TLR cross talk has obvious advantages for the host in protecting against infectious agents, because it enhances the initial immune reaction to pathogen infection and better primes the host for mounting a more robust adaptive immune response. The concept that multiple TLR-ligand interactions are required for effective host resistance to pathogens has important implications for the design of vaccinations and immunotherapies against infectious diseases. Several studies have convincingly shown the improved efficacy of treatment with multiple TLR ligands compared with single TLR ligands in stimulating cellular immune responses in vivo. For example, co-administration of poly I:C and CpG ODNs increased serum cytokine production in a mouse tumor model when compared to the administration of either of the ligands alone51. Bone-marrow-derived DCs exposed to both poly I:C and a TLR7 ligand more effectively stimulated cytotoxic T lymphocyte responses compared to DCs exposed to either TLR ligand alone52. These studies provide an important conceptual foundation to examine the protective efficacy of multiple TLR-ligand combinations in vaccines against infectious diseases. However, synergistic amplification of the inflammation response may be detrimental, because it can result in immune over-activation, which hampers immune homeostasis. As a consequence of an overactive response, the function of various organ systems may be compromised, resulting in multiple organ dysfunction syndrome (MODS) and death. Cytokines (TNF-α and IL-6) are important components of the immune system because they act as messengers between cells, but they are also involved in many pathological aspects of the cascade leading to systemic inflammatory response syndrome (SIRS) and ultimately MODS. According to the two-hit hypothesis53, patients who survive the initial inflammatory insult may die following a relatively minor second event that would not normally be life-threatening. In this study, viral (poly I:C) stimulation as a relatively minor secondary insult, led to an exaggerated secondary inflammatory response. Thus, understanding the mechanism of this two-hit phenomenon may help to devise novel therapeutic strategies to prevent overwhelming and life-threatening inflammatory conditions such as septic shock and trauma-induced SIRS.