MARCO variants are associated with phagocytosis, pulmonary tuberculosis susceptibility and Beijing lineage

Thuong, Nt T. T.; Tram, Tt T. B.; Dinh, Td D.; Thai, Pv V. K.; Heemskerk, Dorothee; Bang, Nd D.; Chau, Tt T. H.; Russell, David G.; Thwaites, Guy; Hawn, Tr R.; Caws, Maxine; Dunstan, Sarah J.

doi:10.1038/gene.2016.43

Cited by 43 publications

(39 citation statements)

References 30 publications

(42 reference statements)

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“…For example, beyond consistent enrichment for immune-associated GO and KEGG terms, the top 20 strongest DEG signals between the Mentawai and the Korowai include genes involved in antigen presentation in both innate and adaptive immune cells ( MARCO and SIGLEC7, respectively; MARCO p = 2.7×10 −14 ; SIGLEC7 p = 9.7×10 −14 ; these genes are also differentially expressed between Sumbanese and the Korowai ( MARCO p = 4.2×10 −10 ; SIGLEC7 p = 4.9×10 −12 ; supplementary figure 11). Polymorphisms within MARCO, which is expressed on the surface of macrophages, have been repeatedly shown to associate with susceptibility of infection by Mycobacterium tuberculosis and Streptococcus pneumoniae in multiple populations worldwide 47–50 ; some of these variants have been subsequently shown to have a direct impact on antigen binding 51 . Our MethylMix analyses identify differences in SIGLEC7 expression as being driven, at least in part, by methylation differences in its promoter region (Figure 4C).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Natri

Bobowik

Kusuma

et al. 2019

Preprint

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34Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional 35 patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. 36 However, it has been largely excluded from the human genomics sequencing boom of the last decade. 37 To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide 38 CpG methylation and gene expression measurements in over 100 individuals from three locations that 39 capture the major genomic and geographical axes of diversity across the Indonesian archipelago. 40Investigating between-and within-island differences, we find up to 10% of tested genes are differentially 41 expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is 42 closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating 43 with nearby CpG methylation, and many of these genes being differentially expressed between islands. 44Genes identified in our differential expression and methylation analyses are enriched in pathways 45 involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and 46 the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-47 island variation in DNA methylation and gene expression, likely driven by very local environmental 48 differences across sampling sites. Together, these results strongly suggest complex relationships between 49 DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the 50 environment. This has implications for the application of genomic medicine, both in critically 51 understudied Indonesia and globally, and will allow a better understanding of the interacting roles of 52 genomic and environmental factors shaping molecular and complex phenotypes. 53 54 55 56 57 58 59 60 61 Modern human genomics does not equitably represent the full breadth of humanity. While genome 62 sequences for people of European descent now number a million or more, most of the world is deeply 63 understudied 1 . This is particularly true of Indonesia 2 , a country geographically as large as continental 64 Europe and the world's fourth largest by population. Genomic diversity in Indonesia is strikingly 65 different to other well-characterized East Asian populations, such as Han Chinese and Japanese, but this 66 diversity is not captured in large global datasets like the 1000 Genomes Project 3 or the Simons Genome 67 Diversity Project 4 . The first Indonesian genome sequences were only reported in 2016 5 with the first 68 representative survey of diversity across the archipelago only appearing in 2019 6 . This extreme lack of 69 representation extends to molecular phenotypes. To our knowledge, only one genome-wide gene 70 expression study has been published 7 from the region, focused exclusively on host-pathogen interactions 71 with P. falciparum. There are...

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Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Natri

Bobowik

Kusuma

et al. 2019

Preprint

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“…30 This is associated with decreased expression of phagocytic molecules such as the mannose receptor, and may be restored by treatment with azithromycin, which increases the phagocytic capacity of AMs, 31 and may improve patient outcomes. 33,34 In humans, MARCO polymorphisms that reduce phagocytic capacity in monocyte-derived macrophages are linked to tuberculosis susceptibility, 33 and lower MARCO expression on AMs from diabetic mice reduces their ability to phagocytose M. tuberculosis. 33,34 In humans, MARCO polymorphisms that reduce phagocytic capacity in monocyte-derived macrophages are linked to tuberculosis susceptibility, 33 and lower MARCO expression on AMs from diabetic mice reduces their ability to phagocytose M. tuberculosis.…”

Section: Alveolar Macrophagesmentioning

confidence: 99%

“…32 In mice, other phagocytic receptors, such as the macrophage receptor with collagenous structure (MARCO), are important for clearance of respiratory pathogens including Streptococcus pneumoniae and Mycobacterium tuberculosis. 33,34 In humans, MARCO polymorphisms that reduce phagocytic capacity in monocyte-derived macrophages are linked to tuberculosis susceptibility, 33 and lower MARCO expression on AMs from diabetic mice reduces their ability to phagocytose M. tuberculosis. 35 In addition to phagocytosis, AMs secrete numerous cytokines and chemokines, including interleukin-6 (IL-6), tumour necrosis factor-a, monocyte chemoattractant protein 1, RANTES and granulocyte colony-stimulating factor, which recruit other inflammatory cells.…”

Section: Alveolar Macrophagesmentioning

confidence: 99%

Tissue‐resident innate immunity in the lung

2019

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The lung is a unique organ that must protect against inhaled pathogens and toxins, without mounting a disproportionate response against harmless particulate matter and without compromising its vital function. Tissue-resident immune cells within the lung provide local immunity and protection from infection but are also responsible for causing disease when dysregulated. There is a growing appreciation of the importance of tissue-resident memory T cells to lung immunity, but non-recirculating, tissue-resident, innate immune cells also exist. These cells provide the first line of defence against pulmonary infection and are essential for co-ordinating the subsequent adaptive response. In this review, we discuss the main lung-resident innate immune subsets and their functions in common pulmonary diseases, such as influenza, bacterial pneumonia, asthma and inflammatory disorders.

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“…hMDM were differentiated in vitro from peripheral blood monocytes (PBMCs) of PTB patients during 7 days, suggesting that these cells are inactivated or in resting stage, and their activities are not affected by other activated cell types in the patients through intercellular communication. A previous study showed no difference in phagocytic function of hMDM between TB patients and healthy volunteers; however, there was a wide range of phagocytosis abilities among individuals, which is associated with host genotype [Thuong et al., ]. There has been limited understanding of intracellular killing activities of macrophages and its variations in patients with TB.…”

Section: Discussionmentioning

confidence: 99%

Development of ligand‐coated beads to measure macrophage antimicrobial activities

Tram

Thu

et al. 2019

Biology of the Cell

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Background information After macrophage recognises and phagocytoses the microorganism, their phagosome undergoes a maturation process, which creates a hostile environment for the bacterium. The lumen is acidified, and proteolysis occurs to kill and degrade pathogen for further antigen presentation. It is important to understand the association between the macrophage intracellular activities and the outcome of infection. Different methods have been developed to measure the phagosome dynamics of macrophages, but there are still limitations. Results We used Mycobacterium tuberculosis (Mtb) antigens, the causative agent of tuberculosis (TB), as a model of infectious disease. Adopting a fluorescent bead‐based assay, we developed beads coated with trehalose 6,6′dimycolate (TDM) from Mtb cell wall and β‐glucan from yeast cell wall to measure the macrophage phagosomal activities using a microplate reader. We examined the consistency of the assay using J774 cells and validated it using human monocyte‐derived macrophages (hMDM) from healthy volunteers and TB patients. There was a decreased pH and increased proteolysis in the lumen of J774 cells after phagocytosing the ligand‐coated beads. J774 macrophage showed no difference in the acidification and proteolysis in response to control IgG beads, TDM and β‐glucan beads. hMDM from healthy volunteers or TB patients showed heterogeneity in the intracellular activities when treated with ligand‐coated beads. Conclusions and significance The beads coated with specific ligands from Mtb worked well in both macrophage cell line and human primary macrophages, which can be exploited to further study the phagosomal function of macrophage in TB. Our bead model can be applied to different ligands from other pathogens, which could extend the understanding of the associations between macrophage antimicrobial functions and outcomes of infectious diseases and the possible cellular mechanisms involved.

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MARCO variants are associated with phagocytosis, pulmonary tuberculosis susceptibility and Beijing lineage

Cited by 43 publications

References 30 publications

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Tissue‐resident innate immunity in the lung

Development of ligand‐coated beads to measure macrophage antimicrobial activities

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