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Selective inhibition of COX-2 is beneficial to mice infected intranasally with VSV
Nannan Chen1, Andrew Restivo, Carol Shoshkes Reiss
1Department of Biology, New York University, NY 10003, USA.
Abstract:
Cyclooxygenase (COX) is the key enzyme for prostaglandin (PG) synthesis. PGs are mediators of many critical physiological and inflammatory responses. There are two isoforms, COX-1 and COX-2, both of which are constitutively expressed in the central nervous system (CNS). Studies have shown that COX-1 and COX-2 are involved in physiological and pathological conditions of the brain. However, little is known about the role(s) of COX in the host defense system against a viral infection in the CNS. In this report, we used Vesicular Stomatitis Virus (VSV) induced acute encephalitis to distinguish between the contribution(s) of the two isoforms. COX-2 activity was inhibited with a COX-2 selective drug, celecoxib (Celebrex), and COX-1 was antagonized with SC560. We found that inhibition of COX-2 led to decreased viral titers, while COX-1 antagonism did not have the same effect at day 1 post infection. 5-lipooxygenase (5-LO) expression and neutrophil recruitment in the CNS were increased in celecoxib-inhibited mice. Furthermore, mice treated with celecoxib expressed more Nitric Oxide Synthase-1 (NOS-1), a crucial component of the innate immune system in the restriction of VSV propagation. The expression of type 1 cytokines, IFN-gamma and IL-12, were also increased in celecoxib-treated mice.
Insights
Inhibition of cyclooxygenase-2 (COX-2) enhances the central nervous system's antiviral defense against Vesicular Stomatitis Virus (VSV) by boosting innate immunity. COX-1 inhibition did not show similar protective effects.
Area of Science:
- Neuroimmunology
- Virology
- Enzymology
Background:
- Cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2, are crucial for prostaglandin synthesis and are present in the central nervous system (CNS).
- Their roles in CNS viral infections and host defense remain largely uncharacterized.
- Prostaglandins mediate physiological and inflammatory responses within the brain.
Purpose of the Study:
- To investigate the distinct roles of COX-1 and COX-2 in the host immune response to viral encephalitis in the CNS.
- To determine the impact of inhibiting COX-2 on viral load and immune cell infiltration during Vesicular Stomatitis Virus (VSV) infection.
Main Methods:
- Utilized a mouse model of Vesicular Stomatitis Virus (VSV)-induced acute encephalitis.
- Administered a selective COX-2 inhibitor (celecoxib) and a COX-1 antagonist (SC560).
- Assessed viral titers, immune cell recruitment (neutrophils), and expression of key immune mediators like 5-lipooxygenase (5-LO), Nitric Oxide Synthase-1 (NOS-1), IFN-gamma, and IL-12.
Main Results:
- Inhibition of COX-2 with celecoxib significantly reduced viral titers in the CNS.
- COX-1 antagonism did not yield similar reductions in viral load.
- Celecoxib treatment led to increased expression of 5-LO, NOS-1, IFN-gamma, and IL-12, alongside enhanced neutrophil recruitment.
Conclusions:
- COX-2 plays a detrimental role in the CNS antiviral immune response against VSV.
- Selective COX-2 inhibition enhances innate immunity, promoting viral restriction through increased inflammatory mediators and immune cell infiltration.
- Targeting COX-2 may represent a therapeutic strategy for CNS viral infections.
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