Protection from plague via single dose administration of antibody to neutralize the type I interferon response

Abstract

Yersinia pestis is a gram-negative bacterium and the causative agent for the plague. Yersinia spp. use effector proteins of the type III secretion system (T3SS) to skew the host immune response toward a bacterial advantage during infection. Previous work established that mice which lack the type I IFN receptor (IFNAR), exhibit resistance to pulmonary infection by Y. pestis. In this work, we addressed the efficacy of a single dose administration of neutralizing antibody to IFNAR (MAR1) as a preventive treatment for plague. We show that single dose administration of MAR1 provides protection from mortality due to secondary septicemic plague where it appears to reduce the production of serum TNF during the disease phase. We further demonstrate that the T3SS effector protein YopJ is necessary for MAR1-induced protection, however IFNAR-dependent serum TNF was observed independent of YopJ. We further define tissue-specific anti-bacterial roles of IFNAR that are blocked by YopJ activity indicating that YopJ and IFNAR work in parallel to promote disease. The combined data suggest that therapeutic targeting of IFNAR signaling may reduce the hyper-inflammatory response associated with plague.