Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response

Montoya, Dennis; Silva, Bruno J.A.; Teles, Rosane M. B.; Ma, Feiyang; Bryson, Bryan; Sadanand, Saheli; Noel, Teia; Lü, Jing; Sarno, Euzenir Nunes; Arnvig, Kristine B.; Young, Douglas; Lahiri, Ramanuj; Williams, Diana L.; Fortune, Sarah M.; Bloom, Barry R.; Pellegrini, Matteo; Modlin, Robert L.

doi:10.1016/j.celrep.2019.02.109

Cited by 44 publications

(54 citation statements)

References 65 publications

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“…Humoral immunity in leprosy was suggested to be ineffective in pathogen elimination because M. leprae could survive and multiply in humoral immune-dominated L-lep despite the greater antibody responses in L-lep (92,93). Therefore, B cell is the least cell population to be considered in leprosy pathogenesis studies, although it is a major immune cell population with antibodies secretory and antigen presentation functions.…”

Section: B Regulatory Cellmentioning

confidence: 99%

Advances in the Immunology and Genetics of Leprosy

Liu

Zhang

2020

Front. Immunol.

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Section: B Regulatory Cellmentioning

confidence: 99%

Advances in the Immunology and Genetics of Leprosy

Liu

Zhang

2020

Front. Immunol.

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“…In the present study, we used a well-described NHP model of necrotizing myositis (27,45,46) and dual RNA-seq to study the relationship between pathogen and host transcripts. Until now, a limited number of studies have been conducted using dual RNA-seq under in vivo conditions (41,42,(47)(48)(49)(50)(51)(52)(53). In a very recent study, dual RNA-seq was performed on human tissue biopsiy samples obtained from necrotizing soft tissue infections (54).…”

mentioning

confidence: 99%

New Pathogenesis Mechanisms and Translational Leads Identified by Multidimensional Analysis of Necrotizing Myositis in Primates

Kachroo

Eraso

Olsen

et al. 2020

mBio

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A fundamental goal of contemporary biomedical research is to understand the molecular basis of disease pathogenesis and exploit this information to develop targeted and more-effective therapies. Necrotizing myositis caused by the bacterial pathogen Streptococcus pyogenes is a devastating human infection with a high mortality rate and few successful therapeutic options. We used dual transcriptome sequencing (RNA-seq) to analyze the transcriptomes of S. pyogenes and host skeletal muscle recovered contemporaneously from infected nonhuman primates. The in vivo bacterial transcriptome was strikingly remodeled compared to organisms grown in vitro, with significant upregulation of genes contributing to virulence and altered regulation of metabolic genes. The transcriptome of muscle tissue from infected nonhuman primates (NHPs) differed significantly from that of mock-infected animals, due in part to substantial changes in genes contributing to inflammation and host defense processes. We discovered significant positive correlations between group A streptococcus (GAS) virulence factor transcripts and genes involved in the host immune response and inflammation. We also discovered significant correlations between the magnitude of bacterial virulence gene expression in vivo and pathogen fitness, as assessed by previously conducted genome-wide transposon-directed insertion site sequencing (TraDIS). By integrating the bacterial RNA-seq data with the fitness data generated by TraDIS, we discovered five new pathogen genes, namely, S. pyogenes 0281 (Spy0281 [dahA]), ihk-irr, slr, isp, and ciaH, that contribute to necrotizing myositis and confirmed these findings using isogenic deletion-mutant strains. Taken together, our study results provide rich new information about the molecular events occurring in severe invasive infection of primate skeletal muscle that has extensive translational research implications. IMPORTANCE Necrotizing myositis caused by Streptococcus pyogenes has high morbidity and mortality rates and relatively few successful therapeutic options. In addition, there is no licensed human S. pyogenes vaccine. To gain enhanced understanding of the molecular basis of this infection, we employed a multidimensional analysis strategy that included dual RNA-seq and other data derived from experimental infection of nonhuman primates. The data were used to target five streptococcal genes for pathogenesis research, resulting in the unambiguous demonstration that these genes contribute to pathogen-host molecular interactions in necrotizing infections. We exploited fitness data derived from a recently conducted genome-wide transposon mutagenesis study to discover significant correlation between the magnitude of bacterial virulence gene expression in vivo and pathogen fitness. Collectively, our findings have significant implications for translational research, potentially including vaccine efforts.

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“…For example, high-resolution transcriptomics, transposon mutagenesis, and Grad-seq data exist for Streptococcus pneumoniae (Aprianto et al, 2016(Aprianto et al, , 2018Hor et al, 2020;Rowe et al, 2019;van Opijnen and Camilli, 2012;Warrier et al, 2018). More generally, various transposonsequencing approaches have been applied to bacterial pathogens under virulence conditions (Karlinsey et al, 2019;Rendón et al, 2020;Warr et al, 2019), and dual RNAseq has become the gold-standard to chart the transcriptional landscape of pathogens during infection (Montoya et al, 2019;Pisu et al, 2020;Ritchie and Evans, 2019;Westermann et al, 2017). Re-inspection of these data may provide invaluable information on potentially new biological roles carried out by small proteins in bacterial pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Venturini

Svensson

Maaß

et al. 2020

Preprint

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Small proteins are an emerging class of gene products with diverse roles in bacterial physiology. However, a full understanding of their importance has been hampered by insufficient genome annotations and a lack of comprehensive characterization in microbes other than Escherichia coli. We have taken an integrative approach to accelerate the discovery of small proteins and their putative virulence-associated functions in Salmonella Typhimurium. We merged the annotated small proteome of Salmonella with new small proteins predicted with in silico and experimental approaches. We then exploited existing and newly generated global datasets that provide information on small open reading frame expression during infection of epithelial cells (dual RNA-seq), contribution to bacterial fitness inside macrophages (TraDIS), and potential engagement in molecular interactions (Grad-seq). This integrative approach suggested a new role for the small protein MgrB beyond its known function in regulating PhoQ. We demonstrate a virulence and motility defect of a Salmonella ΔmgrB mutant and reveal an effect of MgrB in regulating the Salmonella transcriptome and proteome under infection-relevant conditions. Our study highlights the power of interpreting available “omics” datasets with a focus on small proteins, and may serve as a blueprint for a data integration-based survey of small proteins in diverse bacteria.

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Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response

Cited by 44 publications

References 65 publications

Advances in the Immunology and Genetics of Leprosy

Advances in the Immunology and Genetics of Leprosy

New Pathogenesis Mechanisms and Translational Leads Identified by Multidimensional Analysis of Necrotizing Myositis in Primates

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

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