Virus envelope glycoprotein targeting bispecific T cell engager protects mice from lethal severe fever with thrombocytopenia virus infection

Severe fever with thrombocytopenia syndrome virus (SFTSV) causes a highly fatal disease with no approved antiviral therapy. This study first analyzed peripheral T cell responses in SFTS patients and found that fatal cases showed marked T cell depletion, reduced cytotoxicity, and severe exhaustion, particularly in CD4⁺ T cells. These findings suggest that impaired T cell immunity contributes to disease severity. To restore antiviral T cell function, they developed a bispecific T cell engager (BiTE) targeting CD3 and the SFTSV envelope glycoprotein Gn. In vitro assays demonstrated that the 3A5 BiTE efficiently redirected human T cells to eliminate SFTSV-infected cells and significantly reduced viral replication. Blocking IFN-γ largely abolished this antiviral effect, whereas inhibition of granzyme B or perforin had minimal impact, indicating an IFN-γ–dependent mechanism. In a lethal mouse model, 3A5 BiTE treatment markedly improved survival and reduced viral loads in serum and organs. BiTE therapy also altered immune cell composition, increasing functional T cells while reducing inflammatory neutrophils and regulatory T cells. These results demonstrate that virus-specific BiTEs can revitalize T cell immunity and provide effective protection against lethal SFTSV infection.
(MN)

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

Tick-borne thogotoviruses are highly sensitive to the human interferon-induced restriction factor myxovirus resistance protein A (MxA), which limits their zoonotic potential. Here, Fuchs et al. systematically evaluated the MxA sensitivity of ten globally distributed thogotovirus isolates using cell culture, viral minigenome assays, and mouse infection models. While all THOV-like viruses were potently inhibited by MxA, the Nigerian isolate Jos virus (JOSV) showed complete resistance in MxA-expressing cells and in MxA-transgenic mice. Polymerase reconstitution assays identified the viral nucleoprotein (NP) as the determinant of MxA sensitivity. Chimeric NP analysis and targeted mutagenesis mapped MxA escape to two adjacent NP residues (G327 and R328). Introduction of a single substitution, R328V, into the otherwise MxA-sensitive SiAr126 strain fully abolished MxA-mediated restriction without compromising viral replication or fitness. Recombinant SiAr126-NP(R328V) replicated efficiently in MxA-expressing cells and caused lethal infection in MxA-transgenic mice, whereas wild-type virus was completely restricted. Mechanistically, co-immunoprecipitation and imaging studies demonstrated that the R328V mutation disrupts NP–MxA interaction, permitting nuclear import of viral ribonucleoproteins. Collectively, these data provide direct experimental evidence that a single amino acid change enables thogotoviruses to evade human innate immunity, substantially increasing their virulence and zoonotic potential
(TMR)

Thrombocytopenia in Severe Fever with Thrombocytopenia Syndrome Due to Platelets with Altered Function Undergoing Cell Death Pathways

Severe Fever with Thrombocytopenia Syndrome (SFTS) is an important tick borne viral disease in East Asia. An important clinical manifestation of SFTS is thrombocytopenia. To understand the mechanism by which SFTS virus causes thrombocytopenia, platelets from surviving and fatal human cases, as well as from a C57/BL6 mice model were analyzed. Platelet alterations were assessed through RNA transcriptome profiling, ELISA, flow cytometry and quantitative RT-PCR. In humans transcriptome analysis showed that platelets upregulated genes related to type 1 interferon signaling and neutrophil activation. These changes were more significant in survivors than fatal cases. Immunoassays demonstrated increased levels of platelet activation marker CD62P and platelet–neutrophil aggregates. This occur because platelets activate neutrophils to form extracellular traps which capture the virus but result in massive platelets destruction. Platelets underwent multiple death pathways, most notably pyroptosis. In contrast while mice had thrombocytopenia there was no detection of platelet activation or viral proteins in platelets. Instead of widespread death, mice platelets triggered adaptive immunity which led to clearance of viremia through antibodies. 
(SWM)

Interferon and TLR genes, but not endogenous bornavirus-like elements, limit BoDV1 replication after intracerebral infection

Borna disease virus 1 (BoDV1) is a neurotropic RNA virus, but the host factors limiting its replication in the brain are not fully understood. Endogenous bornavirus-like elements (EBLNs) have been proposed to suppress BoDV1 through piRNA-mediated mechanisms. This study aimed to evaluate the relative roles of interferon signaling, Toll-like receptor pathways, and EBLN-derived piRNAs in controlling BoDV1 replication in vivo. Neonatal mice were intracerebrally infected with a GFP-expressing recombinant BoDV1. Viral replication was analyzed in wild-type mice and knockout mice lacking the interferon-γ receptor (Ifngr1), Toll-like receptor 7 (Tlr7), or all piRNA-producing EBLNs. Viral RNA levels and infected brain cells were assessed by RT-qPCR and histological analyses. BoDV1 replication was significantly increased in Ifngr1- and Tlr7-deficient mice, indicating that interferon-γ signaling and TLR7-dependent innate immunity restrict viral growth in the brain. In contrast, deletion of EBLN-derived piRNAs had no effect on viral replication. These results demonstrate that classical immune pathways, rather than endogenous viral elements, are the primary factors limiting BoDV1 replication after intracerebral infection.
(MN)

A novel accessory gene product of tick-borne Dhori-Orthomyxovirus, encoded by overlooked spliced transcripts of RNA segment 6

This study identifies and characterizes a previously unrecognized accessory gene product encoded by RNA segment 6 of Dhori virus (DHOV), a tick-borne orthomyxovirus within the genus Thogotovirus. Contrary to the long-held assumption that Dhori-like viruses do not use RNA splicing, the authors demonstrate that DHOV segment 6 undergoes splicing in both mammalian and tick cells. This splicing event generates a novel protein, termed M2-248, which consists of the N-terminal portion of the canonical matrix protein fused to a unique C-terminal sequence translated from a −1 shifted reading frame. The splicing sites and the M2-specific sequence are conserved among Dhori-like viruses. M2-248 expression was confirmed by RT-PCR, mass spectrometry, and western blotting, and the protein was shown to be incorporated into released virions and to interact with the matrix protein. Using reverse genetics, the authors generated recombinant DHOV lacking M2 expression and demonstrated that loss of M2 does not impair viral replication, assembly, or particle morphology in cell culture. However, M2-deficient virus exhibited markedly reduced virulence in mice, with improved survival despite only modest reductions in viral replication and inflammatory cytokine induction. Functional analyses showed that, unlike the related Thogotovirus ML protein, M2-248 does not act as a type I interferon antagonist. These findings reveal an unexpected coding strategy in Dhori-like orthomyxoviruses and identify M2-248 as a novel virulence factor acting through an interferon-independent mechanism.
(TMR)

Comparison of the biological properties of bat-derived filovirus envelope glycoproteins

Several novel filoviruses have recently been identified in bats, including Lloviu, Bombali, Mengla, and Dehong viruses, but their biological properties and zoonotic potential remain unclear. This study aimed to compare the functional characteristics of envelope glycoproteins (GPs) from bat-derived filoviruses with those of pathogenic filoviruses such as Ebola and Marburg viruses. Using virus-like particles and vesicular stomatitis virus pseudotypes, the authors examined GP-mediated particle formation, antigenicity, cell entry mechanisms, and cell tropism. All bat-derived filovirus GPs supported the formation of filamentous particles and mediated cellular entry via known filovirus attachment factors, including TIM-1 and C-type lectins, although entry efficiency was generally lower than that of Ebola virus GP. Antigenic analyses showed limited cross-reactivity between bat-derived filovirus GPs and antibodies against Ebola or Marburg viruses, though partial neutralization was observed for some GPs. Infection assays revealed that bat-derived filovirus GPs could mediate entry into a broad range of mammalian cells, including human cells, while displaying virus- and host-specific differences.
(MN)

Experimental challenge of African green monkeys with contemporary Hendra virus isolates produces divergent clinical disease

Hendra virus (HeV) is a highly pathogenic zoonotic paramyxovirus that causes severe disease in humans and animals. While all confirmed human cases have been associated with genotype 1 (HeV-g1), a genetically distinct genotype 2 (HeV-g2) has recently been identified in bats and horses, raising questions about its pathogenic potential. This study aimed to compare the disease severity caused by contemporary HeV-g1 and HeV-g2 isolates using the African green monkey (AGM) model. AGMs were experimentally infected via intranasal and intratracheal routes with either HeV-g1 or HeV-g2 and monitored for clinical signs, survival, viral replication, pathology, and immune responses. HeV-g1 infection resulted in uniformly severe and lethal disease, characterized by acute respiratory distress, systemic viral dissemination, and extensive tissue pathology. In contrast, HeV-g2 infection caused markedly milder disease, with most animals surviving and showing limited clinical signs, lower viral loads, and minimal pathological changes. Importantly, HeV-g2–infected animals mounted robust neutralizing antibody responses without detectable infectious virus in tissues. These findings demonstrate that contemporary HeV isolates can cause divergent clinical outcomes and indicate that HeV-g2 has reduced pathogenicity in primates compared with HeV-g1, providing critical insights for risk assessment and preparedness strategies.
(MN)