Current research for a vaccine against Lassa hemorrhagic fever virus

Warner, Bryce M; Safronetz, David; Stein, Derek R

Professional antigen-presenting cells (APC), such as macrophages and dendritic cells (DCs), are the primary target cells for LASV infection, and initial infection typically involves myeloid lineage cells and APC. 9,10 An early determinant of disease progression in arenavirus infection is the activation status of virally infected APC. During LASV infection, APC fail to undergo activation or maturation, leading to ineffective antigen processing and presentation despite LASV being able to replicate at high levels within these cells. 9 This is in contrast to Mopeia virus (MOPV), a non-pathogenic Mammarenavirus very similar to LASV, but one that induces APC activation leading to effective adaptive immunity while also replicating at high levels within APC. 3 Infection with MOPV leads to classically activated APC with upregulation of CD80, CD86, and CD40, along with secretion of innate cytokines such as type I interferons (IFN) and interleukin-6. 11 The immature state of infected APC persists during LASV infection even though cells migrate to the draining lymph nodes of infected individuals. 12 During early LASV infection, the type I IFN response has been shown to be an important mediator of protection 13 NHPs infected with LASV that have a strong IFNα response within the first few days of infection fare better than animals with minimal IFNα early on during infection. Additionally, pathogenic and lethal LF models have been characterized using mice lacking the IFNα/β receptor and thus unable to respond to IFNα or IFNβ. This is in contrast to wild-type mice, which are resistant to LASV infection. [14] [15] [16] Type I IFN signaling provides an important barrier to virus replication as well as a bridge to the virus-specific adaptive immune response. Therefore, the ability of LASV to alter the type I IFN response may allow for unchecked viral replication and an escape of protective adaptive immune responses. There is evidence that LASV can antagonize the innate IFN response and other cellular mechanisms that lead to both innate and adaptive immune responses, which may be critical for viral clearance and reduced pathogenesis. As already mentioned, LASV prevents APC activation and maturation, which is achieved through reduced RNA sensing in infected DCs. 9 The Z protein of LASV also binds to the caspase recruitment domain of RIG-I and MDA5, preventing signaling by both proteins. 17 The nucleocapsid protein of LASV can also inhibit type I IFN signaling by degrading dsRNA and by binding to IκB kinase-ε, preventing activation of IRF3 and NF-κB. 18, 19 There is also evidence that LASV can use TAM receptors, AXL and TYRO3, for cell entry. 20, 21 The activation of these receptors leads to upregulation of suppressor cytokine signaling proteins and inhibition of type I IFN signaling pathways. LASV can use the abovementioned strategies to prevent RIG-I signaling, leading to type I IFN responses in infected cells. These strategies play an important role in preventing APC activation, leading to adaptive immune responses and viral clearance. The ability to alter the function of APC is likely a critical determinant of pathogenesis during LASV infection, as an absent adaptive immune response is typically seen in fatal LF cases. 22, 23 Overall, there is strong evidence that altered APC function during LASV infection correlates with a severe disease outcome. Knowledge of how LASV modulates the innate immune system can have important implications for the development