Abstract
Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures and death, the mechanisms of which have not been well characterized. We have previously shown that the matrix protein Z of pathogenic arenaviruses, including LASV and LCMV, can strongly inhibit the ability of the innate immune protein RIG-I to suppress type I interferon (IFN-I) expression, which serves as a mechanism of viral immune evasion and virulence. Here, we show that Z proteins of diverse LASV isolates derived from rodents and humans have a high degree of sequence variations at their N- and C-terminal regions and produce variable degrees of inhibition of human RIG-I (hRIG-I) function in an established IFN-β promoter-driven luciferase (LUC) reporter assay. Additionally, we show that Z proteins of four known LCMV strains can also inhibit hRIG-I at variable degrees of efficiency. Collectively, our results confirm that Z proteins of pathogenic LASV and LCMV can inhibit hRIG-I and suggest that strain variations of the Z proteins can influence their efficiency to suppress host innate immunity that might contribute to viral virulence and disease heterogeneity.
Highlights
Lassa fever is an acute viral illness that is endemic in several western African nations, where it is estimated to infect about 300,000 to 500,000 people annually and to cause 5000 deaths yearly [1].Currently there are no FDA-approved vaccines and limited treatment options for Lassa fever.The disease is caused by Lassa virus (LASV), a zoonotic RNA virus in the family of Arenaviridae with a natural reservoir in the local rodents Mastomys natalensis, Mastomys erythroleucus, and African wood mouse Hylomyscus pamfi [2,3,4]
We have shown that the Z protein of pathogenic arenaviruses including LASV can inhibit IFN-I production by directly binding to and inhibiting the innate immune proteins RIG-I and MDA5, collectively known as the RIG-I-like receptors (RLRs), and in doing so, it acts as a potential viral virulent factor [18]
We showed that all LASV Z proteins tested can inhibit human RIG-I (hRIG-I) function (Figure 2A), regardless of their host species or geographical locations, confirming our previous findings [18] that inhibition of hRIG-I is a conserved feature among LASV Z
Summary
Lassa fever is an acute viral illness that is endemic in several western African nations, where it is estimated to infect about 300,000 to 500,000 people annually and to cause 5000 deaths yearly [1].Currently there are no FDA-approved vaccines and limited treatment options for Lassa fever.The disease is caused by Lassa virus (LASV), a zoonotic RNA virus in the family of Arenaviridae with a natural reservoir in the local rodents Mastomys natalensis, Mastomys erythroleucus, and African wood mouse Hylomyscus pamfi [2,3,4]. Lassa fever is an acute viral illness that is endemic in several western African nations, where it is estimated to infect about 300,000 to 500,000 people annually and to cause 5000 deaths yearly [1]. The general case-fatality rate is relatively low at approximately 1%, but it can be as high as 15% among hospitalized patients and ~50% in occasional epidemics [6,7,8]. The reasons for this diverse disease heterogeneity are unknown but can be attributed to several factors, such as co-infection with other pathogens, host’s pre-existing immunity, the amount of viral inoculum, and the relatively high genetic diversity among the LASV isolates
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