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Less Severe Inflammation in Cyclic GMP-AMP Synthase (cGAS)-Deficient Mice with Rabies, Impact of Mitochondrial
Pannatat Areekul1, Thansita Bhunyakarnjanarat2,3, Sakolwan Suebnuson1
1Department of Research and Development, Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok 10330, Thailand.
Abstract:
Activation of cGAS, a receptor recognizing cytosolic DNA, in macrophages might be associated with rabies (an RNA virus) through mitochondrial damage. A similar mortality rate was observed between cGAS-deficient (cGAS-/-) and wild-type (WT) mice post-CVS-11 strain injection. However, 2 out of 12 cGAS-/- mice (but not WT) survived for 15 days post-injection. At 7 days post-infection, less severe brain inflammation in cGAS-/- mice was demonstrated by the viral abundance in the hippocampus, the expression of proinflammatory genes (TNF-α and IL-1β), and the Evans blue dye assay (blood-brain barrier defect) with the presence of higher anti-inflammatory genes (TGF-β and arginase-1). Fecal Proteobacteria was more prominent in the infected WT mice, while serum cytokines (TNF-α and IL-1β) were similar in both mouse strains. There were less prominent responses against the rabies virus in cGAS-/- macrophages than in WT cells, as indicated by supernatant IL-6 and the gene expression of TLR-3, RIG-1, MDA-5, and iNOS. On the other hand, mitochondrial injury and cGAS activation were more prominent in WT macrophages over cGAS-/- cells, as indicated by cGAS expression, supernatant cGAMP (a secondary messenger of cGAS), and mitochondrial oxidative stress (MitoSox) together with a decrease in mitochondrial DNA and maximal respiration (extracellular flux analysis). In conclusion, (i) rabies-damaged mitochondria led to cGAS activation that was less severe in cGAS-/- than in WT, (ii) rabies-induced dysbiosis was demonstrated, and (iii) cGAS manipulation and gut-brain axis-associated inflammation warrants further investigation.
Insights
Mice lacking cGAS, a DNA sensor, showed reduced brain inflammation and improved survival following rabies virus infection, suggesting cGAS activation exacerbates disease severity.
Area of Science:
- Immunology
- Neuroscience
- Virology
Background:
- The cyclic GMP-AMP synthase (cGAS) pathway, a key sensor of cytosolic DNA, is implicated in innate immunity.
- Rabies virus, an RNA virus, can induce mitochondrial damage, potentially activating cGAS.
- The role of cGAS in rabies virus infection and its impact on neuroinflammation and survival remain unclear.
Purpose of the Study:
- To investigate the role of cGAS in the host response to rabies virus infection.
- To determine the effect of cGAS deficiency on neuroinflammation, viral load, and survival.
- To explore the interplay between mitochondrial damage, cGAS activation, and the gut-brain axis in rabies.
Main Methods:
- Comparison of wild-type (WT) and cGAS-deficient (cGAS-/-) mice infected with the CVS-11 rabies virus strain.
- Assessment of viral load, gene expression (pro-inflammatory and anti-inflammatory markers), blood-brain barrier integrity, and survival rates.
- Analysis of gut microbiota composition (fecal Proteobacteria) and serum cytokine levels.
- Evaluation of macrophage responses, mitochondrial injury, and cGAS pathway activation (cGAMP, MitoSox, mitochondrial respiration).
Main Results:
- cGAS-/- mice exhibited reduced brain inflammation, lower viral burden in the hippocampus, and enhanced expression of anti-inflammatory genes compared to WT mice.
- While overall mortality was similar, a subset of cGAS-/- mice survived longer.
- Rabies infection induced gut dysbiosis (increased Proteobacteria) in WT mice.
- WT macrophages showed more prominent mitochondrial injury and cGAS activation than cGAS-/- macrophages.
Conclusions:
- Mitochondrial damage during rabies infection activates cGAS, contributing to neuroinflammation and disease severity.
- cGAS deficiency mitigates rabies-induced neuroinflammation and enhances survival.
- Rabies virus infection is associated with gut dysbiosis, and the cGAS-mediated gut-brain axis warrants further investigation.
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