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Mihai G Netea

Publications and source records attributed to Mihai G Netea.

6 recordsLinked to original sources
PubMed2026

Spatially Distinct Bone Marrow Sites Are Asymmetrically Impacted by Inflammatory Cardiovascular Disease.

Cardiovascular disease, a leading cause of mortality globally, is increasingly recognized to involve complex bone marrow-driven inflammatory mechanisms, yet the impact on spatially distinct bone marrow sites and comorbidities remains poorly understood. To address this, we developed MarrowMet, a methodology for whole-body, site-specific quantification of bone marrow activity. The approach involves intravenously injecting the metabolic tracer 18F-fluorodeoxyglucose (18F-FDG) in mice, followed by bone excision to quantify site-specific bone marrow activity, with values then superimposed on a whole-body mouse atlas. After establishing that 18F-FDG bone marrow uptake strongly correlated with inflammatory activity, we applied MarrowMet to map site-specific activation patterns across diverse cardiovascular pathologies, including mouse models of inflammatory atherosclerosis, acute ischemic events, acute respiratory distress syndrome, metabolic syndrome, and aging. MarrowMet guided the selection of bone marrow regions of interest for in-depth mass cytometric analyses, with the skull and sternum emerging as critical sites exhibiting distinct immune and metabolic profiles in cardiovascular disease. These results challenge the prevailing view that femoral marrow represents systemic activity. Together, this work lays a foundation for whole-body exploration of bone marrow heterogeneity, yielding critical insights into cardiovascular disease and associated inflammatory responses, and MarrowMet can be readily adopted to profile other immune mechanisms in a variety of pathologies, including cancer and autoimmune diseases.

(18)F-FDG↗
PubMed2026

Kmt2c and Kmt2d histone methyltransferase deficiencies compromise macrophage function.

Methylation of histone (H) 3 lysine (K) 4 (H3K4) has a well-established role in innate immune responses, but the contribution of H3K4 methyltransferases Kmt2c and Kmt2d in innate immunity is incompletely understood. Using conditional knockout mouse models, we investigated how Kmt2c- and Kmt2d-deficiencies affect innate immune cell function. Through functional, transcriptomic, and metabolic analyses, we delineate the consequences of disrupted epigenetic regulation on macrophage biology. Our findings reveal that loss of Kmt2c or Kmt2d in macrophages leads to impaired pro-inflammatory cytokine response and phagocytotic capacity, as well as skewed energy metabolism toward glycolysis, highlighting the critical role of H3K4 methylation-dependent chromatin regulation in shaping innate immune cell behavior. This study provides the first comprehensive characterization of innate immune system dysfunction in mouse models with conditional Kmt2c and Kmt2d deletions and offers mechanistic insight into how epigenetic regulators control fundamental immune processes.

Animals↗
PubMed2026

Resistome and microbiome-immune interactions in an Eastern European population with high antibiotic use.

The gut microbiome influences host health, affecting gastrointestinal, metabolic, immune, cardiovascular, and neurological functions. A balanced microbiome is associated with favorable health outcomes. However, excessive antibiotic use and dietary habits can disrupt this ecosystem, leading to dysbiosis and affecting body homeostasis. This first comprehensive metagenomic analysis of the gut microbiome in a healthy Romanian cohort, a population underrepresented in microbiome studies and characterized by high antibiotic consumption, addresses a gap in current microbiome research. We report an enrichment of Enterobacteriaceae although overall composition is more comparable to other European than non-European cohorts. Community configurations align with established enterotype patterns, and our analysis provides insight into their relationship with within-phylum diversity. The analysis of antimicrobial resistance provides insight into the prevalence of resistance genes within this reservoir. We specifically report the presence of cfr(E), a Clostridioides difficile gene, and tet(X5), a variant from the ubiquitous tet family, genes not previously reported in healthy European populations. Integration with data from the European Centre for Disease Prevention and Control links the overall prevalence of resistance genes in this reservoir to antibiotic classes with higher community consumption in this population, notably beta-lactams and quinolones, highlighting potential targets for antibiotic stewardship programs. Finally, we investigate the relationship between the microbial profile and the systemic immune responses, inferred from correlations with in vitro cytokine production. Notably, we identify potential immune-priming roles for Collinsella, Flavonifractor, and Bifidobacterium species.IMPORTANCEThis first comprehensive study of the healthy gut microbiome in a Romanian cohort addresses a gap in current microbiome research, dominated by data sets from a limited number of regions. It sets a baseline for the microbiome and resistome composition of this population, and, while definitions of "healthy" microbiomes, or baseline resistomes, remain lacking, such study helps contextualize future studies and support the monitoring of dynamics. The Enterobacteriaceae abundance suggests a microbiome composition potentially influenced by antimicrobial consumption, a relevant pattern in a region with a high burden of nosocomial infections. In addition, the prevalence of antimicrobial resistance genes and the concordance with commonly used antibiotics in the community reinforce the need to address antibiotic use in public health strategies. Although gut microbiome-immunity relationships remain incompletely understood, our findings support a role for microbiome composition in immune-related traits and provide a valuable resource for future studies.

Humans↗
PubMed2026

Co-regulation of HIV control and cytomegalovirus pp65-specific IL-1β and TNF-α responses by genetic variants in the MHC region.

The spontaneous control of HIV infection in the absence of antiretroviral therapy, termed HIV control, is associated with genetic variation in the Major Histocompatibility Complex (MHC) locus. These variants are known to influence the immune response to HIV itself. However, people living with HIV are often co-infected with other pathogens that can also elicit immune responses, which might also be regulated by these variants. Here, we assessed whether genetic variants associated with HIV control influence cytokine responses to various co-pathogens. HIV-control-associated single nucleotide polymorphisms (SNPs) were enriched among variants regulating TNF-α and IL-1β production upon CMV pp65 peptide pool stimulation. The top enriched SNPs, rs1128175-A and rs2853971-A, were linked to lower odds of HIV control and increased cytokine responses to CMV. These SNPs were in linkage disequilibrium (LD) with classical HLA alleles HLA-B*07:02 and HLA-C*07:02. Intracellular cytokine staining showed CMV serostatus-dependent production of TNF-α by monocytes and CD8 T cells. The rs1128175-A/rs2853971-A/HLA-B*07:02/HLA-C*07:02 haplotype was associated with increased IFN-γ production by CD8 T cells upon CMV pp65 peptide pool stimulation, indicating an effect on memory responses. Quantitative trait locus (QTL) mapping showed that rs1128175 and rs2853971 influence HLA-B and HLA-C expression, DNA methylation levels and cell-type-specific cis-effects on chromatin accessibility, as well as CD8 T cell subset abundance. These QTL associations suggest that variants associated with poor HIV control are linked to heightened pro-inflammatory responses to CMV pp65 through effects on antigen presentation, epigenetic modifications, gene expression and immune cell repertoire, potentially negatively affecting HIV control status.

Humans↗
PubMed2026

HIV immunological nonresponders show low SKAP1 concentration and DNA hypermethylation in the SKAP1 promotor region.

OBJECTIVE: The aim of this study was to improve understanding of biological pathways underlying inadequate CD4 + T-cell restoration after initiating antiretroviral treatment as these so called Immunological nonresponders are at increased risk for morbidity and mortality while treatment options are lacking. DESIGN: We compared baseline multiomics data from 88 Immunological nonresponders and 1467 immunological responders that participated in the 2000HIV study, separated into a discovery and validation cohort. METHODS: We measured expression levels of 2367 plasma proteins, comparing the immunological responders and nonresponders. As this highlighted low Src kinase-associated phosphoprotein 1 (SKAP1) levels in Immunological nonresponders, we measured intracellular SKAP1 levels in CD4 + T-cells, investigated DNA methylation and assessed single-nucleotide polymorphisms (SNPs). We also explored whether HIV or CMV infection may influence SKAP1 expression. RESULTS: SKAP1 plasma levels were significantly lower in Immunological nonresponders in both cohorts. SKAP1 plasma concentrations reflected intracellular levels in CD4 + T-cells. DNA methylation analysis showed significant hypermethylation at the SKAP1 promotor region. Three SNPs close to the SKAP1 gene were associated with poor Immunological response. Preliminary data suggest that HIV or CMV may influence SKAP1 levels. CONCLUSION: Our data show decreased SKAP1 concentrations in immunological nonresponders, potentially driven by hypermethylation of the SKAP1 promoter. Downregulation of SKAP1, which is known to play a role in T cell proliferation and migration, may therefore contribute to the poor restoration of CD4 + cell count after ART.

Humans↗