Biology subjects

Simmons, J. D.

Publications and source records attributed to Simmons, J. D..

6 recordsLinked to original sources

bioRxiv2026

Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection

Myeloid cells are essential mediators of host defense against Mycobacterium tuberculosis (Mtb), yet the metabolic programs that sustain their function during chronic infection remain poorly defined. Here, using scRNA-seq we identified a striking, coordinated decline in mitochondrial electron transport chain gene expression across diverse myeloid populations as Mtb disease progressed in mice. This transcriptional remodeling was associated with broad changes in immune and metabolic pathways, including reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. Accordingly, loss of Complex I in macrophages (Ndufs4 knockdown) reduced MHC-II surface expression, dysregulated inflammatory gene expression, and limited control of Mtb replication. Finally, analysis of single-cell transcriptomic data from Mtb-exposed human household contacts identified an almost identical transcriptional program enriched in IGRA+ individuals, supporting a role for mitochondrial respiratory remodeling in human TB. Together, these findings demonstrate that mitochondrial bioenergetic competence is required to sustain macrophage effector function during chronic Mtb infection and suggest that mitochondrial restoration may boost protective responses in TB patients.

immunology↗

bioRxiv2025

Adaptive-like NK cell responses to influenza correlate with humoral immunity and are influenced by age and sex

Influenza remains a global health threat, infecting approximately one billion people annually and causing significant mortality, particularly among older adults. While hemagglutination inhibition (HAI) antibody titers are a standard correlate of immunity against influenza, they do not reliably predict protection in high-risk populations. Using multiomic single-cell profiling, we identified a distinct subset of adaptive-like NK cells that respond to influenza antigen, predominantly in younger females. These TNFSF10+LGALS9+ NK cells exhibit features of adaptive NK cells but lack classical cytomegalovirus-driven markers observed in previous studies. Notably, their increased frequency correlates with high pre-existing HAI titers, suggesting a link between adaptive-like NK responses and humoral immunity. Together, our findings identify an NK subset influenced by age and sex that may contribute to influenza protection, expanding the known diversity of adaptive-like NK cells. These insights could inform future vaccine strategies, particularly for aging populations, by integrating NK responses into assessments of vaccine efficacy.

immunology↗

bioRxiv2025

Antiviral CD4+ T and myeloid cell responses to influenza vaccines are attenuated in older adults

Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults; however, older adults remain significantly at risk for severe influenza-related illness. Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo assays with human samples to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens. We found that older adults mounted equivalent antibody titers to younger adults but had fewer influenza-specific CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets. These data suggest that with aging, transcriptional programming alterations in myeloid cells contribute to reduced antiviral T cell responses, and formulating vaccines tailored to myeloid responses is necessary to improve outcomes in older adults.

immunology↗

bioRxiv2024

Multi-omic latent variable data integration reveals multicellular structure pathways associated with resistance to tuberculin skin test (TST)/interferon gamma release assay (IGRA) conversion in Uganda

Understanding the mechanisms of early clearance of Mycobacterium tuberculosis (Mtb) may illuminate new therapeutic strategies for tuberculosis (TB). We previously found genetic, epigenetic, and transcriptomic signatures associated with resistance (resister, RSTR) to tuberculin skin test (TST)/interferon gamma release assay (IGRA) conversion among highly exposed TB contacts. We hypothesized that integration of these datasets with multi-omic latent factor methods would detect pathways differentiating RSTR patients from those with latent infection (LTBI) which were not differentiated by individual dataset analyses. We pre-filtered and scaled features with the largest change between LTBI and RSTR groups for 126 patients with data in at least two of five data modalities: single nucleotide polymorphisms (SNP), monocyte RNAseq (baseline and Mtb-stimulated conditions), and monocyte epigenetics (methylation and ATAC-seq). Using multiomic latent factor analysis (MOFA), we generated ten latent factors on the subset of 33 patients with all five datasets available, four of which were different between LTBI and RSTR (FDR < 0.1). Factor 4, which was the most integrated of the significant factors, showed the greatest difference between RSTR and LTBI groups (FDR < 0.001). Three additional latent factor data integration methods also distinguished the RSTR and LTBI groups and identified overlapping features with MOFA. Using pathway analysis and a cluster-based enrichment method, we identified biologic functions associated with latent factors and found that MOFA Factors 2-4 include functions related to cell-cell adhesion, cell shape, and development of multicellular structures. In summary, latent variable integration methods uncovered signatures associated with resistance to TST/IGRA conversion that were not detected within individual dataset analyses and included pathways associated with cellular interactions and multicellular structures. Author SummaryTuberculosis (TB) is a leading cause of preventable death worldwide. Previous research has identified some genetic and molecular patterns that are linked to resistance to TB in people who are highly exposed to the bacterium that causes the disease but do not develop an infection. We took genetic, epigenetic, and gene expression data from people who were not infected after exposure to TB within in their household and compared them with people who did develop a latent form of TB disease after similar exposure. We used a special method to analyze these datasets in an integrated way, rather than separately. This approach revealed four key factors that clearly distinguished between the resistant individuals and those with latent infection. One of these factors, in particular, showed a strong difference. We found that these factors were related to important biological processes such as how cells stick together, their shape, and how they form tissues. This method allowed us to see new patterns in the biological pathways linked to TB resistance that were not evident when looking at each type of data on its own.

genomics↗

bioRxiv2024

Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon gamma release assay (IGRA) conversion (RSTR), which suggests that they employ IFN{gamma}-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. In contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid and cholesterol associated pathways including in the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived HDL from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFN{gamma}-independent mechanisms. IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist who are either resistant to infection or contain Mtb with IFN{gamma}-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.

immunology↗

bioRxiv2022

A Single-Cell Molecular Atlas of White Adipose Tissue Shows Differences in Myeloid and Lymphoid Cell Polarization in Type 2 Diabetes and HIV Infection

Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. We generated a comprehensive SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH with a spectrum of metabolic health. Glucose intolerance was associated with increased lipid-associated macrophages and CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Many of these findings were present in a separate group of 32 diabetic HIV-negative persons, suggesting these changes are not specific to HIV.

immunology↗