Extra-pulmonary control of respiratory defense

Pneumonia persists as a public health crisis, representing the leading cause of death due to infection. Whether respiratory tract infections progress to pneumonia and its sequelae such as acute respiratory distress syndrome and sepsis depends on numerous underlying conditions related to both the causative agent and host. Regarding the former, pneumonia burden remains staggeringly high, despite the effectiveness of pathogen-targeting strategies such as vaccines and antibiotics. This demands a greater understanding of host features that collaborate to promote immune resistance and tissue resilience in the infected lung. Such features inside the pulmonary compartment have drawn much attention, where major advances have been made related to resident and recruited immune activity. By comparison, extra-pulmonary processes guiding pneumonia susceptibility are relatively elusive, constituting the focus of this review. Here we will highlight examples of when, how, and why tissues outside of the lungs dispatch signals that modulate local immunity in the airspaces. Topics include the liver, gut, bone marrow, brain and more, all of which contribute in direct and indirect ways to pneumonia outcome. When tuned appropriately, it has become clear that these responses can serve protective roles, and this will be considered distinctly from what would otherwise be aberrant responses characteristic of pneumonia-induced organ injury and sepsis. Further advances in this area may reveal novel targetable areas for clinical intervention that are not confined to the intra-pulmonary space.