Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / JOB Viviana

Complement Evaders-new bacterial strategy to persist in the human blood

Blood infections caused by bacterial pathogens are particularly lethal in hospital settings. Once bacteria, such as Pseudomonas aeruginosa, enter the circulation, it must deal with the blood’s innate immune system. However, the strategies employed by this pathogen to resist the  complement system and phagocytic cells have never been studied in the whole blood model. By studying the survival of a set of six strains of Pa in human whole blood, we have shown that resistance to the microbicidal activity of complement is the main driver of bacterial survival. We also discovered that complement sensitive bacteria were able to avoid total eradication, thanks to the formation of a subpopulation called "evaders" resistant to the lytic action of complement. According to the studied strains, these "evaders" represent between 0,0001 and 0,01 % of the initial population. [1]. Evaders are formed in other opportunistic pathogenic bacteria such as Acinetobacter baumannii, Burkholderia multivorans, Escherichia coli, Klebsiella pneumoniae  and Yersinia enterocolitica. Although genetically identical to the rest of the complement-sensitive population, these "evaders" are developing a new strategy enabling them to persist in the bloodstream and thus spread throughout the body, particularly in the absence of effective antibiotic treatments.

Two mechanisms can explain the appearance of "evaders" :
- random mechanism : randomly, bacteria undergo epigenetic / phenotypic modifications some of which predispose them to increased resistance to stress induced by the complement system (red bacteria). When stress is applied, all bacteria except those having acquired this phenotype in particular, are eliminated. When stress is removed, these variant phenotypes divide and generate a population identical to the starting population composed mainly of sensitive bacteria and a weak proportion of "evaders".
- mechanism triggered by stress : the application of stress by the complement system induces the onset phenotypic changes leading to increased resistance to this stress. All bacteria except those having acquired this particular phenotype, are eliminated when stress is applied. When stress is removed, these phenotypic variants divide and generate a population identical to the starting population, at know devoid of "evaders".

Reference :
[1] Pont S, et al (2021) PLoS Pathogens. DOI : 10.1371/journal.ppat.1008893