Associate Professor, Manitoba Health Research Chair Professor in Immunology, Department of Immunology, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba. © copyright 2011 Requirement for live parasites for maintenance of resistance to Leishmania major.       In this study, I showed that L. major-infected mice can be manipulated to mount an exclusive type  1 immunity that completely eliminate parasites (contrary to the existing dogma that L. major persists  indefinitely at the infection site and its draining lymph nodes in resistant individuals or mice).  However, complete parasite elimination leads to loss of Leishmania-specific effector cells and  immunity to reinfection. This seminal observation, which has been cited as one of the milestone  discoveries in immunobiology of cutaneous leishmaniasis (Noben Trauth & Sacks, Nat Rev Immunol,  2002 11:845), has enormous implications for vaccine designs against leishmaniasis.  They suggest  that persistence of live parasites is required for maintenance of anti-Leishmania immunity, and could  explain why heat-killed Leishmania vaccine confers weak and short-term anti-Leishmania immunity.  • Uzonna, J. et al., 2001. J. Immunol. 167:6967; • Uzonna, J. &. Bretscher. 2001 Eur. J. Immunol. 31:3175. Discovery of effector memory and central memory Leishmania-specific CD4+ T cells.       In this seminal manuscript, we showed that live parasites are important for maintaining  Leishmania-specific effector memory cells that mediate delayed type hypersensitivity (DTH) reaction,  rapid IFN-g secretion and parasite destruction. However, our study also revealed the induction of  central memory CD4+ T cells that are capable of mediating delayed anti-Leishmania immunity in the  absence of live parasites. This is the first report of the induction and function of CD4+ central memory T cells during a protozoan infection. Significance: Our study underscores the need to target both effector and central memory arms of T  cells in vaccination strategies against leishmaniasis. • Uzonna, J.E., C. Zaph*, S. Beverley, and P. Scott. Nat Med 2004: 1104-1110. Regulation of anti-Leishmania primary and memory responses by phosphoinositide 3  kinase (PI3K).      My laboratory has continued to be in the forefront of identifying host factors that regulate anti-  Leishmania immunity. We focused on PI3K because they play important role in regulating cellular  processes including inflammation, immune regulation, proliferation, etc. We found that mice with an  inactive knock-in mutation are hyper-resistant to L. major (developed minimal or no lesion and rapidly control parasite). This enhanced resistance was independent of mouse genetic background.  Paradoxically, the enhanced resistance was associated with dramatically impaired T cell proliferation  and IFN-g response. We found that enhanced resistance was related to impaired regulatory T cell  expansion and function. Interestingly, despite this enhanced primary resistance, deficiency of p110d  signaling significantly impaired secondary (memory) anti-Leishmania immunity such that these mice  were unable to control secondary virulent L. major challenge. This impaired memory response was  related to inability to generate effector memory-like T cells. Significance: For the first time, this study demonstrated the role of p110d isoform of PI3K in  resistance to L. major that in the absence of concomitant induction of Treg, minimal T cell  proliferation and IFN-g is sufficient for complete resolution of L. major infection. It further showed that  this enzyme could be a novel therapeutic target for treatment of leishmaniasis. Indeed, we have  patented this as a treatment regimen for leishmaniasis. In addition, this study suggests that the  quality of anti-Leishmania memory response is regulated by PI3K.  • Liu, D, et al. 2009 J. Immunol 199:1559-1566; • Liu & Uzonna, 2010 J. Immunol In press. Inoculation of killed parasites causes loss of established anti-Leishmania immunity.      While vaccination with killed parasites or parasite-derived molecules do not elicit any significant  protective immunity, recovery from primary (natural or experimental) L. major infection in both  humans and animals results in long lasting and solid immunity against virulent challenge. This so-  called infection-induced resistance is regarded as a gold standard for development of any vaccine  against leishmaniasis, and is a very strong indication that vaccination against leishmaniasis is  feasible. For the first time, we showed that inoculation of killed Leishmania major into immune mice  leads to rapid and sustained loss of infection-induced immunity by an IL-10 and Treg dependent  mechanisms.   Significance: This study could help explain why unlike active infection, vaccination with whole heat-  killed Leishmania does not confer immunity and in some cases could predispose individuals in  endemic regions who may have developed immunity due to natural exposure to become more  susceptible to new infections. It suggests a new approach that can lead to a truly effective anti-  Leishmania vaccine. This work has been cited more than 30 times and has been cited as a milestone  in Leishmania immunology research.   • Okwor et al., 2009. Proc Natl Acad Sci U S A. 106:13951-6. Discovery of a novel pathologic T cell population in experimental African trypanosomiasis.         In the process of determining the cellular origin of IL-10 and IFN-g in trypanosome-infected mice, I  discovered and characterized a novel matrix-adherent lymphocyte population that play critical role in  regulating the outcome of T. congolense infection in mice. These cells express the ab TCR receptor,  CD3 and CD4 molecules and appear to be restricted by MHC class II molecules. The induction and  activation of this unique cell is trypanosome-dependent, but its effect is trypanosome-independent,  suppressing both antigen- and mitogen-activated T and B cells. Significance: I take pride in my contribution to this aspect of research because until then, very little  was known about the nature of immune cells mediating suppression in Trypanosomiasis. Generalized  immunosuppression has been known to be a feature of African trypanosomiasis, but hitherto, the  cells mediating it and the mechanisms have remained elusive. This discovery formed a strong  foundation upon which numerous important discoveries on the mechanisms of acute death  (susceptibility) and resistance in experimental African trypanosomiasis were made.  • Uzonna, J. et al., 1998. J. Immunol., 161:6189