The protozoan parasite Leishmania causes cutaneous lesions that are often refractory to drug treatment. In murine leishmaniasis, CD4+ Th1 cells producing IFN? activate macrophages to become classically activated adopting an M1 phenotype generating antimicrobial molecules such as nitric oxide that contribute to parasite elimination. However, parasites persist indefinitely despite the induction of a Th1 adaptive immune response. In contrast to M1 macrophages, IL-4/IL-13 signaling activates macrophages to become M2 macrophages, which do not exhibit the same capacity to kill Leishmania parasites. We hypothesize the persistent parasites detected during Leishmania infection are due to the presence of M2 macrophages in lesions that serve as safe havens for parasites. Preliminary in vitro data suggests M2 macrophages are infected at higher rates and exhibit impaired parasite killing in response the IFN?/LPS. Transcripts indicative of M2 populations such as Arg1, Ym1, CD206 and dectin-1 are elevated during Leishmania infection suggesting M2 macrophages are present in leishmanial lesions. This proposal will characterize the macrophages within lesions by defining the M1/M2 phenotype of these cells and demonstrating the function of M2 macrophages in promoting parasite infection. We will accomplish this by altering the frequency of M2 macrophages either by generating M2 cells using dermal IL-4c administration or reducing the numbers of M2 cells through mouse models deficient in IL- 4/IL-13 signaling. Monocytes are recruited to the site of infection and are a source of macrophages, and may be a source of M2 macrophages providing shelter for parasite persistence. We will use a congenic mouse model to transfer monocytes into Leishmania-infected mice and follow the fate of these cells as they enter and persist in lesions. The cytokine environment will be manipulated in the tissue to skew infiltrating monocytes towards M1 or M2 cells and the effects on the outcome of infection will be determined. This study will define the role of M2 macrophages during leishmaniasis providing a mechanism by which parasites evade the immune response and a potential therapeutic strategy for parasite control.
Leishmania is a protozoan parasite that lives in macrophages and infects over 12 million people and threatens nearly 350 million people worldwide causing disfiguring cutaneous lesions. The purpose of this proposal is to characterize the macrophages that may act as safe havens for parasites in the skin, as well as determine how monocytes entering the lesion differentiate into different types of macrophages. Due to the importance of this parasite in the developing world, this work will provide insights for the development of therapeutics that lead to pathogen elimination, and these findings will also transcend the field of Leishmania providing a deeper understanding of the roles of macrophages and monocytes in disease pathology in other settings.
| Gómez, Daniela; Diehl, Malissa C; Crosby, Erika J et al. (2015) Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation. J Immunol 195:3531-6 |
