ABSTRACT
Many acute viral infections target tissue MÏs, yet the mechanisms of MÏ-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal MÏs restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection. With peritoneal cell populations infected with the filovirus, wild-type (WT) Ebola virus (EBOV), or a BSL2 model virus, recombinant vesicular stomatitis virus encoding Ebola virus glycoprotein (rVSV/EBOV GP), we examined the mechanism conferring protection. Here, we demonstrate that restricted virus replication in MÏs required CD154/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-γ production, which induced proinflammatory polarization of MÏs, protecting the cells from infection. These CD40-dependent events protected mice against virus challenge. CD40-/- mice were exquisitely sensitive to intraperitoneal challenge with a dose of rVSV/EBOV GP that was sublethal to CD40+/+ mice, exhibiting viremia within 12 h of infection and rapidly succumbing to infection. This study identifies a previously unappreciated role for MÏ-intrinsic CD40 signaling in controlling acute virus infection.
Subject(s)
CD40 Antigens/metabolism , Immunity, Innate , Macrophages/immunology , Macrophages/virology , RNA Viruses/physiology , Signal Transduction , Virus Diseases/immunology , Virus Replication/physiology , Acute Disease , Animals , CD40 Ligand/metabolism , Ebolavirus/physiology , Glycoproteins/immunology , Humans , Interferon-gamma/metabolism , Interleukin-12/biosynthesis , Mice, Inbred C57BL , Models, Biological , Peritoneum/pathology , Peritoneum/virology , TNF Receptor-Associated Factor 6/metabolism , Virus Diseases/virologyABSTRACT
During the 2013-2016 Ebola virus (EBOV) epidemic, a significant number of patients admitted to Ebola treatment units were co-infected with Plasmodium falciparum, a predominant agent of malaria. However, there is no consensus on how malaria impacts EBOV infection. The effect of acute Plasmodium infection on EBOV challenge was investigated using mouse-adapted EBOV and a biosafety level 2 (BSL-2) model virus. We demonstrate that acute Plasmodium infection protects from lethal viral challenge, dependent upon interferon gamma (IFN-γ) elicited as a result of parasite infection. Plasmodium-infected mice lacking the IFN-γ receptor are not protected. Ex vivo incubation of naive human or mouse macrophages with sera from acutely parasitemic rodents or macaques programs a proinflammatory phenotype dependent on IFN-γ and renders cells resistant to EBOV infection. We conclude that acute Plasmodium infection can safeguard against EBOV by the production of protective IFN-γ. These findings have implications for anti-malaria therapies administered during episodic EBOV outbreaks in Africa.
