Overview

Also Known As:TLR5 KO

Mice that are homozygous for the toll-like receptor 5 (Tlr5) knock-out have increased fat mass, increased serum triglyceride and cholesterol levels, increased blood pressure, and higher than normal production of pro-inflammatory cytokines interferon gamma and interleukin 1 beta in adipose tissue. Homozygotes offer a model of metabolic syndrome for which the hyperphagia, obesity, hyperglycemia, insulin resistance, colomegaly, and increased pro-inflammatory cytokines can be transferred from diseased homozygotes to wild-type hosts by tranplanting gut microbiota.

Donating Investigator

Dr. Richard A. Flavell, Yale University School of Medicine

Genetic overview

Genetic Background	Generation
	N10+pN1F13 (2019-06-12 00:00:00)

Tlr5^tm1Flv

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Tlr5	toll-like receptor 5

View Genetics

Research Applications

Internal/Organ Research
Immunology, Inflammation and Autoimmunity Research
Diabetes and Obesity Research

View All Research Applications

Base Price

Starting at:

$236.78 Domestic price for female 4-week

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Details

Detailed Description

The toll-like receptor gene targeted in this strain is a sensor for monomeric flagellin, a component of bacterial flagella known to be a virulence factor. These mice have been used to investigate the mechanism of flagellin detection and signalling in antibacterial immune responses to Salmonella typhimurium and Pseudomonas aeruginosa. The gene has been found to be essential for the recognition of bacterial flagellin both in vivo and ex vivo. Mice that are homozygous for this targeted deletion are viable and fertile. Transcripts of this gene are absent from bone marrow-derived macrophages in homozygotes.

Relative to controls, homozygotes have increased fat mass throughout the body, particularly in visceral fat, a substantial increase in serum triglyceride and cholesterol levels, increased blood pressure, and higher than normal production of pro-inflammatory cytokines interferon gamma and interleukin 1 beta in adipose tissue. Basal insulin levels and insulin production in response to a glucose challenge are significantly elevated, and the response to exogenous insulin is reduced compared with that of controls. The ability to restore blood glucose to baseline levels after administration of a bolus of glucose is impaired, and a mild elevation in blood glucose levels is found after an overnight fast. After 8 weeks on a high fat diet fasting glucose concentrations exceed 120 mg/dL, inflammatory infiltrates are found in the pancreatic islets, and hepatic steatosis is observed.

Homozygotes offer a model of metabolic syndrome for which the hyperphagia, obesity, hyperglycemia, insulin resistance, colomegaly, and increased pro-inflammatory cytokines can be transferred from diseased homozygotes to wild-type hosts by tranplanting gut microbiota. Treatment of homozygotes with broad spectrum antibiotics for 12 weeks corrects the metabolic syndrome. Hysterectomy re-derivation to upgrade the microbial flora of homozygotes results in diminished severity of colitis and a more uniform phenotype of mild inflammation and obesity, including a 20% increase in body mass at 20 weeks of age.

Development

A targeting vector was used to replace the coding region with a loxP-flanked neomycin resistance cassette inserted in the opposite transcriptional orientation. 129S1/Sv Oca2⁺ Tyr⁺ Kitl⁺-derived W9.5 embryonic stem (ES) cells were used to create the mutation. Resultant male chimeric mice were mated to C57BL/6 females. The donating investigator reported that this strain was backcrossed ten times to C57BL/6/Ncr mice (see SNP note below).

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, at least 1 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Feuillet V; Medjane S; Mondor I; Demaria O; Pagni PP; Galan JE; Flavell RA; Alexopoulou L. 2006. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci U S A 103(33):12487-12492PubMed: 16891416 MGI: J:111778
Vijay-Kumar M; Aitken JD; Carvalho FA; Cullender TC; Mwangi S; Srinivasan S; Sitaraman SV; Knight R; Ley RE; Gewirtz AT. 2010. Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5. Science 328(5975):228-31PubMed: 20203013 MGI: J:158055

View All References

Genetics

Tlr5^tm1Flv

Allele Symbol: Tlr5^tm1Flv

Allele Name	targeted mutation 1, Richard Flavell
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)
Gene Symbol and Name	Tlr5, toll-like receptor 5
Gene Synonym(s)
Strain of Origin	129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺
Chromosome	1
Molecular Note	A loxP-flanked neomycin selection cassette replaced the coding exon for the gene. mRNA expression in mutant and WT BM-derived macrophages was assessed by RT-PCR. Transcripts were absent in mutant but not in WT macrophages.
Mutations Made By	Dr. Richard Flavell, Yale University School of Medicine

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Tlr5^tm1Flv related

Internal/Organ Research
- Gastrointestinal Defects
  - colitis
Diabetes and Obesity Research
- Hyperglycemia
- Insulin Resistance
Immunology, Inflammation and Autoimmunity Research
- Inflammation

Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - Tlr deficiency
- Inflammation
  - Tlr deficiency
- CD Antigens, Antigen Receptors, and Histocompatibility Markers
  - genes regulating susceptibility to infectious disease and endotoxin
  - Tlr deficiency

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Tlr5^tm1Flv/Tlr5^tm1Flv
involves: 129S1/Sv * C57BL/6

adipose tissue phenotype

abnormal adipose tissue physiology
- adipose tissue has a higher than normal production of interferon gamma and interleukin 1 beta

increased epididymal fat pad weight
- at 20 weeks of age the epididymal fat pads are approximately 2 fold greater than normal

increased total body fat amount
- magnetic resonance imaging shows increased fat mass throughout the body, especially the visceral fat

digestive/alimentary phenotype

abnormal gut flora balance
- the gut microbiotica shows enrichment or reduction of 116 bacterial phylotypes relative to wild-type controls and transplanting gut microbiota from homozygotes to germ-free control hosts confers many aspects of the metabolic disease phenotype

increased susceptibility to induced colitis
- while 10% of homozygotes have severe colitis and and additional 30% have less severe colitis, the severity of colitis is greatly attenuated in homozygotes rederived into a cleaner environment

endocrine/exocrine gland phenotype

increased susceptibility to induced pancreatitis
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

growth/size/body region phenotype

increased body weight

increased susceptibility to diet-induced obesity
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

obese
- by 4 weeks of age the body mass is an average of 15% above that of normal controls and in homozygotes rederived into a clean facility the body mass at 20 weeks of age is 20% greater than normal controls in both males and females

hematopoietic system phenotype

decreased neutrophil cell number
- neutrophils are absent from BALFs from challenged mutants but wild-type show significant accumulation

homeostasis/metabolism phenotype

abnormal glucose homeostasis
- after a 15 hour fast homozygotes on a normal diet have slightly elevated glucose levels and when non-fasting homozygotes are administered a bolus of glucose they display an impaired ability to restore blood glucose to baseline levels
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

abnormal physiological response to xenobiotic
- decimation of the gut microbiota by treatment with broad spectrum antibiotics for 12 weeks beginning at wean age corrects the metabolic syndrome that develops in the absence of antibiotics

increased circulating cholesterol level
- significantly higher serum cholesterol levels

increased circulating insulin level
- basal serum insulin levels are significantly higher than normal, with an average over .55 nm/mL

increased circulating triglyceride level
- significantly higher serum triglyceride levels

increased susceptibility to diet-induced obesity
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

insulin resistance
- although food restriction prevents increased body and fat pad mass, increased serum glucose, lipids, and insulin, food restricted homozygotes still have a decreased response to exogenous insulin
- the amount of insulin produced in response to a glucose challenge is significantly increased to approximately 1.2 nm/mL, serum levels of lipocalin 2 are elevated, and the number and size of pancreatic islets that stain positive for insulin is increased

immune system phenotype

abnormal cytokine secretion
- after i.p. injection with flagellin, wild-type mice show elevated serum levels of Il-6 at 2 hours and Il-12 at 2 and 4 hours after challenge but mutants are unresponsive
- elevated Il-6 and Il-12 mRNA levels are detected in cultured wild-type dendritic cells in response to flagellin; mutant DCs show little response although response to LPS is similar to wild-type
- increases in Il-6 and keratinocyte chemoattractant in BALFs after challenge are present in wild-type but absent in mutants

abnormal dendritic cell physiology
- mutant cells show normal responses to LPS injection
- when mutants are injected i.p. with flagellin, splenic cells show no response after 6 hours, whereas cells from wild-type mice display maturation markers in response to flagellin

abnormal response to transplant
- when wild-type bone marrow is transplanted into Tlr5 mutants, significant amounts of Il-6 are found in sera upon flagellin challenge; when Tlr5 -null bone marrow is put into wild-type mice, flagellin challenge only results in a small Il-6 response

decreased neutrophil cell number
- neutrophils are absent from BALFs from challenged mutants but wild-type show significant accumulation

increased susceptibility to autoimmune diabetes

increased susceptibility to bacterial infection
- at dose of 6 x 10⁶ cfu, mutants succumb to infection in 2 days
- infection with P. aeruginosa (1 x 10⁶ cfu) results in similar survival rates to wild-type at 7 weeks of age (~85-90%)
- when infected by i.p. with S. typhimurium (SB300) and a non-flagellated form (SB762) wild-type and mutants show similar survival time and bacterial load in spleens and livers

increased susceptibility to induced colitis
- while 10% of homozygotes have severe colitis and and additional 30% have less severe colitis, the severity of colitis is greatly attenuated in homozygotes rederived into a cleaner environment

increased susceptibility to induced pancreatitis
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

lung inflammation
- after intranasal (i.n.) challenge with flagellin, at 10 and 24 hours after challenge bronchoalveolar lavage fluids (BALFs) from mutants show no cell infiltration while wild-type mice have elevated cell content and infiltration

behavior/neurological phenotype

abnormal eating behavior

polyphagia
- homozygotes consume approximately 10% more food than wild-type controls and have greater stool output

liver/biliary system phenotype

hepatic steatosis
- when homozygotes are fed a high-fat diet they develop inflammatory infiltrates in the pancreatic islets, have fasting glucose concentrations greater than 120 mg/dL, and display hepatic steatosis

respiratory system phenotype

lung inflammation
- after intranasal (i.n.) challenge with flagellin, at 10 and 24 hours after challenge bronchoalveolar lavage fluids (BALFs) from mutants show no cell infiltration while wild-type mice have elevated cell content and infiltration

cardiovascular system phenotype

hypertension

increased systemic arterial blood pressure

increased systemic arterial diastolic blood pressure
- average is raised to approximately 110mm Hg

increased systemic arterial systolic blood pressure
- average is increased to appoximately 130mm Hg

Genotype: Tlr5^tm1Flv/Tlr5^tm1Flv
involves: 129S1/Sv

cellular phenotype

abnormal leukocyte migration
- flagellin-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

hematopoietic system phenotype

abnormal leukocyte migration
- flagellin-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

immune system phenotype

abnormal leukocyte migration
- flagellin-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

References

Feuillet V; Medjane S; Mondor I; Demaria O; Pagni PP; Galan JE; Flavell RA; Alexopoulou L. 2006. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci U S A 103(33):12487-12492PubMed: 16891416 MGI: J:111778
Vijay-Kumar M; Aitken JD; Carvalho FA; Cullender TC; Mwangi S; Srinivasan S; Sitaraman SV; Knight R; Ley RE; Gewirtz AT. 2010. Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5. Science 328(5975):228-31PubMed: 20203013 MGI: J:158055

Additional References

Hussain S; Johnson CG; Sciurba J; Meng X; Stober VP; Liu C; Cyphert-Daly JM; Bulek K; Qian W; Solis A; Sakamachi Y; Trempus CS; Aloor JJ; Gowdy KM; Foster WM; Hollingsworth JW; Tighe RM; Li X; Fessler MB; Garantziotis S. 2020. TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury. Elife 9PubMed: 31989925 MGI: J:291199

Additional - Tlr5^tm1Flv related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tlr5 Alt1
- Standard PCR:Tlr5{tm1Flv}
- Genotyping resources and troubleshooting
Breeding Considerations

When maintained as a live colony, homozygotes may be bred together.
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Homozygote
Citation
When using the TLR5 KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #008377 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX12 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for Tlr5<tm1Flv>

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:TLR5 KO

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Tlr5tm1Flv

Allele Symbol: Tlr5tm1Flv

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Tlr5tm1Flv related

Mammalian Phenotype Terms by Genotype

Genotype: Tlr5tm1Flv/Tlr5tm1Flvinvolves: 129S1/Sv * C57BL/6

adipose tissue phenotype

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

behavior/neurological phenotype

liver/biliary system phenotype

respiratory system phenotype

cardiovascular system phenotype

Genotype: Tlr5tm1Flv/Tlr5tm1Flvinvolves: 129S1/Sv

cellular phenotype

hematopoietic system phenotype

immune system phenotype

References

Additional References

Additional - Tlr5tm1Flv related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Tlr5^tm1Flv

Allele Symbol: Tlr5^tm1Flv

Genotype: Tlr5^tm1Flv related

Genotype: Tlr5^tm1Flv/Tlr5^tm1Flv
involves: 129S1/Sv * C57BL/6

Genotype: Tlr5^tm1Flv/Tlr5^tm1Flv
involves: 129S1/Sv

Additional - Tlr5^tm1Flv related