Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection.
Cathelicidin antimicrobial peptides are effectors of innate immune defense in mammals. Humans and mice have only one cathelicidin gene, whereas domesticated mammals such as the pig, cow, and horse have multiple cathelicidin genes. We hypothesized that the evolution of multiple cathelicidin genes provides these animals with enhanced resistance to infection. To test this, we investigated the effects of the addition of cathelicidins by combining synthetic cathelicidin peptides in vitro, by producing human keratinocytes that overexpress cathelicidins in culture, or by producing transgenic mice that constitutively overexpress cathelicidins in vivo. The porcine cathelicidin peptide PR-39 acted additively with human cathelicidin LL-37 to kill group A Streptococcus (GAS). Lentiviral delivery of PR-39 enhanced killing of GAS by human keratinocytes. Finally, transgenic mice expressing PR-39 under the influence of a K14 promoter showed increased resistance to GAS skin infection (50% smaller necrotic ulcers and 60% fewer surviving bacteria). Similarly constructed transgenic mice designed to overexpress their native cathelicidin did not show increased resistance. These findings demonstrate that targeted gene transfer of a xenobiotic cathelicidin confers resistance against infection and suggests the benefit of duplication and divergence in the evolution of antimicrobial peptides.
Lee
Phillip H A
PH
Division of Dermatology, University of California at San Diego, San Diego, CA 92161, USA.
Ohtake
Takaaki
T
Zaiou
Mohamed
M
Murakami
Masamoto
M
Rudisill
Jennifer A
JA
Lin
Kenneth H
KH
Gallo
Richard L
RL
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D017192:Skin Diseases, Bacterial / Q000517:prevention & control*; D013290:Streptococcal Infections / Q000517:prevention & control; D013297:Streptococcus pyogenes; D013552:Swine; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; C072212:PR 39; D054804:Cathelicidins
Nat Med. 2000 Jan;6(1):49-55
10613823
Semin Cutan Med Surg. 2000 Mar;19(1):19-61
10834604
Vet Res. 2000 May-Jun;31(3):277-96
10863946
Int Microbiol. 1998 Dec;1(4):279-84
10943375
Oncology (Williston Park). 2000 Aug;14(8 Suppl 6):9-16
10989819
Blood. 2001 Jan 1;97(1):297-304
11133774
J Invest Dermatol. 2001 Jul;117(1):91-7
11442754
Clin Microbiol Infect. 2001;7 Suppl 2:1-7
11525214
J Cell Physiol. 2001 Nov;189(2):133-43
11598898
Nature. 2001 Nov 22;414(6862):454-7
11719807
Curr Opin Hematol. 2002 Jan;9(1):18-22
11753073
Eur J Cancer Care (Engl). 2001 Mar;10(1):56-62
11827268
Drug Resist Updat. 2001 Aug;4(4):225-32
11991677
Arch Pharm Res. 2002 Apr;25(2):111-36
12009024
Curr Opin Biotechnol. 2002 Jun;13(3):267-74
12180104
J Mol Med (Berl). 2002 Sep;80(9):549-61
12226737
N Engl J Med. 2002 Oct 10;347(15):1151-60
12374875
Infection. 2002 Oct;30(5):257-61
12382082
J Dent Res. 2002 Dec;81(12):845-50
12454100
J Allergy Clin Immunol. 2002 Dec;110(6):823-31
12464945
Nature. 2003 Apr 3;422(6931):522-6
12660734
J Invest Dermatol. 2003 May;120(5):810-6
12713586
Int J Infect Dis. 2003 Mar;7(1):46-52
12718810
J Pharm Pharm Sci. 2003 Jan-Apr;6(1):67-83
12753730
J Hosp Infect. 2003 Oct;55(2):156-7
14529646
Proc Natl Acad Sci U S A. 1980 Dec;77(12):7380-4
6261253
Anal Biochem. 1987 Apr;162(1):156-9
2440339
Proc Natl Acad Sci U S A. 1989 Mar;86(5):1563-7
2466292
FEMS Microbiol Lett. 1991 Aug 1;66(2):219-24
1936949
Eur J Biochem. 1991 Dec 18;202(3):849-54
1765098
J Biol Chem. 1993 Mar 15;268(8):6058-63
8449963
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11035-9
7972004
J Leukoc Biol. 1997 May;61(5):624-9
9129212
Infect Immun. 1998 Apr;66(4):1671-9
9529097
Chem Biol. 1998 Apr;5(4):197-207
9545431
J Clin Invest. 1999 Apr;103(8):1113-7
10207162
Nature. 1999 Jun 10;399(6736):590-3
10376600
Science. 1999 Oct 1;286(5437):113-7
10506557