The genotoxin colibactin exacerbates lymphopenia and decreases survival rate in mice infected with septicemic Escherichia coli.
Sepsis is a life-threatening infection. Escherichia coli is the first known cause of bacteremia leading to sepsis. Lymphopenia was shown to predict bacteremia better than conventional markers of infection. The pks genomic island, which is harbored by extraintestinal pathogenic E. coli (ExPEC) and encodes the genotoxin colibactin, is epidemiologically associated with bacteremia. To investigate a possible relationship between colibactin and lymphopenia, we examined the effects of transient infection of lymphocytes with bacteria that were and those that were not producing the genotoxin. A mouse model of sepsis was used to compare the virulence of a clinical ExPEC isolate with its isogenic mutant impaired for the production of colibactin. We observed that colibactin induced double-strand breaks in the DNA of infected lymphocytes, leading to cell cycle arrest and to cell death by apoptosis. E. coli producing colibactin induced a more profound lymphopenia in septicemic mice, compared with the isogenic mutant unable to produce colibactin. In a sepsis model in which the mice were treated by rehydration and antibiotics, the production of colibactin by the bacteria was associated with a significantly lower survival rate. In conclusion, we demonstrate that production of colibactin by E. coli exacerbates lymphopenia associated with septicemia and could impair the chances to survive sepsis.
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse EA 4666 UFR de Médecine, CAP-Santé (FED 4231), Université de Picardie Jules Verne, Amiens, France.
Ingrid
I
Marcq
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Patricia
P
Martin
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Delphine
D
Payros
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Gabriel
G
Cuevas-Ramos
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Michèle
M
Boury
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Claude
C
Watrin
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse.
Jean-Philippe
JP
Nougayrède
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse Neuro-gastroenterologie et Nutrition, UMR INRA/ENVT 1331.
Maïwenn
M
Olier
UMR1043, Inserm USC 1360, INRA UMR 5282, CNRS UPS, Centre de Physiopathologie de Toulouse Purpan, UPS, Université de Toulouse Hôpital Purpan, Service de bactériologie-Hygiène, CHU Toulouse, Toulouse.
Eric
E
Oswald
D000818:Animals; D016923:Cell Death; D053903:DNA Breaks, Double-Stranded; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000150:complications / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D008214:Lymphocytes / Q000382:microbiology / Q000502:physiology; D008231:Lymphopenia / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity*; D010455:Peptides / Q000235:genetics / Q000633:toxicity*; D061065:Polyketides / Q000633:toxicity*; D018805:Sepsis / Q000150:complications / Q000473:pathology*; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000633:toxicity*
D009153:Mutagens; D010455:Peptides; D061065:Polyketides; D037521:Virulence Factors; C569566:colibactin
E. coli; colibactin; lymphonia; sepsis; toxin