Dual RNAseq of human leprosy lesions identifies bacterial determinants linked to host immune response

Montoya, Dennis; Silva, Bruno J.A.; Teles, Rosane M. B.; 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:10.1101/354407

Cited by 2 publications

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References 70 publications

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“…In the past decade, advanced sequencing platforms have accelerated the identification of both host and pathogen gene expression signatures associated with immunopathogenesis, clinical progression, and response to treatment of infectious diseases (23)(24)(25)(26)(27). We predicted that an assessment of genes that are differentially expressed between infected patients might identify genes associated with disease out-come that could be useful as targets for therapeutic design or as predictors of treatment failure.…”

Section: Introductionmentioning

confidence: 99%

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

et al. 2019

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Patients infected with Leishmania braziliensis develop chronic lesions that often fail to respond to treatment with antiparasite drugs. To determine whether genes whose expression is highly variable in lesions between patients might influence disease outcome, we obtained biopsies of lesions from patients before treatment with pentavalent antimony and performed transcriptomic profiling on these clinical samples. We identified genes that were highly variably expressed between patients, and the variable expression of these genes correlated with treatment outcome. Among the most variable genes in all the patients were components of the cytolytic pathway, and the expression of these genes correlated with parasite load in the skin. We demonstrated that treatment failure was linked to the cytolytic pathway activated during infection. Using a host-pathogen marker profile of as few as three genes, we showed that eventual treatment outcome could be predicted before the start of treatment in two separate cohorts of patients with cutaneous leishmaniasis (n = 21 and n = 25). These findings raise the possibility of point-of-care diagnostic screening to identify patients at high risk of treatment failure and provide a rationale for a precision medicine approach to drug selection in cutaneous leishmaniasis. This work more broadly demonstrates the value of identifying genes of high variability in other diseases to better understand and predict diverse clinical outcomes.

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Section: Introductionmentioning

confidence: 99%

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

et al. 2019

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“…RNA sequencing data of leprosy skin lesions was analyzed from [ 31 ]. Briefly, frozen tissue sections of nine lepromatous leprosy skin lesions, taken at the time of diagnosis after written consent was obtained and before any treatment was started, were lysed in Qiagen RLT buffer (Qiagen, Hilden, Germany) and homogenized with silica beads.…”

Section: Methodsmentioning

confidence: 99%

A phylogenomic study quantifies competing mechanisms for pseudogenization in prokaryotes—The Mycobacterium leprae case

et al. 2018

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BackgroundPseudogenes are non-functional sequences in the genome with homologous sequences that are functional (i.e. genes). They are abundant in eukaryotes where they have been extensively investigated, while in prokaryotes they are significantly scarcer and less well studied. Here we conduct a comprehensive analysis of the evolution of orthologs of Mycobacterium leprae pseudogenes in prokaryotes. The leprosy pathogen M. leprae is of particular interest since it contains an unusually large number of pseudogenes, comprising approximately 40% of its entire genome. The analysis is conducted in both broad and narrow phylogenetic ranges.ResultsWe have developed an informatics-based approach to characterize the evolution of pseudogenes. This approach combines tools from phylogenomics, genomics, and transcriptomics. The results we obtain are used to assess the contributions of two mechanisms for pseudogene formation: failed horizontal gene transfer events and disruption of native genes.ConclusionsWe conclude that, although it was reported that in most bacteria the former is most likely responsible for the majority of pseudogenization events, in mycobacteria, and in particular in M. leprae with its exceptionally high pseudogene numbers, the latter predominates. We believe that our study sheds new light on the evolution of pseudogenes in bacteria, by utilizing new methodologies that are applied to the unusually abundant M. leprae pseudogenes and their orthologs.

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Dual RNAseq of human leprosy lesions identifies bacterial determinants linked to host immune response

Cited by 2 publications

References 70 publications

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

A phylogenomic study quantifies competing mechanisms for pseudogenization in prokaryotes—The Mycobacterium leprae case

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