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MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease
Allison R Hanaford1, Elizaveta A Olkhova2, Ryan Liao1
1Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle WA USA.
Insights
Toll-like receptor (TLR) signaling does not drive Leigh syndrome (LS) progression. Inhibiting MyD88, a key TLR signaling molecule, only modestly improved survival in a mouse model of this severe pediatric mitochondrial disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Genetic mitochondrial diseases (GMDs) are diverse, with Leigh syndrome (LS) being the most common pediatric form, characterized by severe multi-systemic progressive neuroinflammation.
- Innate immune cells and peripheral macrophages contribute to LS brain pathology, but the mechanisms of immune activation are unclear.
- Mitochondrial components like RNA and DNA can trigger innate immune responses via Toll-like receptors (TLRs), suggesting a potential role in LS.
Purpose of the Study:
- To investigate the role of Toll-like receptor (TLR) signaling in the pathogenesis of Leigh syndrome (LS).
- To determine if MyD88-dependent TLR pathways contribute to disease onset and progression in a mouse model of LS.
Main Methods:
- Generated a mouse model deficient in both Ndufs4 (modeling LS) and MyD88 (inhibiting TLR signaling).
- Assessed the impact of MyD88 deficiency on survival, symptom onset, and disease progression in the Ndufs4 (-/-) mice.
- Administered prophylactic enrofloxacin to assess its effects on survival and disease course.
Main Results:
- Loss of MyD88 in Ndufs4 (-/-) mice led to statistically significant increases in survival and delayed some symptom onset, but the benefits were modest.
- MyD88-mediated immune signaling was not identified as a primary driver of LS pathogenesis.
- Prophylactic enrofloxacin treatment modestly decreased survival and accelerated disease, suggesting potential interactions between antibiotics and mitochondrial disease.
Conclusions:
- MyD88-dependent TLR signaling is not a primary driver of Leigh syndrome.
- Further investigation is warranted into the effects of antibiotics like enrofloxacin in the context of mitochondrial diseases.
- Understanding innate immune mechanisms in LS remains critical for developing effective treatments.
Abstract:
Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the Ndufs4(-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient Ndufs4(-/-)/MyD88(-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of MyD88 in Ndufs4(-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient MyD88(-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.
