T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis.
To study the impact of T-box transcription factor (T-bet) on initiation and progression of Staphylococcus aureus sepsis and arthritis, T-bet-deficient mice (T-bet(-/-)) and their wild-type controls (T-bet(+/+)) were intravenously inoculated with 8 x 10(6) S. aureus. Already 48 h after inoculation of S. aureus, T-bet-deficient mice displayed increased frequency (62% versus 19%, P = 0.002) as well as severity of arthritis compared with wild-type controls. The bacterial counts were significantly increased in T-bet(-/-) mice compared with T-bet(+/+) as measured in kidneys 72 h after the inoculation (4.3 +/- 1.8 x 10(7) versus 3.2 +/- 3.2 x 10(6) colony-forming units (CFU); P = 0.003). As expected, T-bet-deficient mice displayed significantly decreased production of IFN-gamma (10-15-fold) at 24 and 72 h after bacterial inoculation compared with wild-type mice. Interestingly, in the absence of T-bet, serum IL-4 was decreased at 24 h. IL-6 did not differ at early stage of infection but was sixfold increased in T-bet(-/-) mice over T-bet(+/+) animals at 72 h postinoculation. Ten days after the inoculation, T-bet(-/-) mice still displayed significantly more pronounced weight loss and increased serum IL-6 levels, probably due to increased bacterial burden compared with T-bet(+/+) mice. The cumulative mortality was 19% in T-bet mice (5/27) and 0% (0/27) in control animals (P = 0.05). In conclusion, T-bet plays an important role in early response to S. aureus infection, protecting against bacterial accumulation, cachexia and septic death. Furthermore T-bet downregulates joint inflammation in the early phase of disease.
Hultgren
Olof H
OH
Department of Clinical Immunology, Göteborg University Gulhedsgatan 10A S-413 46 Göteborg, Sweden. olof.hultgren@immuno.gu.se
Verdrengh
Margareta
M
Tarkowski
Andrej
A
D000818:Animals; D001170:Arthritis, Infectious / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D001835:Body Weight; D015169:Colony Count, Microbial; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007596:Joints / Q000473:pathology; D007668:Kidney / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D013211:Staphylococcus aureus / Q000254:growth & development; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D000098815:T-bet Transcription Factor
D015850:Interleukin-6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma