Toll-like receptor 4 stimulation before or after Streptococcus pneumoniae induced sepsis improves survival and is dependent on T-cells.
BACKGROUND
Endotoxin tolerance improves outcomes from gram negative sepsis but the underlying mechanism is not known. We determined if endotoxin tolerance before or after pneumococcal sepsis improved survival and the role of lymphocytes in this protection.


METHODS
Mice received lipopolysaccharide (LPS) or vehicle before or after a lethal dose of Streptococcus pneumoniae. Survival, quantitative bacteriology, liver function, and cytokine concentrations were measured. We confirmed the necessity of Toll-like receptor 4 (TLR4) for endotoxin tolerance using C3H/HeN (TLR4 replete) and C3H/HeJ (TLR4 deficient) mice. The role of complement was investigated through A/J mice deficient in C5 complement. CBA/CaHN-Btk(xid/)/J mice with dysfunctional B cells and Rag-1 knockout (KO) mice deficient in T and B cells delineated the role of lymphocytes.


RESULTS
Endotoxin tolerance improved survival from pneumococcal sepsis in mice with TLR4 that received LPS pretreatment or posttreatment. Survival was associated with reduced bacterial burden and serum cytokine concentrations. Death was associated with abnormal liver function and blood glucose concentrations. Endotoxin tolerance improved survival in A/J and CBA/CaHN-Btk(xid/)/J mice but not Rag-1 KO mice.


CONCLUSIONS
TLR4 stimulation before or after S. pneumoniae infection improved survival and was dependent on T-cells but did not require an intact complement cascade or functional B cells.
University of Venda, Department of Microbiology, Venda, South Africa.
Edgar
E
Musie
University of Virginia, Department of Medicine, Division of Infectious Diseases and International Health, Charlottesville, Virginia, United States of America.
Christopher C
CC
Moore
University of Virginia, Department of Medicine, Division of Infectious Diseases and International Health, Charlottesville, Virginia, United States of America.
Edward N
EN
Martin
University of Virginia, Department of Medicine, Division of Infectious Diseases and International Health, Charlottesville, Virginia, United States of America.
W Michael
WM
Scheld
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology*; D018805:Sepsis / Q000097:blood* / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D001786:Blood Glucose; D016207:Cytokines; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002443:Ceftriaxone; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase