Distinct negative-sense RNA viruses induce a common set of transcripts encoding proteins forming an extensive network.

The large group of negative-strand RNA viruses (NSVs) comprises many important pathogens. To identify conserved patterns in host responses, we systematically compared changes in the cellular RNA levels after infection of human hepatoma cells with nine different NSVs of different virulence degrees. RNA sequencing experiments indicated that the amount of viral RNA in host cells correlates with the number of differentially expressed host cell transcripts.

Protection of eIF2B from inhibitory phosphorylated eIF2: A viral strategy to maintain mRNA translation during the PKR-triggered integrated stress response.

The integrated stress response (ISR) protects cells from a variety of insults. Once elicited (e.g.

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection.

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals induce human NLRP1 inflammasome assembly by activating MAP kinase p38: While the ribotoxic stress response to UV and microbial molecules exclusively activates p38 through MAP3K ZAKα, infection with arthropod-borne alphaviruses, including Semliki Forest and Chikungunya virus, activates p38 through ZAKα and potentially other MAP3K.

Shielding the mRNA-translation factor eIF2B from inhibitory p-eIF2 as a viral strategy to evade protein kinase R-mediated innate immunity.

The interferon-regulated kinase PKR (protein kinase RNA-activated) is a potent innate immune factor against a broad range of viruses. Being part of the integrated stress response (ISR), its restrictive effect is predominantly exerted by phosphorylating the eukaryotic translation-initiation factor eIF2, thereby turning it into an inhibitor of translation-initiation factor eIF2B. A plethora of viruses are known to evade the shutdown of cellular mRNA translation by interfering either with PKR activation or with eIF2 phosphorylation.

Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo.

Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron-sized "specks" to maximize caspase-1 activation and the maturation of IL-1 cytokines. Caspase-1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space.

Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B.

Viral infection triggers activation of the integrated stress response (ISR). In response to viral double-stranded RNA (dsRNA), RNA-activated protein kinase (PKR) phosphorylates the translation initiation factor eIF2, converting it from a translation initiator into a potent translation inhibitor and this restricts the synthesis of viral proteins. Phosphorylated eIF2 (eIF2-P) inhibits translation by binding to eIF2's dedicated, heterodecameric nucleotide exchange factor eIF2B and conformationally inactivating it.

NSs of the mildly virulent sandfly fever Sicilian virus is unable to inhibit interferon signaling and upregulation of interferon-stimulated genes.

Phleboviruses (order , family ) are globally emerging arboviruses with a wide spectrum of virulence. Sandfly fever Sicilian virus (SFSV) is one of the most ubiquitous members of the genus and associated with a self-limited, incapacitating febrile disease in travellers and military troops. The phleboviral NSs protein is an established virulence factor, acting as antagonist of the antiviral interferon (IFN) system.

Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein.

eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition.

RNA-activated protein kinase (PKR) is a major innate immune factor that senses viral double-stranded RNA (dsRNA) and phosphorylates eukaryotic initiation factor (eIF) 2α. Phosphorylation of the α subunit converts the eIF2αβγ complex into a stoichiometric inhibitor of eukaryotic initiation factor eIF2B, thus halting mRNA translation. To escape this protein synthesis shutoff, viruses have evolved countermechanisms such as dsRNA sequestration, eIF-independent translation by an internal ribosome binding site, degradation of PKR, or dephosphorylation of PKR or of phospho-eIF2α.

NSs Protein of Sandfly Fever Sicilian Phlebovirus Counteracts Interferon (IFN) Induction by Masking the DNA-Binding Domain of IFN Regulatory Factor 3.

Sandfly fever Sicilian virus (SFSV) is one of the most widespread and frequently identified members of the genus (order , family ) infecting humans. Being transmitted by sandflies, SFSV causes a self-limiting, acute, often incapacitating febrile disease ("sandfly fever," "Pappataci fever," or "dog disease") that has been known since at least the beginning of the 20th century. We show that, similarly to other pathogenic phleboviruses, SFSV suppresses the induction of the antiviral type I interferon (IFN) system in an NSs-dependent manner.

Phleboviruses and the Type I Interferon Response.

The genus Phlebovirus of the family Bunyaviridae contains a number of emerging virus species which pose a threat to both human and animal health. Most prominent members include Rift Valley fever virus (RVFV), sandfly fever Naples virus (SFNV), sandfly fever Sicilian virus (SFSV), Toscana virus (TOSV), Punta Toro virus (PTV), and the two new members severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV). The nonstructural protein NSs is well established as the main phleboviral virulence factor in the mammalian host.