Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium.
Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i) characteristics of susceptibility to two infections in vivo; (ii) architecture of lung granulomata assessed by immune staining; and (iii) expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.
Kondratieva
Elena
E
Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
Logunova
Nadya
N
Majorov
Konstantin
K
Averbakh
Mikhail
M
Apt
Alexander
A
D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006099:Granuloma / Q000382:microbiology* / Q000473:pathology*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000473:pathology; D007958:Leukocyte Count; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009162:Mycobacterium avium / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology; D010641:Phenotype; D014376:Tuberculosis / Q000235:genetics / Q000382:microbiology
D018925:Chemokines
Tuberculosis (Edinb). 2008 Nov;88(6):576-85
18667358
Nat Rev Microbiol. 2007 Jan;5(1):39-47
17160001
J Infect Dis. 2009 Apr 15;199(8):1222-32
19302011
Tuber Lung Dis. 2000;80(1):15-25
10897380
J Leukoc Biol. 2001 Jan;69(1):43-9
11200066
Clin Exp Immunol. 2004 Jan;135(1):19-28
14678260
J Histochem Cytochem. 2004 Jun;52(6):837-9
15150293
Annu Rev Immunol. 1993;11:129-63
8476559
Annu Rev Immunol. 2004;22:599-623
15032590
Rheumatology (Oxford). 2004 May;43(5):569-73
14970401
Biochem Biophys Res Commun. 2001 Feb 23;281(2):378-82
11181058
Cell Microbiol. 2006 Feb;8(2):218-32
16441433
Blood. 2008 Jan 1;111(1):42-9
17928531
Infect Immun. 2006 Jul;74(7):4295-309
16790804
J Exp Med. 2001 Dec 17;194(12):1847-59
11748285
FEMS Immunol Med Microbiol. 1999 Feb;23(2):149-58
10076912
Infect Immun. 2007 Oct;75(10):4762-8
17664269
Clin Exp Immunol. 1990 Jun;80(3):324-31
2115416
Infect Immun. 2003 Feb;71(2):697-707
12540548
J Immunol. 2000 Jul 1;165(1):483-92
10861087
Annu Rev Genomics Hum Genet. 2007;8:163-92
17492906
Tuber Lung Dis. 1997;78(1):57-66
9666963
Trends Microbiol. 2001 Aug;9(8):397-403
11514223
Immunology. 2006 May;118(1):122-30
16630029
Methods. 2001 Dec;25(4):402-8
11846609
J Immunol. 2000 Nov 15;165(10):5921-31
11067954
Clin Exp Immunol. 1994 Nov;98(2):210-6
7955524
J Immunol. 2010 Feb 1;184(3):1227-34
20028653
Infect Immun. 2005 Mar;73(3):1744-53
15731075
Infect Immun. 2000 Feb;68(2):577-83
10639420
J Pathol. 2006 Nov;210(3):298-305
17001607
Infect Immun. 1995 Sep;63(9):3381-7
7642266
Immunology. 2008 Nov;125(3):281-8
19128361
Infect Immun. 2002 Sep;70(9):5322-7
12183593
Tuberculosis (Edinb). 2009 May;89(3):195-8
19345146
Microbes Infect. 2006 Apr;8(4):1179-88
16513383
J Pathol. 2004 Oct;204(2):217-28
15376257