HSV-1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes

ABSTRACT

Inflammasomes are multiprotein complexes that recognize pathogens and pathogen- or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory IL-1β, IL-18, and IL-33 cytokines, which in turn activate other immune gene expression and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules such as NLRP3 and AIM2, or nuclear sensor IFI16, an adaptor protein, ASC, and an effector protein, procaspase-1. Herpes simplex virus (HSV-1), a ubiquitous virus that infects humans and establishes life long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early during in vitro infection of human foreskin fibroblasts (2-4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1β. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times post infection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2 and ASC levels were not decreased. Also, caspase-1 was “trapped” in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1β was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.