Determinant role for Toll-like receptor signalling in acute mycobacterial infection in the respiratory tract

Toll-like receptors (TLRs) are a vital component of the innate branch of the immune system in its battle against mycobacterial infections. Extensive in vitro studies have demonstrated a role for both TLR2 and TLR4 in recognition of mycobacterial components, whereas the in vivo situation appears less clear, with results depending on the infection model. In the present work, the importance of TLR signalling in the course of mycobacterial infection was investigated in a human-like infection model using TLR-knockout mice. TLR2−/− and TLR4−/− mice infected with Mycobacterium tuberculosis by aerosol, or for the first time, intranasally with Mycobacterium bovis bacillus Calmette–Guérin (BCG), displayed increased susceptibility at an early stage of infection in the respiratory tract, while at a later stage of infection, the TLR deficiency appeared to be overcome. The higher susceptibility was correlated to impaired pro-inflammatory responses to BCG components, and reduced induction of anti-bacterial activity by infected macrophages from TLR2−/− mice, and to a lesser extent from TLR4−/− mice. These findings demonstrate a role for TLR signalling in protection against mycobacterial infection specifically in the respiratory tract at the acute phase, whereas the TLR deficiency can be compensated at a later stage of infection.