RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family , SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1 MyD88 mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease. SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

“…Despite the high awareness within the medical community in SFTS-endemic areas, and the use of antiviral therapy such as ribavirin, the case fatality rate of SFTS is still as high as 15%, which is the same as other severe viral diseases including viral hemorrhagic fevers (15). In SFTS, inflammatory cytokine storms (11,(16)(17)(18)(19) as well as impairment of immune responses including innate immunity (14,(20)(21)(22)(23)(24)(25), antiviral T cell function (26), and antiviral humoral responses (27) have important roles in the pathogenic progress of lethal infections. Immune impairment and high viral loads are also characteristics of several other viral hemorrhagic fevers (28), but these diseases differ in terms of pathology and pathogenesis, about which little is known for SFTS.…”

Exploration of the mechanisms of Ge Gen Decoction against influenza A virus infection

“…* P < 0.05, ** P < 0.01 vs the model group. # P < 0.05, ## P < 0.01 vs the control group Toll-like receptors, which are pattern recognition receptors, play essential roles in recognizing pathogens and in inducing cascade signaling and immune responses [36][37] . TLR7 recognizes the single-stranded RNA of influenza viruses and triggers an immune response through a series of cascade reactions [35,38] .…”

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals

“…For HPV detection, the same samples were used to determine HPV genotype using the AnyplexTM II HPV28 real-time PCR (Seegene, Seoul, Korea) as described before 41 . HPV genotypes were classified as High (genotypes 16,18,31,33,35,39,45,51,52,56,58,59, 66 and 68) and low (6,11,40,42,43,44,54,61 and 70) oncogenic risk as described 41 .…”

“…ADAR1 has been found to regulate innate immune responses and the IFN-signaling pathway [8][9][10] . Loss of ADAR1 function causes a severe autoimmune disease, as A-to-I editing is an intracellular mechanism that distinguishes cellular versus pathogen-derived nucleic acids 11 .…”