van der Ven, A. | Search bioRxiv

bioRxiv2022

HIV-linked gut dysbiosis associates with cytokine production capacity in viral-suppressed people living with HIV

People living with HIV (PLHIV) are exposed to chronic immune dysregulation, even when virus replication is suppressed by antiretroviral therapy (ART). Given the emerging role of the gut microbiome in immunity, we hypothesized that the gut microbiome may be related to the cytokine production capacity of PLHIV. To test this hypothesis, we collected metagenomic data from 143 ART-treated PLHIV and assessed the ex vivo production capacity of eight different cytokines (IL-1{beta}, IL-6, IL-1Ra, IL-10, IL17, IL22, TNF and IFN-{gamma}) in response to different stimuli. We also characterized CD4+ T cell-counts, HIV reservoir and other clinical parameters. Compared to 190 age- and sex-matched controls and a second independent control cohort, PLHIV showed microbial dysbiosis that was correlated with viral reservoir levels, cytokine production capacity and sexual behavior. Notably, we identified two genetically different P. copri strains that were enriched in either PLHIV or healthy controls. The control-enriched strain was negatively associated with IL-10, IL-6 and TNF production, independent of age, sex and sexual behavior, and positively associated with CD4+ T cell-level, whereas the PLHIV-enriched strain showed no associations. Our findings suggest that modulating the gut microbiome may be a strategy to modulate immune response in PLHIV. Novel PointsO_LIWe identified compositional and functional changes in the gut microbiome of PLHIV that were strongly related to sexual behavior. C_LIO_LIHIV-associated bacterial changes are negatively associated with HIV reservoir. The relative abundance of Firmicutes bacterium CAG 95 and Prevotella sp CAG 5226 both show a negative association with CD4+ T cell-associated HIV-1 DNA. C_LIO_LIPrevotella copri and Bacteroides vulgatus show association with PBMC production capacity of IL-1{beta} and IL-10 that is independent of age, sex, BMI and sexual behavior. C_LIO_LIWe observed two genetically different P. copri strains that are enriched in PLHIV and healthy individuals, respectively. C_LIO_LIThe control-related P. copri strain specifically shows a negative association with IL-10, IL-6 and TNF production and a positive association with CD4+ T cell-level. This suggests it plays a potential protective role in chronic inflammation, which may be related to enrichment of a specific epitope peptide. C_LI

microbiology↗

bioRxiv2021

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

ObjectiveFibroblast growth factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders. MethodsPatients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense variants and two copy number variants (CNVs) were studied by co-expression of wild-type and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their functional active beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B). ResultsFour variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by developmental and epileptic encephalopathy (DEE). We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on Nav1.2 and Nav 1.6, including loss- as well as gain-of function changes in fast inactivation as well as loss-of function changes in slow inactivation. InterpretationFor the first time, we could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.

neuroscience↗