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BIOMD0000000527 - Kaiser2014 - Salmonella persistence after ciprofloxacin treatment

 

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Reference Publication
Publication ID: 24558351
Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD.
Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
PLoS Biol. 2014 Feb; 12(2): e1001793
Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.  [more]
Model
Original Model: BIOMD0000000527.origin
Submitter: Roland Regoes
Submission ID: MODEL1312170001
Submission Date: 17 Dec 2013 18:51:15 UTC
Last Modification Date: 10 Oct 2014 10:48:03 UTC
Creation Date: 25 Mar 2014 16:03:05 UTC
Encoders:  Vijayalakshmi Chelliah
   Roland Regoes
set #1
bqbiol:hasVersion Human Disease Ontology primary bacterial infectious disease
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:isVersionOf Gene Ontology response to antibiotic
set #4
bqbiol:hasTaxon Taxonomy Salmonella enterica subsp. enterica serovar Typhimurium str. DT104
Taxonomy Mus musculus
set #5
bqmodel:is BioModels Database MODEL1312170001
Notes
Kaiser2014 - Salmonella persistence after ciprofloxacin treatment

The model describes the bacterial tolerance to antibiotics. Using a mouse model for Salmonella diarrhea, the authors have found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states. One, the fast-growing population that spreads in the host's tissues and the other, slow-growing "persister" population that hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotics. However, this can be killed by adding agents that directly stimulate the host's immune defense.

This model is described in the article:

Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD.
PLoS Biol. 2014 Feb 18;12(2):e1001793.

Abstract:

In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 24558351 Submission Date: 17 Dec 2013 18:51:15 UTC Last Modification Date: 10 Oct 2014 10:48:03 UTC Creation Date: 25 Mar 2014 16:03:05 UTC
Mathematical expressions
Rules
Rate Rule (variable: L)      
Physical entities
Compartments Species
Lymph node L    
Global parameters
mu1 r1 c1 t1
mu3 r3 c3 t3
mu5 r5 c5 t5
mu10 r10 c10 t10
Reactions (0)
Rules (1)
 
 Rate Rule (name: L) d [ L] / d t= piecewise(mu1+(r1-c1)*L, (time >= 0) && (time <= t1), mu3+(r3-c3)*L, (time > t1) && (time <= t3), mu5+(r5-c5)*L, (time > t3) && (time <= t5), mu10+(r10-c10)*L, (time > t5) && (time <= t10))
 
 Lymph node Spatial dimensions: NaN  Compartment size: 1.0  (Units: dimensionless)
 
 L
Compartment: Lymph node
Initial amount: 0.0  (Units: dimensionless)
 
Global Parameters (16)
 
   mu1
Value: 297.78957   (Units: per_day)
Constant
 
   r1
Value: 2.8195198   (Units: per_day)
Constant
 
   c1
Constant
 
   t1
Value: 1.0   (Units: day)
Constant
 
   mu3
Constant
 
   r3
Value: 4.5867007   (Units: per_day)
Constant
 
   c3
Value: 5.042901   (Units: per_day)
Constant
 
   t3
Value: 3.0   (Units: day)
Constant
 
   mu5
Constant
 
   r5
Value: 1.8812956   (Units: per_day)
Constant
 
   c5
Value: 2.497735   (Units: per_day)
Constant
 
   t5
Value: 5.0   (Units: day)
Constant
 
   mu10
Constant
 
   r10
Value: 0.3757764   (Units: per_day)
Constant
 
   c10
Value: 2.43E-7   (Units: per_day)
Constant
 
   t10
Value: 10.0   (Units: day)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000527

Curator's comment: (updated: 25 Mar 2014 16:02:34 GMT)

Figure 4B of the reference publication is reproduced here. Copasi v4.11 (Build 64) was used to run the simulation. The figure was generated using Gnuplot.

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