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Published on: April 28, 2019
Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain
Jessica K Roth-Cross1, Susan J Bender, Susan R Weiss
1Department of Microbiology, University of Pennsylvania, School of Medicine, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6076, USA.
Abstract:
The coronavirus mouse hepatitis virus (MHV) induces a minimal type I interferon (IFN) response in several cell types in vitro despite the fact that the type I IFN response is important in protecting the mouse from infection in vivo. When infected with MHV, mice deficient in IFN-associated receptor expression (IFNAR(-/-)) became moribund by 48 h postinfection. MHV also replicated to higher titers and exhibited a more broad tissue tropism in these mice, which lack a type I IFN response. Interestingly, MHV induced IFN-beta in the brains and livers, two main targets of MHV replication, of infected wild-type mice. MHV infection of primary cell cultures indicates that hepatocytes are not responsible for the IFN-beta production in the liver during MHV infection. Furthermore, macrophages and microglia, but not neurons or astrocytes, are responsible for IFN-beta production in the brain. To determine the pathway by which MHV is recognized in macrophages, IFN-beta mRNA expression was quantified following MHV infection of a panel of primary bone marrow-derived macrophages generated from mice lacking different pattern recognition receptors (PRRs). Interestingly, MDA5, a PRR thought to recognize primarily picornaviruses, was required for recognition of MHV. Thus, MHV induces type I IFN in macrophages and microglia in the brains of infected animals and is recognized by an MDA5-dependent pathway in macrophages. These findings suggest that secretion of IFN-beta by macrophages and microglia plays a role in protecting the host from MHV infection of the central nervous system.
Insights
Mouse hepatitis virus (MHV) triggers a weak type I interferon (IFN) response in cells, but this immune signaling is crucial for protection. Macrophages and microglia in the brain recognize MHV via MDA5, producing IFN-beta to combat central nervous system infection.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Type I interferon (IFN) is vital for antiviral defense but is minimally induced by mouse hepatitis virus (MHV) in vitro.
- Mice lacking the IFN-associated receptor (IFNAR(-/-)) show severe MHV disease, highlighting IFN's in vivo importance.
Purpose of the Study:
- To investigate the cellular sources and recognition pathways of type I IFN during MHV infection.
- To understand the role of IFN-beta in protecting the central nervous system from MHV.
Main Methods:
- Infection of IFNAR(-/-) mice to assess the in vivo role of type I IFN.
- Analysis of IFN-beta production in primary cell cultures (hepatocytes, macrophages, microglia, neurons, astrocytes).
- Quantification of IFN-beta mRNA in macrophages lacking various pattern recognition receptors (PRRs).
Main Results:
- MHV infection led to severe disease and broader tissue tropism in IFNAR(-/-) mice.
- Hepatocytes did not produce IFN-beta in the liver; macrophages and microglia produced IFN-beta in the brain.
- MDA5, a pattern recognition receptor, was essential for MHV recognition and IFN-beta induction in macrophages.
Conclusions:
- Macrophages and microglia are key producers of IFN-beta in the brain during MHV infection.
- The MDA5-dependent pathway mediates MHV recognition in macrophages.
- IFN-beta secreted by brain-resident immune cells contributes to host defense against MHV-induced central nervous system disease.
