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Thongchai Luxameechanporn, MD; Virat Kirtsreesakul, MD; James Klemens, MD; Paneez Khoury, MD; Kenneth Thompson, MD, PhD; Robert M. Naclerio, MD

Arch Otolaryngol Head Neck Surg. 2005;131:1001-1006.

Objectives  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.

Design  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 µg 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.

Main Outcome Measure  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.

Author Affiliations: Section of Otolaryngology–Head and Neck Surgery, Department of Surgery (Drs Luxameechanporn, Kirtsreesakul, Klemens, Khoury, and Naclerio), and Department of Pathology (Dr Thompson), University of Chicago, Chicago, Ill; and Department of Otolaryngology, Prince of Songkla University, Hat Yai, Songkla, Thailand (Dr Kirtsreesakul).