Biology subjects

Sundararaj, K. P.

Publications and source records attributed to Sundararaj, K. P..

3 recordsLinked to original sources

bioRxiv2026

Cocaine-Enriched Oral Streptococcus parasanguinis Promotes Neuroimmune Dysfunction and Memory Impairment

Chronic cocaine use is associated with neuroinflammation and cognitive dysfunction, but the underlying mechanisms remain unclear. We previously identified oral enrichment of Streptococcus parasanguinis (SP) and other species in individuals with cocaine use disorder (CUD), and here demonstrate that cocaine selectively enhanced SP growth in vitro. To investigate causality, antibiotic-pretreated wild-type C57BL/6 mice received chronic oral inoculation of SP, S. salivarius, Neisseria flavescens, or vehicle. SP-treated mice exhibited spatial memory impairment, increased brain IL-1{beta}, and non-region-specific microglial activation, without detectable bacterial translocation into the brain. While amyloid-associated signaling changes were observed across all bacterial treatment groups, only SP induced cognitive deficits and neuroinflammation. Untargeted metabolomics identified distinct SP-associated oral-to-brain metabolite signatures, including cysteine S-sulfate (CSS) and altered histamine-associated metabolites. CSS and histamine induced neuroinflammatory and amyloid-associated responses in vitro. Together, these findings identify a cocaine-associated oral pathobiont that promotes neuroinflammation and neurodegeneration, suggesting a novel oral microbiome-brain axis in CUD.

neuroscience↗

bioRxiv2025

Characterize Oral-to-Blood Microbial DNA Translocation in Individuals with Cocaine Use Disorder

BackgroundCocaine disrupts gut barriers in animal models, potentially enabling microbial translocation and inflammation in the periphery and central nervous system (CNS), but its direct role in inducing inflammation remains controversial. This study aimed to determine if the oral cavity is a source of circulating microbial DNA translocation in individuals with current cocaine use disorder (CUD). ResultsA cross-sectional case-control study was conducted, comparing CUD and demographically matched non-drug controls. Ten CUD (via smoking or vaping) and 24 controls provided paired saliva and blood samples. Microbial 16S rRNA V4 region was sequenced in isolated microbial DNA from saliva and plasma. Single-cell RNA sequencing (scRNAseq) was analyzed in human peripheral blood mononuclear cells. Saliva from CUD, but not plasma, exhibited reduced alpha diversity and altered beta diversity, characterized by enriched Streptococcus and depleted Fusobacterium, Neisseria, and other taxa relative to controls. Controls exhibited low to undetectable microbial translocation in plasma. By contrast, plasma displayed CUD-specific oral enrichment of several Streptococcal species and evidence of translocation into the bloodstream. S. parasanguinis, but not cocaine alone, induced IL-1{beta} and TNF- production in human primary monocytes in vitro. scRNAseq further revealed innate immune activation, impaired T cell function, and heightened susceptibility to infection in CUD. ConclusionsThis pilot study demonstrating that CUD via smoking or snorting exhibited oral microbial dysbiosis and selective oral-to-blood microbial translocation in vivo. These findings suggest that a compromised oral-to-blood barrier, rather than cocaine itself, promotes immune perturbations in CUD.

microbiology↗

bioRxiv2020

Neuraminidase activity mediates IL-6 production through TLR4 and p38/ERK MAPK signaling in MRL/lpr mesangial cells

Mesangial cells (MCs), considered the immune cell of the kidney, secrete a number of cytokines including IL-6, which serves as an autocrine factor for MCs stimulating proliferation. IL-6 is associated with disease in patients and mouse strains with lupus nephritis, promoting tissue damage. Previously, we demonstrated the activity or levels of the enzyme neuraminidase (NEU) is increased in the kidneys of lupus mice and urine of human patients with nephritis and that NEU activity plays a role in mediating IL-6 secretion from lupus prone MRL/lpr primary mouse MCs. In this study, we further elucidate the mechanisms by which NEU activity mediates cytokine production by primary lupus prone MCs. MRL/lpr primary MCs were cultured with lupus serum to stimulate cytokine production in the absence or presence of NEU activity inhibitor. Our results show lupus serum increases NEU activity, and secretion of GM-CSF and MIP1, in addition to IL-6, is significantly reduced when NEU activity is inhibited. mRNA expression of Il-6 and Gm-csf was also increased in response to lupus serum, and reduced when NEU activity was inhibited. Using neutralizing antibodies to specific receptors, inhibitors of MAP kinase signaling pathways, and LPS stimulation we show TLR4 and p38/ERK MAPK play a role in NEU-mediated secretion of IL-6. Together, our results suggest NEU activity plays an important role in the response of lupus prone MCs to factor(s) in lupus serum that stimulates IL-6 expression and secretion through TLR4-p38/ERK MAPK signaling, likely through desialyation of one or more glycoproteins in this pathway.

cell biology↗