ComputOmics Biosys Programme - Metabolomics and genomics of microbial infections and gut microbiome dynamics in patients under going allogeneic hematopoietic stem cell transplantation

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Deciphering the molecular bases of virulence-related phenotypes through multi-omic approaches

Publication . Santamaria, Guillem; Pinto, Francisco Rodrigues; Xavier, João de Bivar; Devis, Mireia Coscollá

Virulence is defined as the degree of disease severity and lethality produced by a pathogen and is conditioned by virulence factors, which vary depending on the pathogen and determine the range of hosts it can infect. As a result, virulence is a complex phenotype, dependent on multiple molecular determinants. Omic techniques are thus a good way to investigate it. This thesis discusses two virulence-related phenotypes in two pathogens: surfactant biosynthesis in Pseudomonas aeruginosa and host specificity in Mycobacterium tuberculosis. P. aeruginosa is an opportunistic gram-negative pathogen that infects immunocompromised patients. Its collective behaviors are crucial during infection. They require the secretion of biosurfactants, secondary metabolites that enable the bacteria to spread through moist surfaces, which is highly regulated by environmental cues. Conversely, M. tuberculosis is a mammal obligate pathogen whose first infection targets are the macrophages. There are several M. tuberculosis lineages, which present host association. Identifying the factors that affect the inclination towards a host can show host-specific virulence patterns. Here, through a multi-omic approach we gained insight about these two phenotypes. We observed that surfactant production is inconsistent across P. aeruginosa’s phylogeny and added an additional layer of regulation of this phenotype, dependent on oxidative stress. Regarding M. tuberculosis, through metabolic modeling we predicted the lineage-specific genomic differences to produce host-correlated convergent alterations in metabolic pathways important for its virulence. Furthermore, we pinpointed candidate genes for their involvement in host specificity, such as Phospholipase C ones. Finally, by using an in vitro infection model we expanded the current knowledge about the adaptation of animal-associated lineages to their hosts and found experimental evidence supporting the involvement of the phospholipase C plcC gene in the adaptation to humans. Metabolism was central in the exploration of these phenotypes. Because it is at the end of the biological information chain, it is closer to phenotype than any other omic dataset. Metabolomics gave a comprehensive picture of the researched biological systems, allowing for the formulation of hypotheses that could later be empirically tested. The bioinformatic pipelines developed in this thesis can be applied to the study of other complex phenotypes in other organisms. The knowledge gained about these virulence related phenotypes might serve as a basis for developing new therapies against these pathogens.

2023-09Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/142899/2018