Abstract
Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (MΦs) were necessary for control of WNV infection. We selectively depleted splenic MΦs, but not draining lymph node MΦs, by injecting mice intravenously with clodronate liposomes several days prior to infecting them with WNV. Mice missing splenic MΦs succumbed to WNV infection after an increased and accelerated spread of virus to the spleen and the brain. WNV-specific Ab and CTL responses were normal in splenic MΦ-depleted mice; however, numbers of NK cells and CD4 and CD8 T cells were significantly increased in the brains of infected mice. Splenic MΦ deficiency led to increased WNV in other splenic innate immune cells including CD11b- DCs, newly formed MΦs and monocytes. Unlike other splenic myeloid subsets, splenic MΦs express high levels of mRNAs encoding the complement protein C1q, the apoptotic cell clearance protein Mertk, the IL-18 cytokine and the FcγR1 receptor. Splenic MΦ-deficient mice may be highly susceptible to WNV infection in part to a deficiency in C1q, Mertk, IL-18 or Caspase 12 expression.
Highlights
West Nile virus (WNV) is a positive-stranded, enveloped, RNA flavivirus and is a member of the Flavivirus genus that are usually transmitted by mosquitos; some members such as the closely-related Japanese encephalitis virus cause viral encephalitis, and central nervous system (CNS) infection (Zika virus; ZIKV) while other members such as dengue virus, yellow fever virus and ZIKV are associated with systemic diseases [1]
The depletion was restricted to MFs in the spleen, as MFs were not depleted from inguinal draining lymph node (LN) (Fig 1C, gating shown in Fig A in S1 File) or popliteal dLNs
We have shown that splenic MFs are required for successful resistance to WNV infection and that splenic MFs most likely contribute to resistance by sensing WNV RNA and restricting viral spread
Summary
West Nile virus (WNV) is a positive-stranded, enveloped, RNA flavivirus and is a member of the Flavivirus genus that are usually transmitted by mosquitos; some members such as the closely-related Japanese encephalitis virus cause viral encephalitis, and central nervous system (CNS) infection (Zika virus; ZIKV) while other members such as dengue virus, yellow fever virus and ZIKV are associated with systemic diseases [1]. There is neither a preventative vaccine nor an effective antiviral treatment for WNV [5, 6] Both innate and adaptive immune responses are required for controlling WNV infections [7,8]. Dendritic cells (DCs) and macrophages (MFs) can be infected by WNV and play a pivotal role in linking innate and adaptive immune responses [7, 15]. Local depletion of subcapsular sinus MFs had little or no effect on either B cell or CTL responses to WNV after it was injected into footpads of mice [18, 19]. We selectively depleted MFs from the spleen by injecting mice i.v. with CLL several days prior to infecting them with WNV. Splenic MF-deficient mice may be highly susceptible to WNV infection in part to a deficiency in the expression of one or more of these proteins
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