The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice.
Epidemiological, clinical, and experimental approaches have convincingly demonstrated that host resistance to infection with intracellular pathogens is significantly influenced by genetic polymorphisms. Using a mouse model of infection with virulent Mycobacterium tuberculosis (MTB), we have previously identified the sst1 locus as a genetic determinant of host resistance to tuberculosis. In this study we demonstrate that susceptibility to another intracellular pathogen, Listeria monocytogenes, is also influenced by the sst1 locus. The contribution of sst1 to anti-listerial immunity is much greater in immunodeficient scid mice, indicating that this locus controls innate immunity and becomes particularly important when adaptive immunity is significantly depressed. Similar to our previous observations using infection with MTB, the resistant allele of sst1 prevents formation of necrotic infectious lesions in vivo. We have shown that macrophages obtained from sst1-resistant congenic mice possess superior ability to kill L. monocytogenes in vitro. The bactericidal effect of sst1 is dependent on IFN-gamma activation and reactive oxygen radical production by activated macrophages after infection, but is independent of NO production. It is possible that there is a single gene that controls common IFN-dependent macrophage function, which is important in the pathogenesis of infections caused by both MTB and L. monocytogenes. However, host resistance to the two pathogens may be controlled by two different polymorphic genes encoded within the sst1 locus. The polymorphic gene(s) encoded within the sst1 locus that controls macrophage interactions with the two intracellular pathogens remains to be elucidated.
Program in Gene Function and Expression, University of Massachusetts Medical School, Boston 02115, USA.
Victor
V
Boyartchuk
Mauricio
M
Rojas
Bo-Shiun
BS
Yan
Ousman
O
Jobe
Nicholas
N
Hurt
David M
DM
Dorfman
Darren E
DE
Higgins
William F
WF
Dietrich
Igor
I
Kramnik
D000818:Animals; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009569:Nitric Oxide / Q000502:physiology; D010586:Phagocytes / Q000502:physiology; D011110:Polymorphism, Genetic; D017382:Reactive Oxygen Species; D013601:T-Lymphocytes / Q000276:immunology
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D007371:Interferon-gamma