Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Abstract

Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, Lassa virus infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect vascular endothelial cells, but are generally considered noncytopathic. Thus, the mechanism of virus-induced vascular injury remains unclear. Using the lymphocytic choriomeningitis virus variant clone 13, a prototype of Lassa virus, we show here that lethal vascular leakage in susceptible mice was completely prevented by type I IFN receptor blockade. Therefore, approaches that target type I IFNs or effector molecules induced by these cytokines may be considered for the treatment of Lassa fever and other severe hemorrhagic viral illnesses.

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…This work supports an immune-stimulating, antiviral role for IFN-α as opposed to an immunosuppressive effect by IFN-β (328, 331, 332). IFN-β specifically inhibits antiviral T-cell responses and promotes viral persistence (331).…”

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

“…Moreover, IFN-α signaling promotes autoimmune (1), viral (2)(3)(4)(5), and bacterial disease pathogenesis (6). Suppression of IFN-α signaling has demonstrated efficacy in multiple autoimmune mouse models (7)(8)(9) and during influenza viral infection (4,10); however, the mechanism by which sphingosine 1-phosphate receptor 1 (S1PR1) signaling prevents IFN-α amplification during these disease states is currently unknown.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Vascular leakage, inflammatory cell infiltration, and endothelial cell loss all contribute to the death of animals. The heightened susceptibility to Clone 13 infection is dependent on type I IFN signaling because cytokine receptor blockade prevents mortality of the infected mice (185). Interestingly, IFN-a concentrations are comparable in bronchoalveolar lavage fluid of Armstrong-and Clone 13-infected mice, suggesting that the elevated type I IFN signaling, rather than production, underlies the lethal type I IFN-mediated immunopathology in this model.…”

“…Although New Zealand Black mice clear the Armstrong infection efficiently, they succumb rapidly to Clone 13 challenge (185). Vascular leakage, inflammatory cell infiltration, and endothelial cell loss all contribute to the death of animals.…”