Manitoba Health Research Chair
Professor in Immunology,
Department of Immunology,
Department of Medical
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
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
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