Paper of the Semester Award
Gene evolutionary trajectories in Mycobacterium tuberculosis reveal temporal signs of selection
Published in PNAS
Álvaro Chiner-Oms, Mariana G. López, Miguel Moreno-Molina, Victoria Furió and Iñaki Comas
Genetic differences between different Mycobacterium tuberculosis complex (MTBC) strains are likely associated with different disease and epidemiological phenotypes. Said differences usually emerge through de novo mutations and are maintained or discarded by a balance of evolutionary forces which includes different types of selection and random population processes. Purifying selection is thought to be weak in MTBC but dominant. Only around 10% of the genes have evidence of genetic drift or positive selection, the latter mainly associated with drug resistance. Using a dataset of ∼5,000 strains representing global MTBC diversity and a methodology that reconstructs the evolutionary trajectory of each gene since the emergence of the MTBC, we have determined the action of past and present selective forces through time, for every single gene.
Almost half of the genes seem to have been under positive selection and/or genetic drift at some point in time, in contrast with previous estimates of 10% or less.
Temporal signals identify genes under positive selection in the past but highly conserved in the present. This includes epitopes that tend to accumulate older mutations, suggesting very early adaptation to host populations.
Temporal signals identify genes that were conserved in the past but under positive selection in the present. Beyond drug-resistant genes, we detected several sensor proteins of two-component systems and toxin-antitoxin systems.
When applied to an enriched drug resistance dataset from high-burden countries our approach correctly identifies changing selection patterns linked to first-line drug use and reveals candidate genes associated with resistance to second-line drugs. We functionally validated one of these genes, Rv1830.
In conclusion, our novel approach allows to incorporate the joint analysis of past and present evolutionary dynamics. Our results reveal hidden signals of the action of evolutionary forces and can be adapted to identify genes involved in different selective pressures.
High overall mortality of Mycobacterium genavense infections and impact of antimycobacterial therapy: Systematic review and individual patient data meta-analysis
Published in the Journal of Infection
Nils Wetzstein, Johanna Kessel, Tobias M. Bingold, Jonathan Carney, Christiana Graf, Benjamin F. Koch, Florian Meier, Justus Baumgarten, Claus P. Küpper-Tetzel, Yascha Khodamoradi, Timo Wolf, Gundolf Schüttfort, Maria J.G.T. Vehreschild, Thomas A. Wichelhaus, Christoph Stephan
Introduction: Mycobacterium genavense is a fastidious slow growing mycobacterium (SGM) that causes disseminated infections in immunocompromised hosts. It has been described in HIV-positive individuals and increasingly in patients without HIV. The infections are difficult to treat and the optimal antimy-cobacterial regimen is still unknown.
Methods: An individual patient data meta-analysis was conducted aiming at including all hitherto published cases of infection with M. genavense. Clinical manifestations, microbiological data, dispositions and immunosuppression were recorded. Antimycobacterial therapies and mortality were analyzed by logistic regression and time-to-event analysis.
Results: We included 223 patients with infection due to M. genavense published from 1992 to 2021. While the majority was HIV positive (n = 171, 76.7%), 52 patients were non-HIV-patients (23.3%), 36 of whom received immunosuppressive therapy (69%). We could confirm the bacterium's tropism for the gastroin-testinal tract with abdominal pain, hepato-/splenomegaly and abdominal lymphadenopathy being major clinical manifestations. More than 90% of patients received antimycobacterial therapy. The regimens consisted mainly of macrolides, rifamycins and ethambutol. Overall mortality was high, but in logistic regression and time-to-event analysis a macrolide containing regimen was associated with better outcomes.
Conclusion: In this first individual patient data meta-analysis of infections with M. genavense we confirm its tropism for the gastrointestinal tract. The high overall mortality underlines the clinical relevance of infection with this bacterium for the individual patient. In addition, our data give a hint that a macrolide containing regimen is associated with better survival.
Who is eligible?
First or last author of the publication, must be an ESM member at the time of the proposal and will be the recipient of the prize.
First or last author can only be awarded one prize a year.
In cases where there are co-first authors, it is sufficient for one of them to be an ESM member.
Submitted papers must have appeared within 6 months of the deadline, defined as the date of online publication
Each quarter, a prize of €500 will go to the first author (to be shared in the case of 2 first authors) and the winner will be asked to present their papers via a webinar during the month following the declaration of the winners. The presentations will be shown live on YouTube and will remain on the ESM website for those who could not watch them live. The 4 winners for each quarter will automatically be entered in the Paper of the Year Hugo David Award.
Proposals and selection process
The deadline for submitting publications will be 31 March, 30 June, 30 September and 31 December each year and the winner for each quarter will be announced within the month following the deadline.
Proposals are to be emailed to the ESM office (firstname.lastname@example.org). Please include an abstract along with a PDF copy of your paper.
The ESM Steering Committee will review the entries.