These Camp (formerly Cnlp) knock-out mice are more susceptible to bacterial infections and may be useful in studies of innate immune response, regulation of immune response, wound healing/angiogenesis and tumor development.
Richard L. Gallo, University of California at San Diego
The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection. Skin lesions, due to Group A Streptococcus infection, are larger and persist longer in homozygotes when compared to controls. Heterozygotes exhibit an intermediate Group A Streptococcus bacterial susceptibility phenotype. Within 1 hour of infection, more uropathogenic E. coli bacteria are attached to urinary bladder mucosa of mutant mice. 48 hours after infection, the number of bacteria in the urinary tract of homozygous mice is higher than wildtype controls. Mutant mice challenged with uropathogenic E. coli developed more severe urinary tract infections and exhibit higher mortality from septicemia when compared to controls. After intranasal Pseudomonasaeruginosa inoculation, CRAMP deficient mice exhibit significantly higher levels of bacterial CFUs compared to controls. When pretreated with flagellin, only one third of infected CRAMP deficient mice survived, compared to complete survival of all infected wildtype mice. Homozygotes also develop more severe infection of Pseudomonas aeruginosa in induced corneal keratitis. An increased invasion rate is observed after oral administration of Listeria monocytogenes to homozygotes. In an experimentally induced skin inflammation model for atopic dermatitis, homozygotes exhibit enhanced swelling and more severe epidermal hypertrophy. The epidermal permeability barrier is functionally impaired in homozygotes. Induced irritation of the skin of homozygous mice by stratum corneum tryptic enzyme or physical abrastion results in reduced inflammatory infiltrate, when compared to controls. In vaccinia virus skin infection (eczema vaccinatum), homozygotes on the BALB/c background have higher levels of virus replication in skin biopsies compared to controls. Knock out mice are more susceptible to meningococcal Neisseria meningitidis infection with higher CFU load and mortality rate. When B and T cells from homozygotes are cultured in Th2-inducing conditions, the mutant B cells produce less IgG1 and IgE, and a higher ratio of mutant IL-4+ T cells is observed, when compared to cultures isolated from wildtype mice. Xenograft tumors growth is accelerated in homozygotes: B16.F10 melanoma tumors grow faster and obtain a larger size, and RMA-S lymphoma cell tumor development is earlier when compared to controls. NK cells isolated from homozygotes display defective cytotoxic activity. Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA or protein) is detected by Northern blot analysis of bone marrow or by Western blot analysis of epidermis from homozygotes.
A targeting vector containing a PGK-neo cassette was used to disrupt exons 3 and 4. The construct was electroporated into unspecified 129X1/SvJ derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to 129/SvJ female mice, and then backcrossed to C57BL/6J for seven generations. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.
|Allele Name||targeted mutation 1, Richard L Gallo|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Camp-; Cnlp-; Cnlp-null; Cramp-ko|
|Gene Symbol and Name||Camp, cathelicidin antimicrobial peptide|
|Gene Synonym(s)||CAP-18; CAP18; CRAMP; Cnlp; Cnlp; Cramp; Cramp; FALL-39; FALL39; HSD26; LL37; MCLP; cathelin related antimicrobial peptide; cathelin-like protein|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Exons 3 and 4, which encode the entire mature domain of the protein, were replaced with a PGK-neo cassette via homologous recombination. Northern blot analysis using a probe to exon 4 confirmed the absence of gene expression in bone marrow of homozygous mutant animals.|
|Mutations Made By|| |
Carlos Aguilera, University of California at San Diego
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