Immune-Mediated Pathologies During Dengue Virus Infection

Flaviviruses are pathogens of global public health concern. They include dengue virus (DENV), West Nile virus (WNV), and zika virus (ZIKV). There are no approved US Food and Drug Administration antivirals for any flavivirus. The type I interferon (IFN-I) system is the first line of defense against viral infection. Activation of IFN-I signaling leads to the induction of hundreds of IFN stimulated genes (ISGs), the products of many serve to limit viral replication. One of these ISGs, Cytidine monophosphate kinase (CMPK2), is a potential anti-flavivirus drug target. CMPK2 is an interferon inducible enzyme with a mitochondrial localization sequence (MLS) at its N-terminus that localizes it to the mitochondria where it plays an important role in maintenance of cellular nucleic acid synthesis. The N-terminal domain (NTD) of human CMPK2 contains no known sequence homology to any other species and the C-terminal domain (CTD) is highly conserved across species and is responsible for its kinase activity. CMPK2 was reported to inhibit human immunodeficiency virus (HIV) and DENV replication. However, the molecular mechanism by which CMPK2 restricts these viruses is unclear. Here we show that expression of CMPK2 inhibits the replication of multiple flaviviruses including ZIKV.  We show that the mitochondrial localization of CMPK2 is required for its antiviral activity. Moreover, we show that the NTD of CMPK2 is sufficient for its antiviral activity thus the kinase activity is not required for CMPK2 antiviral function. Future studies will focus on the molecular mechanisms by which CMPK2 inhibits flavivirus replication. This knowledge will aid in the design of novel therapeutic antiviral strategies.

Learning objectives:
1. Identify CMPK2 as a host restriction factor for multiple flaviviruses.
2. To explain that the mitochondrial localization of CMPK2 is required for its antiviral function, and its kinase function is dispensable.