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Host specific in vitro virulence of different Mycobacterium tuberculosis ecotypes

M Caballer-Gual(1) G Santamaria(1) C Gomis-Olcina(1) C Renau-Minguez(1) A Espert-Rehues(1) P Ruiz-Rodriguez(1) M Coscolla(1)

1:I2SysBio, University of Valencia-FISABIO Joint Unit, 46980 Paterna, Spain

Tuberculosis (TB), a leading cause of adult death from infectious agents worldwide, is caused by a complex of phylogenetically related bacteria comprising various Mycobacterium tuberculosis (MTB) ecotypes. This complex consists of nine human-associated lineages and four animal-associated lineages. A deeper understanding of host-pathogen interactions in TB is essential to comprehend the co-evolution of pathogens and hosts, ultimately leading to the development of novel strategies to control MTB.

We hypothesise that virulence is influenced by host specificity, suggesting that MTB strains exhibit greater virulence in their preferred hosts, and that specific bacterial-host signatures can be identified. To test this hypothesis, we conducted experiments in which bovine and human macrophage cell lines were infected with strains from two animal-associated lineages.

Our analysis demonstrated that preferred host-ecotype combinations, as derived from epidemiological data, resulted in higher necrosis levels and more robust growth dynamics during in vitro infection compared to non-preferred bacterial-host combinations. Additionally, to describe the dynamics of bacteria and host-specific signatures during in vitro infection, we analysed and characterised bacterial and host expression signatures across the different host-pathogen combinations. This approach allowed us to uncover unique patterns and relationships between host and pathogen, providing insights into the mechanisms underlying host-specific virulence.

Further investigations incorporating metabolomic and proteomic analyses could provide additional specific molecular signatures of host-pathogen-specific virulence, advancing our understanding of the complex interactions between MTB and its hosts. This knowledge could ultimately contribute to the development of improved diagnostic tools, therapies, and preventative measures against TB.

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