Cell-specific IRF-3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms

PLoS Pathog. 2007 Jul 27;3(7):e106. doi: 10.1371/journal.ppat.0030106.


Interferon regulatory factor (IRF)-3 is a master transcription factor that activates host antiviral defense programs. Although cell culture studies suggest that IRF-3 promotes antiviral control by inducing interferon (IFN)-beta, near normal levels of IFN-alpha and IFN-beta were observed in IRF-3(-/-) mice after infection by several RNA and DNA viruses. Thus, the specific mechanisms by which IRF-3 modulates viral infection remain controversial. Some of this disparity could reflect direct IRF-3-dependent antiviral responses in specific cell types to control infection. To address this and determine how IRF-3 coordinates an antiviral response, we infected IRF-3(-/-) mice and two primary cells relevant for West Nile virus (WNV) pathogenesis, macrophages and cortical neurons. IRF-3(-/-) mice were uniformly vulnerable to infection and developed elevated WNV burdens in peripheral and central nervous system tissues, though peripheral IFN responses were largely normal. Whereas wild-type macrophages basally expressed key host defense molecules, including RIG-I, MDA5, ISG54, and ISG56, and restricted WNV infection, IRF-3(-/-) macrophages lacked basal expression of these host defense genes and supported increased WNV infection and IFN-alpha and IFN-beta production. In contrast, wild-type cortical neurons were highly permissive to WNV and did not basally express RIG-I, MDA5, ISG54, and ISG56. IRF-3(-/-) neurons lacked induction of host defense genes and had blunted IFN-alpha and IFN-beta production, yet exhibited only modestly increased viral titers. Collectively, our data suggest that cell-specific IRF-3 responses protect against WNV infection through both IFN-dependent and -independent programs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation, Viral
  • Gene Silencing
  • Genetic Predisposition to Disease
  • Interferon Regulatory Factor-3 / antagonists & inhibitors*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-alpha / genetics
  • Interferon-alpha / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Macrophages / virology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / virology*
  • RNA, Messenger / metabolism
  • Virus Replication
  • West Nile Fever / immunology*
  • West Nile virus / immunology
  • West Nile virus / pathogenicity*


  • Interferon Regulatory Factor-3
  • Interferon-alpha
  • RNA, Messenger
  • Interferon-beta