Atypical network topologies enhance the reductive capacity of pathogen thiol antioxidant defense networks

Infectious diseases are a significant health burden for developing countries, particularly with the rise of multi drug resistance. There is an urgent need to elucidate the factors underlying the persistence of pathogens such as Mycobacterium tuberculosis, Plasmodium falciparum and Trypanosoma brucei. In contrast to host cells, these pathogens traverse multiple and varied redox environments during their infectious cycles, including exposure to high levels of host-derived reactive oxygen species. Pathogen antioxidant defenses such as the peroxiredoxin and thioredoxin systems play critical roles in the redox stress tolerance of these cells. However, many of the kinetic rate constants obtained for the pathogen peroxiredoxins are broadly similar to their mammalian homologs and therefore, their contributions to the redox tolerances within these cells are enigmatic. Using graph theoretical analysis, we show that compared to a canonical Escherichia coli redoxin network, pathogen redoxin networks contain unique network connections (motifs) between their thioredoxins and peroxiredoxins. Analysis of these motifs reveals that they increase the hydroperoxide reduction capacity of these networks and, in response to an oxidative insult, can distribute fluxes into specific thioredoxin-dependent pathways. Our results emphasize that the high oxidative stress tolerance of these pathogens depends on both the kinetic parameters for hydroperoxide reduction and the connectivity within their thioredoxin/peroxiredoxin systems.

Automated summary

Infectious diseases pose a significant health burden, especially with the emergence of drug-resistant strains in developing countries. Understanding the factors that contribute to pathogen persistence, such as Mycobacterium tuberculosis and Plasmodium falciparum, is crucial. Pathogen antioxidant defenses, such as peroxiredoxin and thioredoxin systems, play critical roles in their ability to tolerate oxidative stress.