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Less Severe Inflammation in Cyclic GMP–AMP Synthase (cGAS)-Deficient Mice with Rabies, Impact of Mitochondrial Injury, and Gut–Brain Axis
by
, , and
Pannatat Areekul
1,
Thansita Bhunyakarnjanarat
2,3,
Sakolwan Suebnuson
1,
Kollawat Somsri
2,4,
Somchanok Trakultritrung
3,
Kris Taveethavornsawat
3,
Tewin Tencomnao
5,6
,
Siwaporn Boonyasuppayakorn
3 and
Asada Leelahavanichkul
2,3,7,*
1
Department of Research and Development, Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok 10330, Thailand
2
Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
3
Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
4
Chulalongkorn University International Medical Program (CU-MEDi), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
5
Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age Natura), Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
6
Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
7
Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
*
Author to whom correspondence should be addressed.
Biology 2025, 14(11), 1583; https://doi.org/10.3390/biology14111583 (registering DOI)
Submission received: 6 September 2025
/
Revised: 7 November 2025
/
Accepted: 10 November 2025
/
Published: 12 November 2025
(This article belongs to the Special Issue The Role of Gut Microbiota in Human Metabolism and Disease)
Simple Summary
Rabies is a deadly viral disease that attacks the central nervous system and causes death once symptoms appear. Despite being an RNA virus, rabies might be associated with the cytosolic DNA receptor, partly through mitochondrial DNA damage. Here, rabies in cGAS-deficient (cGAS-/-) mice was less severe than wild-type (WT) mice at 7 days post-infection, as indicated by viral burdens in hippocampus, blood–brain barrier defect, and inflammatory gene expression. Serum proinflammatory cytokines and gut permeability defect (FITC-dextran assay) in rabies-infected mice of both mouse strains were similar despite different fecal microbiome patterns. In parallel, cGAS-/- macrophages demonstrated less severe mitochondrial damage (MitoSox, mitochondrial DNA, and extracellular flux analysis) than WT cells after 24 h of incubation with rabies. Further studies on mitochondrial injury and the gut–brain axis in relation to rabies are needed.
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.
Keywords:
rabies; microbiota; macrophages; cGAS; mitochondria
