Alice Hsu
Veterinarian
Blackhorse Pike Animal Hospital
VMD: 2009
PhD: 2008
Graduate Group: Immunology
Thesis Topic: Leishmania mexicana infection
The goal of Alice's project was to better understand how Leishmania mexicana infection induces a non-healing response in mice that are fully capable of controlling infection with L. major via the generation of a strong cell-mediated Th1 response. She found that L. mexicana induces normal T cell proliferation but fails to elicit lymph node (LN) expansion or Th1 differentiation of responding T cells, relative to the strong responses observed in mice infected with L. major. The lab hypothesized that impaired dendritic cell (DC) activation by L. mexicana might be responsible for this partial T cell priming defect, and they found the DCs exposed to the intracellular amastigote form of L. mexicana fails to provide appropriate signals for Th1 effector differentiation of naive T cells. This defect in DC activation appears to result from active inhibition of specific DC responses to the Toll-like receptor 9 (TLR9) ligand, CpG DNA, suggesting a potential role for TLR9 signaling during the normal course of infection with Leishmania. DNA isolated from different Leishmania species are capable of directly activating DCs, suggesting that inhibition of TLR9-dependent DC activation may allow L. mexicana parasites to actively suppress immune responses to Leishmania infection itself. Further, they found that TLR9 plays a role in the early control of L. major infection, whereas few differences in the early response to L. mexicana were observed in the presence or absence of TLR9. Therefore, the capacity to inhibit TLR9 signaling by L. mexicana may have evolved as a strategy to ensure parasite survival. Together, these data suggest that L. mexicana may inhibit TLR9-associated activation of DCs or other cells during the course of infection with L. mexicana, preventing the generation of curative Th1 responses.