Genetic basis of murine antibacterial defense to streptococcal lung infection.
To evaluate the effect of genetic background on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (A/J, DBA/2J, CAST/Ei, FVB/NJ, BALB/cJ, C57BL/6J, 129/SvImJ, and C3H/HeJ) and tlr2-deficient mice (C57BL/6(tlr2-/-)) were infected with three doses of Streptococcus zooepidemicus (500, 5,000, or 50,000 colony-forming units) by alveolar challenge. There was a range of susceptibility between the strains at each dose and time point (6, 24, and 96 h). At the lowest dose, the 129/SvImJ and C3H/HeJ strains had significantly higher bacterial counts at all time points after infection, when compared to A/J, DBA/2J, CAST/Ei, FVB/NJ, which were resistant to infection at the low dose of innoculum. At the medium dose, 129/SvImJ and C3H/HeJ had higher bacterial counts, while A/J, DBA/2J, and BALB/cJ showed reduced streptococcal growth. After the highest dose of Streptococcus, there were minimal differences between strains, suggesting the protective impact of modifier genes can be overcome. TLR2-deficient animals contained increased bacterial load with reduced cytokines after 96 h when compared to C57BL/6J controls suggesting a role of innate immunity in late antibacterial defense. Overall, we identify vulnerable (129/SvlmJ and C3H/HeJ) and resistant (A/J, FVB, and DBA) mouse strains to streptococcal lung infection, which demonstrate divergent genetic expression profiles. These results demonstrate that innate differences in pulmonary host defense to S. zooepidemicus are dependent on host genetic factors.
Hollingsworth
John W
JW
Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, P.O. Box 3136, Durham, NC 27710, USA. holli017@mc.duke.edu
Whitehead
Gregory
G
Berman
Katherine Gray
KG
Tekippe
Erin McElvania
EM
Gilmour
M Ian
MI
Larkin
Jennie E
JE
Quackenbush
John
J
Schwartz
David A
DA
D000818:Animals; D020022:Genetic Predisposition to Disease; D008171:Lung Diseases / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D013045:Species Specificity; D013290:Streptococcal Infections / Q000235:genetics* / Q000382:microbiology; D013291:Streptococcus / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics
C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2
J Immunol. 2002 Jan 1;168(1):372-8
11751983
J Infect Dis. 1996 Nov;174(5):994-1000
8896500
MMWR Morb Mortal Wkly Rep. 1983 Oct 7;32(39):510, 515-6
6412064
Science. 2004 Aug 27;305(5688):1283-6
15333838
Nat Neurosci. 2003 Nov;6(11):1162-8
14517545
Infect Immun. 2001 Jan;69(1):426-34
11119534
Genome Biol. 2003;4(10):R70
14519205
Infect Immun. 2002 Mar;70(3):1547-57
11854243
Microb Pathog. 1999 Sep;27(3):133-43
10455004
J Infect Dis. 1997 Aug;176(2):439-44
9237710
Science. 1998 Dec 11;282(5396):2085-8
9851930
PLoS Biol. 2004 Aug;2(8):E241
15314657
J Immunol. 2004 Jun 15;172(12):7603-9
15187140
Infect Immun. 1997 Jan;65(1):257-60
8975920
Mamm Genome. 2003 Jul;14(7):448-53
12925893
Biotechniques. 2000 Sep;29(3):548-50, 552-4, 556  passim
10997270
Physiol Genomics. 2004 Jul 08;18(2):152-66
15126644
J Med Microbiol. 2000 Dec;49(12):1057-1067
11129716
Scand J Immunol. 2000 Feb;51(2):123-7
10722369
Biotechniques. 2003 Feb;34(2):374-8
12613259
J Infect Dis. 2001 Aug 1;184(3):292-300
11443554
Infect Immun. 2005 Nov;73(11):7718-26
16239576
J Immunol. 2003 Jan 1;170(1):438-44
12496429
J Infect Dis. 2002 Sep 15;186(6):798-806
12198614
J Immunol. 2002 Apr 1;168(7):3507-11
11907112
J Infect Dis. 2003 Mar 1;187(5):854-61
12599060
Infect Immun. 2004 Feb;72(2):788-94
14742522
J Immunol. 1999 Jul 1;163(1):1-5
10384090
J Immunol. 2004 Mar 1;172(5):3132-8
14978119
Infect Immun. 2005 Jan;73(1):298-307
15618166
Immunity. 1999 Oct;11(4):443-51
10549626
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1966-71
12569171
J Clin Microbiol. 1980 Jan;11(1):76-8
7354128
J Immunol. 1999 Apr 1;162(7):3749-52
10201887
Science. 2001 Feb 23;291(5508):1544-7
11222859