Hemolysin and the multifunctional autoprocessing RTX toxin are virulence factors during intestinal infection of mice with Vibrio cholerae El Tor O1 strains.
The seventh cholera pandemic that started in 1961 was caused by Vibrio cholerae O1 strains of the El Tor biotype. These strains produce the pore-forming toxin hemolysin, a characteristic used clinically to distinguish classical and El Tor biotypes. Even though extensive in vitro data on the cytolytic activities of hemolysin exist, the connection of hemolysin to virulence in vivo is not well characterized. To study the contribution of hemolysin and other accessory toxins to pathogenesis, we utilized the model of intestinal infection in adult mice sensitive to the actions of accessory toxins. In this study, we showed that 4- to 6-week-old streptomycin-fed C57BL/6 mice were susceptible to intestinal infection with El Tor strains, which caused rapid death at high doses. Hemolysin had the predominant role in lethality, with a secondary contribution by the multifunctional autoprocessing RTX (MARTX) toxin. Cholera toxin and hemagglutinin/protease did not contribute to lethality in this model. Rapid death was not caused by increased dissemination due to a damaged epithelium since the numbers of CFU recovered from spleens and livers 6 h after infection did not differ between mice inoculated with hemolysin-expressing strains and those infected with non-hemolysin-expressing strains. Although accessory toxins were linked to virulence, a strain defective in the production of accessory toxins was still immunogenic since mice immunized with a multitoxin-deficient strain were protected from a subsequent lethal challenge with the wild type. These data suggest that hemolysin and MARTX toxin contribute to vaccine reactogenicity but that the genes for these toxins can be deleted from vaccine strains without affecting vaccine efficacy.
Olivier
Verena
V
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Haines
G Kenneth
GK
Tan
Yanping
Y
Satchell
Karla J Fullner
KJ
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000633:toxicity*; D001427:Bacterial Toxins / Q000235:genetics / Q000633:toxicity*; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology; D002771:Cholera / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control; D002772:Cholera Toxin / Q000235:genetics / Q000633:toxicity; D015169:Colony Count, Microbial; D005260:Female; D006460:Hemolysin Proteins / Q000235:genetics / Q000633:toxicity*; D007421:Intestine, Small / Q000473:pathology; D008099:Liver / Q000382:microbiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D041241:Vibrio cholerae O1 / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics / Q000633:toxicity*
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D006460:Hemolysin Proteins; C434464:RtxA protein, Vibrio cholerae; D037521:Virulence Factors; C084287:hlyA protein, Vibrio cholerae; D002772:Cholera Toxin; D008666:Metalloendopeptidases; C039814:hemagglutinin-protease
Am J Trop Med Hyg. 1997 May;56(5):533-7
9180604
Infect Immun. 1996 Oct;64(10):4373-7
8926115
Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1071-6
9927695
Infect Immun. 1999 Mar;67(3):1393-404
10024587
Am J Clin Nutr. 1999 May;69(5):1046S-1051S
10232647
Infect Immun. 2005 May;73(5):3018-24
15845509
Infect Immun. 2005 Sep;73(9):6157-64
16113340
J Bacteriol. 2007 Mar;189(5):1827-35
17189368
Infect Immun. 2007 Oct;75(10):5043-51
17698571
Cell. 1999 Dec 10;99(6):625-34
10612398
Infect Immun. 2000 Mar;68(3):1700-5
10678992
Infect Immun. 2000 Apr;68(4):1928-33
10722584
Eur J Clin Microbiol Infect Dis. 2000 Jun;19(6):489-91
10947231
Infect Immun. 2000 Nov;68(11):6487-92
11035765
Infect Immun. 2001 Mar;69(3):1613-24
11179335
Cell Microbiol. 2000 Feb;2(1):11-7
11207559
J Exp Med. 2002 Jun 3;195(11):1455-62
12045243
Microbes Infect. 2003 Nov;5(13):1241-7
14623020
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2123-8
14766976
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9798-803
15199181
Diagn Microbiol Infect Dis. 2004 Aug;49(4):295-7
15313536
Nature. 1972 Sep 15;239(5368):137-8
4561957
Infect Immun. 1974 Jul;10(1):167-72
4601899
Infect Immun. 1979 Dec;26(3):1020-7
118926
Annu Rev Microbiol. 1980;34:341-67
7002028
Proc Natl Acad Sci U S A. 1983 Feb;80(4):1092-5
6341990
Infect Immun. 1983 Aug;41(2):735-41
6874074
Southeast Asian J Trop Med Public Health. 1983 Jun;14(2):181-5
6635756
Nature. 1983 Dec 8-14;306(5943):551-7
6646234
J Bacteriol. 1986 Mar;165(3):715-22
3005236
Infect Immun. 1987 May;55(5):1090-3
3570456
Infect Immun. 1988 Jan;56(1):161-7
3335402
Infect Immun. 1991 Dec;59(12):4310-7
1937792
Vaccine. 1991 Aug;9(8):588-94
1771972
Mol Microbiol. 1993 Aug;9(4):751-60
8231807
J Infect Dis. 1993 Dec;168(6):1536-40
8245542
J Infect Dis. 1994 Dec;170(6):1518-23
7995992
Clin Microbiol Rev. 1995 Jan;8(1):48-86
7704895
Infect Immun. 1995 Jul;63(7):2689-96
7790086
J Infect Dis. 1995 Sep;172(3):883-6
7658089
J Infect Dis. 1995 Oct;172(4):1126-9
7561195
Infect Immun. 1996 Jun;64(6):2362-4
8675353
Infect Immun. 1996 Aug;64(8):2968-73
8757822
Infect Immun. 1999 Feb;67(2):539-45
9916056