Listeria monocytogenes (LM) is an intracellular bacterium that can cause spontaneous abortions in pregnant women and can lead to septicemia and meningitis in immunocompromised individuals. Innate immunity to LM and other pathogens is provided by neutrophils, monocytes and macrophages. Monocytes are bone marrow derived myeloid cells that circulate in the peripheral blood until being mobilized into tissues. Resident monocytes give rise to tissue macrophages and dendritic cells, while inflammatory monocytes provide protection against infections but can also be detrimental during cancer and other autoimmune/inflammatory diseases. Our published data have revealed that the cytokine IL-23 and the receptor for IL-17A and IL-17F (IL- 17RA) are required for protection against LM infection. We have now established that IL-23 is required for optimal monocyte recruitment during LM infection. Based upon these published data and our novel observations, we hypothesize that the IL-23/IL-17 axis regulates the recruitment and function of monocytes during systemic LM infection. A variety of in vivo and in vitro approaches utilizing mice lacking IL-23, IL-17RA, IL-17A, and IL-17F will specifically address the following aims.
Specific Aim 1 will determine how the IL-23/IL-17 axis regulates monocyte recruitment during LM infection. Mice lacking IL-23, IL-17RA, IL- 17A, and IL-17F will be utilized to determine how these molecules influence monocyte recruitment before, and during, LM infection. Furthermore, the direct and indirect impact of these cytokines on monocyte recruiting chemokines will be determined.
Specific Aim 2 will determine how the IL-23/IL-17 axis enhances monocyte function during LM infection. The requirement and sufficiency of the IL-23/IL-17 axis for optimal monocyte effector functions will be determined by measuring monocyte effector molecules that are required for protection against LM. The data obtained from these studies may lead to therapeutic options aimed at regulating monocyte function during infectious and other disease states.
Data generated upon completion of this proposal will result in a detailed understanding of how cytokines (IL- 23/IL-17) regulate the function of monocytes during systemic infection. This knowledge will allow for more effective vaccine generation and lead to strategies to either enhance or limit monocyte function during different disease states including cancer, autoimmunity, and infection.