Biology subjects

Dill-McFarland, K.

Publications and source records attributed to Dill-McFarland, K..

3 recordsLinked to original sources

bioRxiv2024

Human Alveolar and Monocyte-derived Human Macrophage Responses to Mycobacterium tuberculosis

RationaleAlveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis (Mtb). Differences in the response of these distinct cell types is poorly understood and may provide insight into mechanisms of TB pathogenesis. ObjectivesTo determine whether Mtb induces unique and essential anti-microbial pathways in human AMs compared to MDMs. MethodsUsing paired human AMs and 5-day MCSF-derived MDMs from 6 healthy volunteers, we infected cells with Mtb H37Rv for 6 hours, isolated RNA, and analyzed transcriptomic profiles with RNASeq. Main ResultsWe found 681 genes that were Mtb-dependent in AMs compared to MDMs and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). Using hypergeometric enrichment of DEGs in Broad Hallmark gene sets, we found that Type I and II IFN Response were the only gene sets selectively induced in Mtb-infected AM (FDR <0.05). In contrast, MYC targets, unfolded protein response and MTORC1 signaling, were selectively enriched in MDMs (FDR < 0.05). IFNA1, IFNA8, IFNE, and IFNL1 were specifically and highly upregulated in AMs compared to MDMs at baseline and/or after Mtb infection. IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons, stimulated unique transcriptomes. Several DNA sensors and Interferon Regulatory Factors had higher expression at baseline and/or after Mtb infection in AMs compared to MDMs. ConclusionsThese findings demonstrate that Mtb infection induced unique transcriptional responses in human AMs compared to MDMs, including upregulation of the IFN response pathway and specific DNA sensors.

immunology↗

bioRxiv2020

TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium tuberculosis infection by resolving cellular stress from lipids.

Relative deficiency of TOLLIP expression in monocytes is associated with increased tuberculosis (TB) susceptibility in genetic studies, despite antagonizing host innate immune pathways that control Mycobacterium tuberculosis (Mtb) infection. In this study, we investigated the mechanisms by which TOLLIP influences Mtb immunity. Tollip-/- mice developed worsened disease, consistent with prior genetic observations, and developed large numbers of foam cells. Selective TOLLIP deletion in alveolar macrophages (AM) was sufficient to induce lipid accumulation and increased Mtb persistence 28 days after infection, despite increased antimicrobial responses. We analyzed sorted, Mtb-infected Tollip-/- AM from mixed bone marrow chimeric mice to measure global gene expression 28 days post-infection. We found transcriptional profiles consistent with increased EIF2 signaling. Selective lipid administration to Tollip-/- macrophages induced lipid accumulation, and Mtb infection of lipid laden, Tollip-/- macrophages induced cellular stress and impaired Mtb control. EIF2 activation induced increased Mtb replication within macrophages, irrespective of TOLLIP expression, and EIF2 kinases were enriched in human caseous granulomas. Our findings define a critical checkpoint for TOLLIP to prevent lipid-induced EIF2 activation and demonstrate an important mechanism for EIF2 signaling to permit Mtb replication within macrophages.

immunology↗

bioRxiv2018

Social relationships, social isolation, and the human gut microbiota

Social relationships shape human health and mortality via behavioral, psychosocial, and physiological mechanisms, including inflammatory and immune responses. Though not tested in human studies, recent primate studies indicate that the gut microbiome may also be a biological mechanism linking relationships to health. Integrating microbiota data into the 60-year-old Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) further revealed that spouses have more similar microbiota and more bacterial taxa in common than siblings, with no observed differences between sibling and unrelated pairs. These differences held even after accounting for dietary factors. The differences between unrelated individuals and married couples was driven entirely by couples who reported close relationships; there were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Moreover, the microbiota of married individuals, compared to those living alone, has greater diversity and richness, with the greatest diversity among couples reporting close relationships, which is notable given decades of research documenting the health benefits of marriage. These results suggest that human interactions, especially sustained, close marital relationships, influence the gut microbiota.

microbiology↗