Abstract Activation of the DNA-sensing STING axis by RNA viruses plays a role in antiviral response through mechanisms that remain poorly understood. Here, we show that the STING pathway regulates Nipah virus (NiV) replication in vivo in mice. Moreover, we demonstrate that following both NiV and measles virus (MeV) infection, IFNγ-inducible protein 16 (IFI16), an alternative DNA sensor in addition to cGAS, induces the activation of STING, leading to the phosphorylation of NF-κB p65 and the production of IFNβ and interleukin 6. Finally, we found that paramyxovirus-induced syncytia formation is responsible for loss of mitochondrial membrane potential and leakage of mitochondrial DNA in the cytoplasm, the latter of which is further detected by both cGAS and IFI16. These results contribute to improve our understanding about NiV and MeV immunopathogenesis and provide potential paths for alternative therapeutic strategies.
Abstract NK lymphocytes and type I IFN (IFN‐α/β) are major actors of the innate anti‐viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN‐inducing TLR3 agonist. PolyI:C plus IL‐2/IL‐12 induced IFN‐β (but not IFN‐α) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti‐IFNAR1 or anti‐IFN‐β Ab prevented the production of IFN‐γ induced by polyI:C plus IL‐2/IL‐12. Similarly, IFN‐γ production induced by polyI:C plus IL‐12 was reduced in NK cells isolated from IFNAR1 −/− compared with WT mice. The ability of polyI:C plus IL‐12 to induce IFN‐γ production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL‐2/IL‐12, produce IFN‐β that induce, in an autocrine manner, the production of IFN‐γ and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.
Weekly injections of monoclonal antibodies (mAb) to T-cell regulatory molecules, into animals challenged with a progressively growing epithelial cell tumor 3152-PRO, decreased tumor incidence and caused significantly slower tumor growth, compared with animals given identical treatments of control rat mAb. Some of the mAb showed significant synergy with rIL-2 in the successful therapeutic treatment of 3152-PRO. Furthermore, spleen cells from treated mice generated strong tumor-specific cytotoxic activity. The successful elimination of progressively growing 3152-PRO tumor rendered animals specifically resistant to a secondary challenge of 3152-PRO tumor cells, but not to 2237-PRO or 3256-PRO, two other, noncrossreactive tumors.
We conducted an in-depth characterization of the Nipah virus (NiV) isolate previously obtained from a Pteropus lylei bat in Cambodia in 2003 (CSUR381). We performed full-genome sequencing and phylogenetic analyses and confirmed CSUR381 is part of the NiV-Malaysia genotype. In vitro studies revealed similar cell permissiveness and replication of CSUR381 (compared with 2 other NiV isolates) in both bat and human cell lines. Sequence alignments indicated conservation of the ephrin-B2 and ephrin-B3 receptor binding sites, the glycosylation site on the G attachment protein, as well as the editing site in phosphoprotein, suggesting production of nonstructural proteins V and W, known to counteract the host innate immunity. In the hamster animal model, CSUR381 induced lethal infections. Altogether, these data suggest that the Cambodia bat-derived NiV isolate has high pathogenic potential and, thus, provide insight for further studies and better risk assessment for future NiV outbreaks in Southeast Asia.
Analysis of measles virus (MV) pathogenesis requires the development of an adequate small animal model of MV infection. In this study, permissivity to MV infection was compared in human and transgenic murine T lymphocytes, expressing different levels of the human MV receptor, CD46. Whereas MV binding and entry correlated with CD46 expression, higher levels of MV replication were always observed in human T lymphocytes. This suggests the existence of intracellular factors, acting posterior to virus entry, that could limit MV replication in murine lymphocytes and should be considered when creating new animal models of MV infection.
Atopic dermatitis (AD) is a chronic inflammatory skin disease, affecting 10–20% of children. Measles vaccination has been reported to have contradictory effects on incidence of AD in children. Therefore, we performed the first prospective, double‐blind, placebo‐controlled study to analyze the evolution of AD in infants after measles vaccination. The study included 12 infants (10–14 months old) with AD, randomly assigned to two groups: while the first group received a single dose of a standard measles vaccine ROUVAX, the second was treated with placebo (vehicle). Infants were followed‐up for 6 months after administration of ROUVAX/placebo for the clinical signs associated with AD, by determination of SCORAD index. In addition, serum was taken before vaccination and 1 month later to determine the presence of seroconversion and to analyze the progression of serum levels of CCL18 (PARC) and E‐selectin, known to be distinct serum markers that reflect clinical features of AD. In the vaccinated group, five of six children seroconverted 1 month after treatment and one infant showed a 50% improvement of SCORAD. Serum levels of CCL18 were significantly decreased in two treated infants (of four analyzed for this group) and E‐selectin slightly decreased in one infant (of three analyzed by this test). In placebo‐treated group the SCORAD improved in one patient and serum levels of CCL18 and E‐selectin did not change. These data suggest that measles vaccination not only does not aggravate AD, but may also improve some of the immunological parameters of this allergic disease. Inclusion of a higher number of patients in a similar study should give a more comprehensive overview of the benefit of measles vaccination on the clinical evolution of AD patients, and potentially open new avenues to the clinical application of the anti‐inflammatory effect of measles virus proteins.
