Infection of Dendritic Cells by Lymphocytic Choriomeningitis Virus

Abstract

Dendritic cells (DCs) comprise the major antigen-presenting cells (APCs) of the host, uniquely programmed to stimulate immunologically naïve T lymphocytes. Viruses that can target and disorder the function of these cells enjoy a selective advantage. The cellular receptor for lymphocytic choriomeningitis virus (LCMV), Lassa fever virus (LFV), and several other arenaviruses is α-dystroglycan (α-DG). Among cells of the immune system, CD11c + and DEC-205 + DCs primarily and preferentially express α-DG. By selection, strains and variants of LCMV generated as quasi-species that bind α-DG with high affinity replicate in the majority of CD11c + and DEC-205 + (>75%) DCs, causing a generalized immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to α-DG display minimal replication in CD11c + and DEC-205 + DCs (<10%), rarely replicate in the white pulp, and generate a robust anti-LCMV CTL response that clears the virus infection. Hence, receptor-virus interaction on DCs in vivo is an essential step in the initiation of virus-induced immunosuppression and viral persistence. Investigation into the mechanism of how virus-infected DCs cause immunosuppression reveals loss of MHC class II surface expression and costimulatory molecules on surface of such DCs. As a consequence DCs are unable to act as APCs, initiate immune responses, and have a defect in migration into the T cell area. These data indicate that LCMV infection influences DC maturation and migration, leading to decreased T cell stimulatory capacity of DCs, events essential for the initiation of immune responses. Because several other viruses known to cause immunosuppression (HIV, measles) interact with DCs, the observations noted here are likely a common selective mechanism by which viruses also are able to evade the host s immune system.

Analysis of Human Peripheral Blood Samples from Fatal and Nonfatal Cases of Ebola (Sudan) Hemorrhagic Fever: Cellular Responses, Virus Load, and Nitric Oxide Levels

“…In vitro studies of Ebola-Z virus revealed that suppression of immune responses can take place within infected cells (4,5,15,16,17) and that direct contact of virion particles with T cells can render them unresponsive (10). In addition, dendritic cells infected with Ebola-Z virus have been shown to be functionally impaired and are poor stimulators of T cells (24), as has also been described for measles virus (29,32) and lymphocytic choriomeningitis virus (33). Since dendritic cells are key components in adaptive immune responses, it is reasonable to assume that the degree to which these cells are infected or impaired has a direct impact on antigen processing and the recruitment and activation of effector cells.…”

Lymphocytic choriomeningitis infection of the central nervous system

“…Further studies in adult mice demonstrated that enhanced viral infiltration into the white pulp of the spleen was associated with increased binding to α-DG (152) and that clone 13 also more effectively targeted fibroblastic reticular cells resulting in decreased conduit function of the spleen (160). The disruption in splenic function (158,160), physical destruction of dendritic cells (161), and inhibition of dendritic cell differentiation and maturation (162,163) are likely contributors to the immunosuppression observed during clone 13 infection. More recently, it has also been revealed that inhibitory molecule such as PD-1 (164) and IL-10 (165) are upregulated early following clone 13 infection and also contribute to the immunosuppressive milieu.…”

Mechanism of T cell exhaustion in a chronic environment

“…It has been also demonstrated that chronic LCMV preferentially and persistently infects mDCs among DC populations (78). Therefore, the enhanced infection of DCs, followed by reduced T cell stimulatory capacity, is probably one of the mechanisms by which chronic pathogens initiate immunosuppression within the host (79,80). More interestingly, independent of preferential DC infection by chronic pathogens, it has been reported that the functional impairment of DCs is associated with the exhaustion of T cell function and progression of disease during HIV, HBV, HCV, and LCMV infections (81)(82)(83)(84)(85)(86).…”