Phenylacetylglutamine mediates Cerebrovascular dysfunction in SARS-CoV-2 infection combined with Mthfr deficiency
Description: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have a profound impact on neurological health, with cerebrovascular disorders (CVDs) and cognitive deficits identified as major complications of COVID-19, particularly in the elderly with sex-specific effects. Interestingly, common polymorphisms (20-40% worldwide prevalence) in Methylene tetrahydrofolate reductase (MTHFR), which impair its function, are associated with increased risk and severity of acute and post-acute COVID-19, as well as enhanced risk of CVDs, suggesting it as a genetic risk factor for COVID-19. Mthfr-deficient (Mthfr+/-) mice, which model these polymorphisms, exhibit cognitive impairment and cerebrovascular deficits with advancing age. MTHFR is a key enzyme in folate metabolism that affects several physiological processes, including nucleotide synthesis, epigenetic regulation, antioxidant defense, and amino acid homeostasis. Emerging evidence also links gut microbiome dysbiosis in COVID-19-associated neuropathology. Specifically, phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, is associated with severe long COVID symptoms and adverse patient outcomes. PAGln levels increase with age, which can lead to major cardiovascular events, endothelial cell dysfunction and cognitive impairments. Notably, a probiotic formulation containing Lactobacillus spp (plantarum, rhamnosus, reuteri 1E) and Bifidobacterium spp. (bifidum, and animalis), termed L3B2, reduces PAGln levels in mice, suggesting its therapeutic potential. Our preliminary data show that acute experimental infection with mouse-adapted SARS-CoV-2 (MA10) in Mthfr+/– mice elevates PAGln serum levels and causes cerebrovascular deficits characterized by neuroinflammation and blood-brain barrier disruption. We hypothesize that Mthfr deficiency, combined with SARS-CoV-2 infection, worsens gut microbiota dysbiosis, elevates PAGln levels, and leads to PAGln-mediated cerebrovascular deficits and cognitive impairment and propose the following aims: 1. Investigate the role of altered metabolites (including PAGln) and gut microbiota dysbiosis in SARS-CoV-2-induced cerebrovascular dysfunction and cognitive deficits in adult and aged Mthfr+/- mice. 2. Determine the impact of PAGln on cerebrovascular pathology and cognitive deficits in mice. 3. Investigate whether probiotic L3B2 supplementation reduces PAGln-mediated cerebrovascular pathology and cognitive deficits in SARS-CoV-2 infected Mthr+/- mice.
Funder: American Heart Association
Amount: $231,000
Funding type: fellowship
Funder scheme: Career Development Award
Start date: 2026-04-01
End date: 2029-03-31
Investigators: Meenakshi Umar, Meenakshi Umar
Institution: Tulane University Health Sciences Center
Funded outputs count: 0
Funder award ID: 26CDA1609846
OpenAlex ID: G7310600191