The complexity of the host response to infection.

The host response to infection involves a wide array of cells and soluble mediators, which include but are not limited to monocytes, endothelial cells, and platelets and components of the complement, inflammatory, and coagulation cascades. Rather than showing the detailed connections, this figure is intended to convey the interdependent, redundant, and pleiotropic nature of the host response. Several factors modulate the phenotype, including the type of pathogen, and host factors such as genetic make-up, age, gender, and the health of other organ systems (liver and kidney are shown as examples). Normally, the host mechanisms are highly coordinated in both space and time to defend the host against pathogens. However, when the response is disproportionate to the threat (eg, excessive, sustained, or poorly localized), then the balance of power shifts in favor of the pathogen, resulting in the sepsis phenotype. Given the highly integrated and nonlinear nature of this response, it will be difficult to identify a single component whose therapeutic modulation will short-circuit the sepsis cascade and improve outcome. As long as the complexity of the sepsis response remains outside our grasp the best hope for therapeutic advances will depend on broad base targeting, in which multiple components are targeted at the same time.