Heartland virus infection in hamsters deficient in type I interferon signaling: Protracted disease course ameliorated by favipiravir

Abstract

Heartland virus (HRTV) is an emerging tick-borne virus (Bunyaviridae, Phlebovirus) that has caused sporadic cases of human disease in several central and mid-eastern states of America. Animal models of HRTV disease are needed to gain insights into viral pathogenesis and advancing antiviral drug development. Presence of clinical disease following HRTV challenge in hamsters deficient in STAT2 function underscores the important role played by type I interferon-induced antiviral responses. However, the recovery of most of the infected animals suggests that other mechanisms to control infection and limit disease offer substantial protection. The most prominent disease sign with HRTV infection in STAT2 knockout hamsters was dramatic weight loss with clinical laboratory and histopathology demonstrating acute inflammation in the spleen, lymph node, liver and lung. Finally, we show that HRTV disease in hamsters can be prevented by the use of favipiravir, a promising broad-spectrum antiviral in clinical development for the treatment of influenza.

The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

“…Most clinical treatments are limited to therapeutic plasma exchange (Oh et al, 2017) and supportive care. A standard nucleoside analog class of inhibitors, such as ribavirin and favipiravir, has been tested for antiviral activities against SFTSV and HRTV infections, as they have been tested experimentally for other bunyaviral infections, including Hantaan virus (HTNV), Crimean Congo hemorrhagic fever virus (CCHFV), and Rift Valley Fever virus (RVFV) (Beaucourt and Vignuzzi, 2014;Delang et al, 2018;Tani et al, 2018;Westover et al, 2017). However, these nucleoside analogs are clinically ineffective (Liu et al, 2013) and are associated with adverse side effects.…”

First report of Lihan Tick virus (Phlebovirus, Phenuiviridae) in ticks, Colombia

“…Amblyomma americanum ticks appear to be the main vector for HRTV transmission. To date, more than 30 cases of HRTV infection, including two deaths, have been reported in the United States (13)(14)(15). The status of HRTV in subtropical and tropical regions of the Americas remains unknown.…”

Immune Modulation and Immune-Mediated Pathogenesis of Emerging Tickborne Banyangviruses

“…Although infection of C57/BL6 mice with SFTSV demonstrated SFTSV antigen positive-macrophage and platelets in the spleen of infected animals, the clinical signs do not mirror clinical symptoms seen in severe/fatal SFTS patients; infected C57/BL6 mice only exhibited leukopenia at one time point post-infection, which was resolved days later [64]. Susceptibility of animals to either SFTSV or HRTV is achieved when components of the innate immune system are abolished [65][66][67][68][69]. SFTSV caused lethal infection in IFN α/β receptor knockout (IFNAR −/− ) mice, and signal transduction and activator of transcription 2 knockout (STAT2 −/− ) mice and hamsters [66,68,69].…”

“…SFTSV caused lethal infection in IFN α/β receptor knockout (IFNAR −/− ) mice, and signal transduction and activator of transcription 2 knockout (STAT2 −/− ) mice and hamsters [66,68,69]. HRTV infection was lethal in IFN α/β/γ receptor knockout (AG129) mice [67]. Larger animal models such as macaques have been assessed for SFTSV infection as well, however, they do not exhibit all clinical signs seen in SFTS patients [66,70].…”