Dataset Information

Proteome remodeling in the Mycobacterium tuberculosis PknG knockout: molecular hints for the role of this kinase in cell envelope biogenesis and hypoxia.

ABSTRACT: Tuberculosis, a pulmonary disease caused by the etiological agent Mycobacterium tuberculosis, is the leading cause of death by a single infectious agent among human beings. One of M. tuberculosis's pathogenic hallmarks is its ability to persist in a dormant state in the host for long periods, reinitiating the infectious cycle when favorable environmental conditions are found. Thus, it is not surprising that this pathogen has developed different mechanisms to withstand the stressful conditions found in the host. In particular, the Ser/Thr protein kinase PknG has gained special relevance since it regulates nitrogen metabolism and facilitates bacterial survival inside macrophages. Nevertheless, the molecular mechanisms underlying these effects are far from being elucidated. To further investigate these issues, we performed quantitative proteomics analyses of protein extracts from M. tuberculosis H37Rv and a mutant derivative lacking PknG. Our results show that in the absence of PknG the mycobacterial proteome was remodeled since 6.5% of the proteins encoded by M. tuberculosis presented significant changes in its relative abundance when compared to the wild-type strain. The main biological processes affected by PknG deletion were the biosynthesis of cell envelope components and the response to hypoxic conditions. Altogether, the results presented here allow us to postulate that PknG regulation of bacterial fitness to stress conditions in host macrophages might be an essential mechanism underlying its reported effect on intracellular bacterial survival.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mycobacterium Tuberculosis H37rv

TISSUE(S): Response To Bacterium

DISEASE(S): Tuberculosis

SUBMITTER: Analía Lima

LAB HEAD: Rosario Durán

PROVIDER: PXD023956 | Pride | 2021-06-02

REPOSITORIES: Pride

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Proteome remodeling in the Mycobacterium tuberculosis PknG knockout: Molecular evidence for the role of this kinase in cell envelope biogenesis and hypoxia response.

Lima Analía A Leyva Alejandro A Rivera Bernardina B Portela María Magdalena MM Gil Magdalena M Cascioferro Alessandro A Lisa María-Natalia MN Wehenkel Annemarie A Bellinzoni Marco M Carvalho Paulo C PC Batthyány Carlos C Alvarez María N MN Brosch Roland R Alzari Pedro M PM Durán Rosario R

Journal of proteomics 20210524

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is among the deadliest human pathogens. One of M. tuberculosis's pathogenic hallmarks is its ability to persist in a dormant state in the host. Thus, this pathogen has developed mechanisms to withstand stressful conditions found in the human host. Particularly, the Ser/Thr-protein kinase PknG has gained relevance since it regulates nitrogen metabolism and facilitates bacterial survival inside macrophages. Nevertheless, the molecu ...[more]

PMID: 34044169

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Project description:Analysis of transcriptional response to Plasmodium berghei ANKA infection in cerebral malaria susceptible C57BL/6 mouse brains as well as cerebral malaria resistant BXH2 mice which carry a severe hypomorphic Irf8-R294C allele. Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a loss-of-function allele at Irf8 (Irf8-R294C) that causes susceptibility to infection with intracellular pathogens, including Mycobacterium tuberculosis. We report that XH2 are completely resistant to the development of cerebral malaria following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes up-regulated by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes confers protection against experimental cerebral malaria. We also report strong overlap between genes bound and regulated by IRF8 during cerebral malaria and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. In summary, this work defines a common core of IRF8-bound genes forming a critical inflammatory host-response network. Comparison of whole brain transcript profiles for wildype C57BL/6 mice versus severely hypomorphic Irf8-R294C BXH2 mice following experimental infection with Plasmodium berghei ANKA (d7). Baseline (d0) profiles are also compared. Pleaes note that each sample record represents 2-4 replicates and sample data table contains mean, standard error of the mean (SEM), and quality for the replicates. The non_normalized data matrix contains raw data for each replicate (total 12 samples).

			Action	DRS
	KO1.txt	Txt
	KO2.txt	Txt
	PRM_200805_Mtb_KO1.raw	Raw
	PRM_200805_Mtb_KO1_bis.raw	Raw
	PRM_200805_Mtb_KO2.raw	Raw