Biology subjects

Peterson, G. J.

Publications and source records attributed to Peterson, G. J..

3 recordsLinked to original sources

bioRxiv2025

Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to Mycobacterium tuberculosis

Macrophages serve as important sites of bacterial replication and host immune response during Mycobacterium tuberculosis (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived (MDMs) during later stages of disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb infection. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AM across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had Mtb responses that were more similar to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, specifically in pathways related to cholesterol in AMs as well as MYC targets and Hedgehog signaling in MDMs/BMDMs. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine macrophage expression of IL-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for IL-10 expression in myeloid cells. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses over the course of Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.

immunology↗

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

Peripheral blood T-cell deficiency and hyperinflammatory monocyte responses associate with MAC lung disease

RationaleAlthough nontuberculous mycobacterial (NTM) disease is a growing problem, available treatments are suboptimal and diagnostic tools are inadequate. Immunological mechanisms of susceptibility to NTM disease are poorly understood. ObjectiveTo understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in individuals with MAC lung disease (MACDZ). MethodsWe synthesized 15mer MAC-, NTM-, or MAC/Mtb-specific peptides and stimulated peripheral blood mononuclear cells (PBMC) with pools of these peptides. We measured T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mav-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. Measurements and Main ResultsWe were unable to detect T-cell responses against the peptide libraries or Mav lysate that has increased reactivity in MACDZ subjects compared to controls. T-cell responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and Mav-infected monocytes derived from MACDZ subjects compared to controls. ConclusionsPeripheral blood T-cell responses to Mycobacterial antigens and the frequency of Th1 and Th1* cell populations are diminished in individuals with MAC disease. In contrast, MACDZ subjects had hyperinflammatory monocyte responses. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation.

immunology↗