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.

The SARS‐CoV‐2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'‐O‐ribose cap needed for viral immune escape. We find that the host cap 2'‐O‐ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS‐CoV‐2 replication. Using in silico target‐based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti‐SARS‐CoV‐2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co‐substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro , in ex vivo , and in a mouse infection model and synergizes with existing COVID‐19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection‐induced hyperinflammation and reduces lung fibrosis markers ex vivo . Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID‐19.

Orthomyxo- and bunyaviruses steal the 5′ cap portion of host RNAs to prime their own transcription in a process called “cap snatching.” We report that RNA modification of the cap portion by host 2′-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces , called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S -adenosyl- l -methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging highly pathogenic phlebovirus. The syndrome is characterized by the substantial production of inflammatory cytokines and chemokines, described as cytokine storm, which correlates with multi-organ failure and high mortality. SFSTV nonstructural (NSs) protein was suggested to mediate the pathogenesis by inhibiting antiviral interferon signaling in the host. However, whether SFTSV NSs protein mediates the induction of fatal cytokine storm remains unaddressed. We demonstrated that SFTSV NSs promotes the hyper-induction of cytokine/chemokine genes in vitro, reminiscent of cytokine storm. Using gene deletion and pharmacological intervention, we found that the induced cytokine storm is driven by the transcription factor NF-κB. Our investigation revealed that TANK-binding kinase 1 (TBK1) suppresses NF-κB signaling and cytokine/chemokine induction in its kinase activity-dependent manner, and that NSs sequesters TBK1 to prevent it from suppressing NF-κB, thereby promoting the activation of NF-κB and its target cytokine/chemokine genes. Of note, NF-κB inhibition suppressed the induction of pro-inflammatory cytokines in SFTSV-infected type I interferon (IFN-I) receptor 1-deficient (Ifnar1-/-) mice. These findings establish the essential role of NSs in SFTS pathogenesis and suggest NF-κB as a possible therapeutic target.