Fabienne Tacchini-Cottier studied immunology at Stanford University, California, where she obtained her PhD. She then became "maitre-assistante" at the Department of Pathology, University of Geneva. In 1997 she joined the World Health Organization Immunology Research and Training center (WHO-IRTC) in the Department of Biochemistry, University of Lausanne where she is now director of the WHO-IRTC. In 2007 she was promoted Associate Professor ad personam. Since 2011 she is Associate Professor at the Department of Biochemistry, Faculty of Biology and Medicine of the University of Lausanne. Her research interests are 1) the role of the innate immune response in the modulation of Leishmania specific immune responses, with a focus on the role of neutrophils in this process, and 2) the factors determining the differentiation of CD4+ T helper subsets.
IMMUNE RESPONSES TO LEISHMANIA INFECTION
Mice from the majority of inbred strains (C57BL/6, C3He, Sv129…) are resistant to infection by Leishmania major (L. major), an obligate intracellular protozoan parasite of macrophages in the mammalian host. In contrast, mice from BALB strains are unable to control infection and develop progressive disease. Several subsets of CD4+ T cells distinguishable by the pattern of cytokines they produce in vitro have been described. Among them, Th1 cells are characterized by secretion of IFNγ and LT, while Th2 cells produce IL-4, IL-5 and IL-13. In the murine model of infection with L. major, genetically determined resistance and susceptibility have been clearly shown to result from the appearance of parasite-specific CD4+ T helper 1 (Th1) or T helper 2 (Th2) cells, respectively. This murine model of infection is considered as one of the best experimental system for the study of the mechanisms operating in vivo at the initiation of polarized Th1 and Th2 cell maturation.
Among the several factors influencing Th cell development, cytokines themselves critically regulate this process. Using this model, it has been demonstrated that IL-12 and IL-4 promote Th1 and Th2 cell development, respectively. In addition, cross-talks between different cells at the site of infection also influence the development of a Leishmania-specific immune response.
The aim of our projects is to further investigate the immunological basis accounting for susceptibility or resistance to infection with L. major and other Leishmania species, deciphering the relative importance of different cell populations in protective immunity as well as the different mechanisms involved in T helper differentiation.
I. Role of neutrophils in the immune response to infection with Leishmania parasites
The development of a protective immune response to microorganisms involves complex interactions between the host and the pathogen. The murine model of infection with L. major allows the study of the parameters leading to the development of a protective immune response. Following infection, most strains of mice are able to heal their lesions, while a few fail to control infection, a process linked to the development of specific subsets of T helper cells, Th1 or Th2 respectively. The mechanisms leading to T helper differentiation are complex and not fully understood.
The early events occurring during the first days of parasite inoculation are thought to be critical in the development of the Leishmania-specific immune response. Neutrophils are the first cells arriving massively to the site of infection, and cumulating evidence points to their role as organizers of the immune response. In the presence of Leishmania, neutrophils from resistant strains of mice secrete distinct cytokines and chemokines influencing the microenvironment at the site of parasite inoculation (Figure 1). Transient depletion of neutrophils was shown to significantly affect the course of infection following inoculation with different Leishmania species. We are currently studying in detail how neutrophils regulate the development of Leishmania-specific immune responses, and investigating the impact of neutrophils in the early events shaping the development of the immune response.
Figure 1. L. major induces distinct phenotypes and cytokine secretion in neutrophils from mice resistant (C57BL/6) or susceptible (BALB/c) to infection.
In addition, we recently initiated a study exploring the effects of sandfly salivary gland components on the microenvironment upon parasite inoculation, and we are currently analyzing their impact on the development of Leishmania-specific immune response.
II. Role of Notch signaling in CD4+ T helper differentiation
We are studying CD4+ T helper differentiation for many years, both in vitro and in vivo, using mouse experimental models including cutaneous leishmaniasis models. Recently, we have investigated the role of Notch receptor signaling during CD4+ T helper differentiation. The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+T helper 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the Th2 cytokines IL-5 and IL-. Furthermore, we showed that Notch signaling is required for the secretion of IFNγ by Th1 cells, an effect independent of CSL/RBP-Jk, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jk deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. We are currently pursuing these studies, investigating the role of Notch signaling in the differentiation of other CD4+ T helper subsets, using experimental models of infection with Leishmania parasites.
Collaborations. We are currently collaborating with the groups of Dr James Alexander, University of Strathclyde, Glasgow, Scotland; Dr Pascale Kropf, London School of Hygiene and Tropical Medicine, England; Drs Aldina Barral and Camilla Indiani de Oliveira, Fiocruz Institute, Bahia, Brazil; Dr Christoph Mueller, Institute of Pathology, University of Bern; Dr Freddy Radtke (ISREC/EPFL), Lausanne; Dr Robson MacDonald, Ludwig Center for Cancer Research of the UNIL; Dr Hans Acha-Orbea and Dr Sanjiv Luther Department of Biochemisty, Epalinges, UNIL.
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