Immune Modulation and Immune-Mediated Pathogenesis of Emerging Tickborne Banyangviruses

Abstract

In the last decade, the emergence of several, novel tickborne viruses have caused significant disease in humans. Of interest are the tickborne banyangviruses: Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV), and Guertu virus (GTV). SFTSV and HRTV infection in humans cause viral hemorrhagic fever-like disease leading to mortality rates ranging from 6–30% of the cases. The systemic inflammatory response syndrome (SIRS) associated with SFTSV infection is hypothesized to contribute significantly to pathology seen in patients. Despite the severe disease caused by HRTV and SFTSV, there are no approved therapeutics or vaccines. Investigation of the immune response during and following infection is critical to the generation of fully protective vaccines and/or supportive treatments, and overall understanding of viral immune evasion mechanisms may aid in the development of a new class of therapeutics.

Severe Fever with Thrombocytopenia Syndrome Virus NSs Interacts with TRIM21 To Activate the p62-Keap1-Nrf2 Pathway

“…Therefore, we speculate that NSs increases CD36 expression and its lipid uptake, which facilitates IB formation and, thereby, SFTSV replication. Furthermore, two recent studies have shown that bone marrow aspirates of patients with severe fever with thrombocytopenia syndrome (SFTS) display hemophagocytic lymphohistiocytosis (54) and that macrophages potentially induce the phagocytosis of SFTSV-bound platelets (55). Thus, the SFTSV NSs induces CD36 surface expression on macrophages and phagocytosis by macrophages, which may contribute to the development of thrombocytopenia.…”

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

“…L protein) and the viral envelope glycoproteins (GP), respectively, and the S segment encodes the nucleocapsid protein (N) and a nonstructural protein (NSs) in an ambisense manner [3]. Previous studies by us and others have showed that the NSs proteins of banyangviruses play important roles at the interface of virus-host interactions by interfering with the interferon (IFN) antiviral immune responses [13][14][15][16][17][18][19][20][21][22], thus indirectly bolstering viral replication. However, NSs is neither the essential replication protein nor the structural component.…”

Identifying target cells for a tick-borne virus that causes fatal hemorrhagic fever

“…SFTS, particularly in severe and fatal cases, can be considered a viral hemorrhagic fever (VHF) with systemic manifestations including thrombocytopenia, lymphocytopenia, systemic inflammatory response syndrome (SIRS), gastrointestinal symptoms, hepatic dysfunction, dissem-inated intravascular coagulopathy (DIC), and multiorgan failure with high CFRs (1,6,7). Although SFTS is a life-threatening disease, licensed vaccines and therapeutics specific to SFTS are currently unavailable.…”

“…An estimated CFR of SFTS in Japan is still as high as 27% (5), despite the current availability of a rapid diagnosis and intensive support therapies (6). Several immunological, hematological, and clinical profiling studies suggest that systemic inflammatory responses resembling SIRS, uncontrolled high viral load, and adaptive immune deficiency critically drive fatal disease progression (6)(7)(8)(9)(10). The complex interactions between SFTSV and host immune systems are most likely responsible for the catastrophic immunopathology of SFTS, which hampers effective treatment with antiviral interventions in the late disease stage of severe SFTS.…”

“…Numerous studies have indicated that HFV infects and activates monocytes/ macrophages, which are the primary target cells for HFV, leading to the expression of proinflammatory cytokines/chemokines (21). Moreover, it has been strongly postulated that HFVs activate macrophages that in part trigger SIRS in severe/fatal VHFs including SFTS (7,8,15,21), and play a critical role in inducing endothelial dysfunction, vascular leakage, coagulation abnormalities, hemophagocytic lympho-majority of the infected B cells were classswitched post-germinal center B cells, and those IgG-positive class-switched B cells also infiltrated systemic organs (11). These findings partially contradict the Song et al finding, in that a large fraction of plasmablasts in PBMCs from patients with fatal SFTS did not express IgM and IgG, suggesting that activated and differentiated B cells (i.e., plasmablasts and plasma cells) failed to IgG class switch, potentially explaining the inadequate B cell humoral response in fatalities (9).…”