The temporal role of toll-like receptors in antibacterial host defense

Toll-like Receptors (TLRs) are evolutionarily conserved proteins that recognize microbial molecules and initiate host defense. To investigate how TLRs work together to fight infections, we tested the role of TLRs in host defense against the Gram-negative bacterial pathogen, Salmonella. We show that TLR4, which signals in response to Gram-negative lipopolysaccharide (LPS), is critical for early cytokine production and killing of bacteria by murine macrophages. Interestingly, later on, TLR2, but not TLR4, is required for macrophage responses. MyD88, an adaptor protein directly downstream of TLRs, is required for both early and late responses. TLR4, TLR2 and MyD88 are involved in murine host defense against Salmonella in vivo, which correlates with the defects in host defense observed in vitro . These results show that TLRs are sequentially involved in host defense against bacterial infection.;Since TLR4 is required for early macrophage activation in response to Salmonella, it is unclear how macrophages initially respond to bacteria that evade TLR4. We tested the macrophage response to the Gram-negative bacterial pathogen Brucella, which contains an LPS with low activity and does not efficiently activate TLR4. We show that the macrophage response to Brucella is delayed as compared to Salmonella . However, Brucella activates macrophages through TLR4, TLR2 and MyD88 later in infection. Interestingly, MyD88 is required for macrophage survival after Brucella infection in vitro and plays a role in bacterial clearance in vivo . These results show that by evading TLR4 early, Brucella alters the timing of macrophage responsiveness. Later, Brucella uses TLR signaling through MyD88 to signal for macrophage survival and preserve its intracellular niche within the host.