infected with LCMV through donor tissues has been documented (21). Previously, we showed (18,(35)(36)(37) that rhesus macaques infected with the WE strain of LCMV developed a fatal LF-like disease, providing a valuable model for the study of LF pathogenesis and vaccine development (25,62). The Armstrong (Arm) strain of LCMV (LCMV-Arm) shares 88% amino acid homology with WE (17) but does not induce disease in monkeys.…”

A Live Attenuated Vaccine for Lassa Fever Made by Reassortment of Lassa and Mopeia Viruses

“…An immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) was performed as previously described (29). ML29 antigen was prepared from serum-free culture medium of ML29-infected Vero E6 cells by ultracentrifugation in a Beckman Optima L90K (SW28; 27,000 rpm; 3 h).…”

“…Sera from LASV-infected individuals were used as positive controls. Neutralizing antibodies were determined by plaque reduction neutralization assay using constant doses of virus, Vero E6 cell monolayers, and serial dilutions of plasma (29).…”

Early Blood Profiles of Virus Infection in a Monkey Model for Lassa Fever

“…The murine disease is alleviated by immune suppression (31,44), unlike the acute viral disease in guinea pig and primate models (28,54,52,60). The progression of LCMV-associated hemorrhagic fever in macaques is very similar to that seen for Lassa fever in humans (19,22,46,47,48,68) and provides a practical model for disease studies in wellcontrolled laboratory environments.…”