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A new resistance strategy in pathogenic bacteria


We have highlighted a subpopulation of "evader" bacteria resistant to the lytic action of complement. These rare cells are genetically identical to the rest of the complement sensitive population, and are developing a new strategy allowing them to persist in the blood and to spread throughout the body, particularly in the absence of effective antibiotic treatments.

Published on 1 December 2020
Pseudomonas aeruginosa (Pa) s a Gram-negative bacterium considered as an opportunistic pathogen, mainly found in immunocompromised patients or patients with cystic fibrosis. Pa is a major cause of nosocomial infections leading to pulmonary and urinary pathologies, but is also frequently isolated from the blood of patients with bacteremia. Blood infections caused by this pathogen are particularly lethal compared to sepsis associated with other bacterial species. Once it enters the circulation, Pa 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 whole blood.

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 strain, these "evaders" represent between 0,0001 and 0,01 % of the initial population. These rare cells have also been observed 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.
We were also able to identify new bacterial factors involved in the interaction between Pa and the complement system. We observed that bacteria unable to synthesize certain essential molecules such as biotin (a vitamin) and purines (the basic component of nucleic acids) survive better in plasma than the parental strain. They also identified a contiguous set of three genes (an operon) whose products are predicted to be localized to the Pa membrane. The overexpression of the proteins of this operon confers to the bacterium an increased survival in plasma by a factor of 1,000 compared to the wild strain, and induces an overproduction of alginates in the latter, suggesting the existence of a complex interaction between the bacterial membrane, the secretion of exopolysacharides and the lytic action of complement.


Two mechanisms can explain the appearance of "evaders":

random mechanism: randomly, the bacteria undergo epigenetic/phenotypic modifications, some of which predispose them to an increased resistance to stress induced by the complement system (red bacteria). When stress is applied, all bacteria except those having acquired this particular phenotype are eliminated. When the stress is removed, these phenotypic variants divide and generate a population identical to the starting population composed mainly of sensitive bacteria and a small proportion of "evaders".
stress-triggered mechanism: the application of stress by the complement system induces the appearance of phenotypic modifications leading to an increased resistance to this stress. All bacteria, except those having acquired this particular phenotype, are eliminated when the stress is applied. When the stress is removed, these phenotypic variants divide and generate a population identical to the starting population, i.e. free of "evaders".
The complement system is a defense mechanism composed of about 35 proteins and is part of innate immunity. It acts either by direct bacterial lysis or by opsonophagocytosis (phagocytosis increased by the deposition of osponin C3b on the surface of the pathogen and then taken up by specialized receptors on the phagocytic cells). The action of the complement also contributes to stimulate the inflammation by production of proteins C3a and C5a.
Alginates are polysaccharides and are an important component of biofilms produced by certain bacteria to protect themselves; biofilms that are highly resistant to antibiotics and white blood cells.
Collaboration with the Université Libre de Bruxelles, Department of Molecular Biology, Cellular & Molecular Microbiology, with the Centre Hospitalier Universitaire Grenoble Alpes, Laboratoire de bactériologie-Hygiène hospitalière, and with the TIMC-Imag laboratory, Grenoble INP.

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