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Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota.

Ayres JS, Trinidad NJ, Vance RE - Nat. Med. (2012)

Bottom Line: The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host.In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice.These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular & Cell Biology, Division of Immunology & Pathogenesis, University of California, Berkeley, USA. jayres@berkeley.edu

ABSTRACT
The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobiont, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis-like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant Escherichia coli pathobiont that expanded markedly in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.

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Systemic E. coli-O21:H+ infection is pathogenic in wild-type mice(a) Survival of wild-type female mice injected with live or dead 5×108, 7.5×108 or 1×109 live E. coli-O21:H+. P < 0.0001 for live vs. dead comparisons by Log rank analysis, (n = 5) females for all conditions.(b) Rectal temperature of wild-type female mice injected with 5×108, 7.5×108 or 1×109 live or dead E. coli-O21:H+. At 6 h PI 1×109 live vs. 1×109 dead P = 0.0079, 7.5×108 live vs. 7.5×108 dead P = 0.0079, at 24 h PI 5×108 live vs. 5×108 dead P = 0.0195. (n = 5) for all conditions.(c) Wild-type female mice were inoculated with 5×108 live or dead E. coli-O21:H+ and serum levels of BUN, CPK, ALT and AST were analyzed 24 h post infection. (n = 4) for live infection and (n = 12) females for dead infection. *P < 0.05, **P < 0.01 and *** P < 0.0005 by Student t-test and error bars indicate standard deviation.(d) E. coli-O21:H+ CFUs in liver, lung, spleen and kidneys of wild-type female mice infected with 5×108 live bacteria at 24 and 48 h post infection. (n = 3) at both 24 h and 48 h PI and error bars indicate standard deviation.(e) Survival of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. P < 0.0001 by Log rank analysis. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.(f) Rectal temperature of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.
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Figure 3: Systemic E. coli-O21:H+ infection is pathogenic in wild-type mice(a) Survival of wild-type female mice injected with live or dead 5×108, 7.5×108 or 1×109 live E. coli-O21:H+. P < 0.0001 for live vs. dead comparisons by Log rank analysis, (n = 5) females for all conditions.(b) Rectal temperature of wild-type female mice injected with 5×108, 7.5×108 or 1×109 live or dead E. coli-O21:H+. At 6 h PI 1×109 live vs. 1×109 dead P = 0.0079, 7.5×108 live vs. 7.5×108 dead P = 0.0079, at 24 h PI 5×108 live vs. 5×108 dead P = 0.0195. (n = 5) for all conditions.(c) Wild-type female mice were inoculated with 5×108 live or dead E. coli-O21:H+ and serum levels of BUN, CPK, ALT and AST were analyzed 24 h post infection. (n = 4) for live infection and (n = 12) females for dead infection. *P < 0.05, **P < 0.01 and *** P < 0.0005 by Student t-test and error bars indicate standard deviation.(d) E. coli-O21:H+ CFUs in liver, lung, spleen and kidneys of wild-type female mice infected with 5×108 live bacteria at 24 and 48 h post infection. (n = 3) at both 24 h and 48 h PI and error bars indicate standard deviation.(e) Survival of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. P < 0.0001 by Log rank analysis. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.(f) Rectal temperature of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.

Mentions: To determine if the E. coli-O21:H+ isolate is sufficient to cause disease in wild-type mice with a normal (non-antibiotic treated) microbiota, we intravenously injected normal B6 mice with live or dead E. coli-O21:H+ and monitored disease. Mice were highly susceptible to a systemic challenge of live but not heat-killed bacteria (Fig. 3a). In addition, systemic live E. coli-O21:H+ infection was sufficient to recapitulate the specific pathology associated with AVNM+DSS treatment (Fig. 3b, c). Furthermore, live E. coli-infected mice exhibited tissue colonization patterns and levels similar to what was observed in AVNM+DSS-treated wild-type mice (Fig. 1i, 3d and Supplementary Fig. 2b, c). Thus, in fulfillment of Koch's postulates, a live systemic infection with E. coli-O21:H+ is sufficient to recapitulate the mortality and morbidity associated with AVNM+DSS-induced sepsis.


Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota.

Ayres JS, Trinidad NJ, Vance RE - Nat. Med. (2012)

Systemic E. coli-O21:H+ infection is pathogenic in wild-type mice(a) Survival of wild-type female mice injected with live or dead 5×108, 7.5×108 or 1×109 live E. coli-O21:H+. P < 0.0001 for live vs. dead comparisons by Log rank analysis, (n = 5) females for all conditions.(b) Rectal temperature of wild-type female mice injected with 5×108, 7.5×108 or 1×109 live or dead E. coli-O21:H+. At 6 h PI 1×109 live vs. 1×109 dead P = 0.0079, 7.5×108 live vs. 7.5×108 dead P = 0.0079, at 24 h PI 5×108 live vs. 5×108 dead P = 0.0195. (n = 5) for all conditions.(c) Wild-type female mice were inoculated with 5×108 live or dead E. coli-O21:H+ and serum levels of BUN, CPK, ALT and AST were analyzed 24 h post infection. (n = 4) for live infection and (n = 12) females for dead infection. *P < 0.05, **P < 0.01 and *** P < 0.0005 by Student t-test and error bars indicate standard deviation.(d) E. coli-O21:H+ CFUs in liver, lung, spleen and kidneys of wild-type female mice infected with 5×108 live bacteria at 24 and 48 h post infection. (n = 3) at both 24 h and 48 h PI and error bars indicate standard deviation.(e) Survival of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. P < 0.0001 by Log rank analysis. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.(f) Rectal temperature of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.
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Figure 3: Systemic E. coli-O21:H+ infection is pathogenic in wild-type mice(a) Survival of wild-type female mice injected with live or dead 5×108, 7.5×108 or 1×109 live E. coli-O21:H+. P < 0.0001 for live vs. dead comparisons by Log rank analysis, (n = 5) females for all conditions.(b) Rectal temperature of wild-type female mice injected with 5×108, 7.5×108 or 1×109 live or dead E. coli-O21:H+. At 6 h PI 1×109 live vs. 1×109 dead P = 0.0079, 7.5×108 live vs. 7.5×108 dead P = 0.0079, at 24 h PI 5×108 live vs. 5×108 dead P = 0.0195. (n = 5) for all conditions.(c) Wild-type female mice were inoculated with 5×108 live or dead E. coli-O21:H+ and serum levels of BUN, CPK, ALT and AST were analyzed 24 h post infection. (n = 4) for live infection and (n = 12) females for dead infection. *P < 0.05, **P < 0.01 and *** P < 0.0005 by Student t-test and error bars indicate standard deviation.(d) E. coli-O21:H+ CFUs in liver, lung, spleen and kidneys of wild-type female mice infected with 5×108 live bacteria at 24 and 48 h post infection. (n = 3) at both 24 h and 48 h PI and error bars indicate standard deviation.(e) Survival of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. P < 0.0001 by Log rank analysis. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.(f) Rectal temperature of wild-type female mice infected with 5×108 live E. coli-O21:H+ or E. coli-K12. (n = 8) for both E. coli-O21:H+ and E. coli-K12 injections.
Mentions: To determine if the E. coli-O21:H+ isolate is sufficient to cause disease in wild-type mice with a normal (non-antibiotic treated) microbiota, we intravenously injected normal B6 mice with live or dead E. coli-O21:H+ and monitored disease. Mice were highly susceptible to a systemic challenge of live but not heat-killed bacteria (Fig. 3a). In addition, systemic live E. coli-O21:H+ infection was sufficient to recapitulate the specific pathology associated with AVNM+DSS treatment (Fig. 3b, c). Furthermore, live E. coli-infected mice exhibited tissue colonization patterns and levels similar to what was observed in AVNM+DSS-treated wild-type mice (Fig. 1i, 3d and Supplementary Fig. 2b, c). Thus, in fulfillment of Koch's postulates, a live systemic infection with E. coli-O21:H+ is sufficient to recapitulate the mortality and morbidity associated with AVNM+DSS-induced sepsis.

Bottom Line: The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host.In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice.These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular & Cell Biology, Division of Immunology & Pathogenesis, University of California, Berkeley, USA. jayres@berkeley.edu

ABSTRACT
The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobiont, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis-like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant Escherichia coli pathobiont that expanded markedly in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.

Show MeSH
Related in: MedlinePlus