Evaluation of importance of Toll-like receptor 4 in acute Streptococcus pneumoniae sinusitis in mice.
OBJECTIVE
To investigate the effect of RC-527, a synthetic toll-like receptor 4 (TLR4) agonist, on stimulating the immune response before acute Streptococcus pneumoniae sinusitis in a mouse model, and to determine the importance of TLR4 in modulating the response to S. pneumoniae. Toll-like receptor 4 agonists have been shown to induce protective innate immune responses when administered before some bacterial or viral challenges in mice.


METHODS
We intranasally inoculated BALB/c, TLR4 complex-deficient C3H/HeJ, and wild-type C3H/HeOuJ mice with S. pneumoniae 24 hours after treatment with 10 or 1 microg of RC-527 or vehicle. Bacterial counts from nasal lavage culture and the cell markers GR1, CD11b, CD3, CD4, and CD8 in sinus tissue were quantified at postinoculation days 2, 5, and 14.


METHODS
Immune response induced by RC-527.


RESULTS
Treatment with RC-527 induced an immune response through TLR4, as demonstrated by recruitment of phagocytes in uninfected wild-type C3H/HeOuJ mice, but not in TLR4 complex-deficient C3H/HeJ mice. The immune response was also demonstrated by a significant increase of CD3+, CD4+, and CD8+ T cells in infected and uninfected wild-type C3H/HeOuJ mice, but not in TLR4 complex-deficient C3H/HeJ mice. However, the enhancement of the immune response induced by the TLR4 agonist showed a limited effect on bacterial clearance.


CONCLUSIONS
Our studies in mice suggest that stimulation of TLR4 plays a minor role in the overall response to S. pneumoniae infection of the upper airway, and stimulating this receptor before infection does not significantly enhance the immune response of immunocompetent mice to clear S. pneumoniae infection.
Luxameechanporn
Thongchai
T
Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, Ill 60637, USA.
Kirtsreesakul
Virat
V
Klemens
James
J
Khoury
Paneez
P
Thompson
Kenneth
K
Naclerio
Robert M
RM
D000208:Acute Disease; D000818:Animals; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D017252:CD3 Complex / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006017:Glycolipids / Q000008:administration & dosage / Q000819:agonists; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology*; D012852:Sinusitis / Q000276:immunology / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000187:drug effects / Q000502:physiology*
D039481:CD11b Antigen; D017252:CD3 Complex; D006017:Glycolipids; C500573:RC 527; D051197:Toll-Like Receptor 4