Section: New Results

Axis 4: Human, animal and plant health

Hydrogen peroxide production and myo-inositol metabolism as important traits for virulence of Mycoplasma hyopneumoniae

Mycoplasma hyopneumoniae is the causative agent of enzootic pneumonia. In a previous work, we had reconstructed the metabolic models of this species along with two other mycoplasmas from the respiratory tract of swine: Mycoplasma hyorhinis, considered less pathogenic but which nonetheless causes disease and Mycoplasma flocculare, a commensal bacterium. We had identified metabolic differences that partially explained their different levels of pathogenicity. One important trait was the production of hydrogen peroxide from the glycerol metabolism only in the pathogenic species. Another important feature was a pathway for the metabolism of myo-inositol in M. hyopneumoniae. In the paper accepted this year [9], we tested these traits to understand their relation to the different levels of pathogenicity, comparing not only the species but also pathogenic and attenuated strains of M. hyopneumoniae. Regarding the myo-inositol metabolism, we showed that only M. hyopneumoniae assimilated this carbohydrate and remained viable when myo-inositol was the primary energy source. Strikingly, only the two pathogenic strains of M. hyopneumoniae produced hydrogen peroxide in complex medium. We also showed that this production was dependent on the presence of glycerol. Although further functional tests are needed, this work enabled to identify two interesting metabolic traits of M. hyopneumoniae that might be directly related to its enhanced virulence. This is part of the work of Mariana G. Ferrarini, currently postdoc at Insa and in ERABLE, and of Scheila G. Mucha whose PhD (defended in Sept. 2018) was co-supervised by Arnaldo Zaha and by a member of ERABLE.

Cancer

A member of ERABLE continues deeply involved with the Centre Léon Bérard in Lyon, and in that context, a number of works are running, all related to cancer genomics. In the first [28], an integrated genomic study was performed of 25 tumour tissues from radical prostatectomy of aggressive (defined by the International Society of Urological Pathology) prostate cancer patients (10 African Caribbean and 15 French Caucasian) using single nucleotide polymorphism arrays, whole-genome sequencing, and RNA sequencing. The results showed that African Caribbean tumours are characterised by a more frequent deletion at 1q41-43 encompassing the DNA repair gene PARP1, and a higher proportion of intra-chromosomal rearrangements including duplications associated with CDK12 truncating mutations. Transcriptome analyses showed an over-expression of genes related to androgen receptor activity in African Caribbean tumours, and of PVT1, a long non-coding RNA located at 8q24 that confirms the strong involvement of this region in prostate tumours from men of African ancestry. In a second study [15], gene-expression profiling data was used to build and validate a predictive model of outcome for patients with follicular lymphoma. A robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from such patients was thus developed and validated. Applying this score could allow individualised therapy for patients according to their risk category. In a third study, an integrated analysis highlighted APC11 protein expression as a likely new independent predictive marker for colorectal cancer [6].

In a parallel work by another member of ERABLE [27], it was proposed that cancer Is not (only) a senescence problem. Age is indeed one of the strongest predictors of cancer and risk of death from cancer. Cancer is therefore generally viewed as a senescence-related malady. However, cancer also exists at subclinical levels in humans and other animals, but its earlier effects on the body are poorly known by comparison. What was argued in [27] is that cancer is a significant but ignored burden on the body and is likely to be a strong selective force from early during the lifetime of an organism. It was thus proposed that time has come to adopt this novel view of malignant pathologies to improve our understanding of the ways in which oncogenic phenomena influence the ecology and evolution of animals long before their negative impacts become evident and fatal.

Xylella fastidiosa epidemiological model

Xylella fastidiosa is a notorious plant pathogenic bacterium that represents a threat to crops worldwide. Its subspecies, Xylella fastidiosa subsp. fastidiosa is the causal agent of Pierce’s disease of grapevines. Pierce’s disease has presented a serious challenge for the grapevine industry in the United States and turned into an epidemic in Southern California due to the invasion of the insect vector Homalodisca vitripennis. In an attempt to minimize the effects of Xylella fastidiosa subsp. fastidiosa in vineyards, various studies have been developing and testing strategies to prevent the occurrence of Pierce’s disease, i.e., prophylactic strategies. Research has also been undertaken to investigate therapeutic strategies to cure vines infected by Xylella fastidiosa subsp. fastidiosa. In [18], we explicitly review all the strategies published to date and specifies their current status. Furthermore, an epidemiological model of Xylella fastidiosa subsp. fastidiosa is proposed and key parameters for the spread of Pierce’s disease deciphered in a sensitivity analysis of all model parameters. Based on these results, it is concluded that future studies should prioritise therapeutic strategies, while investments should only be made in prophylactic strategies that have demonstrated promising results in vineyards. This is part of the PhD of Henri Taneli Pusa in the context of the H2020 ITN MicroWine, together with another PhD student of the ITN, Ifigeneia Kyrkou. Ifigeneia was the first author of the paper [18] but the mathematical model is the work of Taneli.