SummaryA zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers’ susceptibility to tuberculosis.
SummaryThe blockade of phagolysosomal fusion is considered a critical mycobacterial strategy to survive in macrophages. However, viable mycobacteria have been observed in phagolysosomes during infection of cultured macrophages, and mycobacteria have the virulence determinant MarP, which confers acid resistance in vitro. Here we show in mice and zebrafish that innate macrophages overcome mycobacterial lysosomal avoidance strategies to rapidly deliver a substantial proportion of infecting bacteria to phagolysosomes. Exploiting the optical transparency of the zebrafish, we tracked the fates of individual mycobacteria delivered to phagosomes versus phagolysosomes and discovered that bacteria survive and grow in phagolysosomes, though growth is slower. MarP is required specifically for phagolysosomal survival, making it an important determinant for the establishment of mycobacterial infection in their hosts. Our work suggests that if pathogenic mycobacteria fail to prevent lysosomal trafficking, they tolerate the resulting acidic environment of the phagolysosome to establish infection.
C oronavirus disease 2019 (COVID-19), caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is an unprecedented global pandemic. 1 Susceptibility to COVID-19 is a concern among patients with inflammatory bowel disease (IBD) who are at increased risk of infection due to immunosuppressive therapy. The receptor angiotensin-converting enzyme (ACE) 2, which mediates SARS-CoV-2 entry into cells, is upregulated in IBD 2 and may therefore increase host susceptibility. International cohorts have reported no increased risk of COVID-19 in patients with IBD 3,4 ; however, these studies do not report the prevalence of SARS-CoV-2 testing and COVID-19 in patients with IBD. Our institution was among the first to initiate large-scale SARS-CoV-2 RNA testing in northern California. We characterized the prevalence and clinical predictors of COVID-19 in patients with IBD.
Gut granules are specialized lysosome-related organelles that act as sites of fat storage in Caenorhabditis elegans intestinal cells. We identified mutations in a gene, glo-3, that functions in the formation of embryonic gut granules. Some glo-3(À) alleles displayed a complete loss of embryonic gut granules, while other glo-3(À) alleles had reduced numbers of gut granules. A subset of glo-3 alleles led to mislocalization of gut granule contents into the intestinal lumen, consistent with a defect in intracellular trafficking. glo-3(À) embryos lacking gut granules developed into adults containing gut granules, indicating that glo-3(1) function may be differentially required during development. We find that glo-3(1) acts in parallel with or downstream of the AP-3 complex and the PGP-2 ABC transporter in gut granule biogenesis. glo-3 encodes a predicted membrane-associated protein that lacks obvious sequence homologs outside of nematodes. glo-3 expression initiates in embryonic intestinal precursors and persists almost exclusively in intestinal cells through adulthood. GLO-3TGFP localizes to the gut granule membrane, suggesting it could play a direct role in the trafficking events at the gut granule. smg-1(À) suppression of glo-3(À) nonsense alleles indicates that the C-terminal half of GLO-3, predicted to be present in the cytoplasm, is not necessary for gut granule formation. Our studies identify GLO-3 as a novel player in the formation of lysosome-related organelles.
Inflammatory bowel disease (IBD) is a complex and multifaceted disorder of the gastrointestinal tract that is increasing in incidence worldwide and associated with significant morbidity. The rapid accumulation of large datasets from electronic health records, high-definition multi-omics (including genomics, proteomics, transcriptomics, and metagenomics), and imaging modalities (endoscopy and endomicroscopy) have provided powerful tools to unravel novel mechanistic insights and help address unmet clinical needs in IBD. Although the application of artificial intelligence (AI) methods has facilitated the analysis, integration, and interpretation of large datasets in IBD, significant heterogeneity in AI methods, datasets, and clinical outcomes and the need for unbiased prospective validations studies are current barriers to incorporation of AI into clinical practice. The purpose of this review is to summarize the most recent advances in the application of AI and machine learning technologies in the diagnosis and risk prediction, assessment of disease severity, and prediction of clinical outcomes in patients with IBD.
Gut granules are cell type‐specific lysosome‐related organelles found within the intestinal cells of Caenorhabditis elegans. To investigate the regulation of lysosome‐related organelle size, we screened for C. elegans mutants with substantially enlarged gut granules, identifying alleles of the vacuolar‐type H+‐ATPase and uridine‐5′‐monophosphate synthase (UMPS)‐1. UMPS‐1 catalyzes the conversion of orotic acid to UMP; this comprises the two terminal steps in de novo pyrimidine biosynthesis. Mutations in the orthologous human gene UMPS result in the rare genetic disease orotic aciduria. The umps‐1(−) mutation promoted the enlargement of gut granules to 250 times their normal size, whereas other endolysosomal organelles were not similarly affected. UMPS‐1::green fluorescent protein was expressed in embryonic and adult intestinal cells, where it was cytoplasmically localized and not obviously associated with gut granules. Whereas the umps‐1(−) mutant is viable, combination of umps‐1(−) with mutations disrupting gut granule biogenesis resulted in synthetic lethality. The effects of mutations in pyr‐1, which encodes the enzyme catalyzing the first three steps of de novo pyrimidine biosynthesis, did not phenotypically resemble those of umps‐1(−); instead, the synthetic lethality and enlargement of gut granules exhibited by the umps‐1(−) mutant was suppressed by pyr‐1(−). In a search for factors that mediate the enlargement of gut granules in the umps‐1(−) mutant, we identified WHT‐2, an ABCG transporter previously implicated in gut granule function. Our data suggest that umps‐1(−) leads to enlargement of gut granules through a build‐up of orotic acid. WHT‐2 possibly facilitates the increase in gut granule size of the umps‐1(−) mutant by transporting orotic acid into the gut granule and promoting osmotically induced swelling of the compartment.
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