Infection of Pro- and Anti-Inflammatory Macrophages by Wild Type and Vaccine Strains of Measles Virus: NLRP3 Inflammasome Activation Independent of Virus Production

In humans and non-human primates, wild type (WT) measles virus (MeV) replicates extensively in lymphoid tissue and induces an innate response characteristic of NF-kappa B and inflammasome activation without type I interferon. In contrast, the live attenuated MeV vaccine (LAMV) replicates poorly in lymphoid tissue with little detectable in vivo cytokine production. To characterize the innate responses of macrophages to WT MeV and LAMV infection, we analyzed primary human monocyte-derived macrophages and phorbol myristic acid-matured monocytic THP-1 cells (M0) polarized to inflammatory (M1) and anti-inflammatory (M2) phenotypes 24 h after MeV infection. LAMV infected macrophages more efficiently than WT MeV but produced less virus than WT MeV-infected macrophages. Both strains induced production of NF-kappa B-responsive cytokines IL-6 and TNF alpha and inflammasome products IL-1 beta and IL-18 without evidence of pyroptosis. Analysis of THP-1 cells deficient in inflammasome sensors NOD-like receptor pyrin (NLRP)3, IFN-gamma-inducible protein 16 (IFI16) or absent in melanoma (AIM)2; adaptor apoptosis-associated speck-like protein containing a CARD (ASC) or effector caspase 1 showed that IL-18 production was dependent on NLRP3, ASC, and caspase 1. However, M1 cells produced IL-1 beta in the absence of ASC or caspase 1 indicating alternate pathways for MeV-induced pro-IL-1 beta processing. Therefore, the innate response to in vitro infection of macrophages with both LAMV and WT MeV includes production of IL-6 and TNF alpha and activation of the NLRP3 inflammasome to release IL-1 beta and IL-18. LAMV attenuation impairs production of infectious virus but does not reduce ability to infect macrophages or innate responses to infection.