Barbara Burleigh

Professor of Immunology and Infectious Diseases

Department of Immunology and Infectious Diseases

665 Huntington Avenue
Building 1, Room 817
Boston, Massachusetts 02115


Chagas’ disease is a tropical parasitic disease that develops over a number of years in individuals that are chronically infected with the kinetoplastid protozoan, Trypanosoma cruzi. As a leading cause of heart failure in Latin America, Chagas’ disease represents a public health problem of exceptional importance in endemic countries as well as an emerging immigrant health issue in the United States.

The vertebrate stages of T. cruzi are obligately intracellular where invasive trypomastigotes gain access to mammalian cells and develop into amastigotes that replicate in the host cell cytoplasm (refer to Figure). During the acute stage of infection in the host, the T.cruzi developmental cycle is essentially lytic and as a result of this 4-5 day cycle, which is repeated many times over the course of several weeks following initial infection, trypomastigotes are readily detectable in the blood and amastigotes can be observed in tissue sections of infected organs. The ensuing immune response results in clearance of the majority of parasites from tissues, however, clearance is incomplete. Parasite persistence within myocytes, neuronal cells and other sites is a key requirement for disease progression in the chronic stage of Chagas’ disease. Therefore, the intracellular life cycle of T. cruzi represents a critical target for chemotherapeutic intervention in both acute and chronic Chagas’ disease.

Cruzi Lifecycle
Host cell invasion and transient residence within lysosomes are requirements for successful establishment of T. cruzi infection.  Mammalian-infective trypomastigotes invade cells within 10-15 min of attachment and are surrounded by a host cell lysosome- or plasma membrane-derived vacuolar membrane that rapidly fuses with host cell lysosomes, such that 100% of internalized parasites are targeted to lysosomes by 60 minutes. Within the vacuole, trypomastigotes begin to transform into amastigote forms (2-8 hr) and gradually egress to become localized in the cytoplasm (8-16 hr). Cytosolic amastigotes begin to divide at ~24 hrs post-invasion and continue to divide every 12 hours for 4-5 days, then differentiate back into trypomastigotes, rupture the host cell and enter the host circulation thereby disseminating infection.

Studies in our laboratory are focused on the molecular requirements for establishment of intracellular infection by T. cruzi as well as the impact of early host-parasite interactions on the host response to this pathogen. We employ a combination of biochemical, molecular and cellular approaches to identify and study host cell signaling pathways and biological processes that regulate parasite entry and intracellular growth of T. cruzi. We have been particularly interested in the role of host cell phosphatidylinositol (PI)-3 kinases in the regulation of T. cruzi invasion, lysosome fusion and vacuole biogenesis. We find that class I PI-3 kinases (p85ab/p110) are primarily responsible forearly invasion steps that appear to be common between the lysosome-dependent and–independent entry pathways. In contrast, class III PI-3 kinase (hVPS34) appears to regulate vacuole biogenesisand cellular retention of internalized parasites.

T. cruzi amastigotes clearly exploit host metabolic and cellular functions to fuel their growth and survival in the host cell. Unfortunately, we have a poor understanding of the nature or extent of the host cell contribution toward the support of intracellular T. cruzi infection.To approach this, we have begun to optimize parameters to carry out a genome-wide silencing screen (with small interfering RNA: siRNA) to identify host cell pathways and functional networks that provide the critical intracellular environment for T. cruzi infection. By moving away from single gene targets—the current model for studying T.cruzi-host cell interactions—toward an integrated view of host cellular pathways and functional networks our goal is obtain a global view of the critical biology at the T. cruzi-host cell interface. It is the understanding of these basic processes that will guide efforts toward effective prevention or control of Chagas’ disease.

Host response to infection
As an early response to infection in vitro and in vivo, T. cruzi, induces aprominent type I IFN response in vivo as a component of the innate immune response to this pathogen. The precise role of type I IFNs in T. cruzi infection is currently unclear due to conflicting reports presented in the literature. Using mice lacking the type I IFN receptor (IFNAR-/-) we demonstrated that type I IFNs are not required for host protection against T. cruzi. In stark contrast, we observed thatsensitivity to type I IFNs is ultimately detrimental to the host followingchallenge with a lethal dose of parasites, where mice lacking the type I IFN receptor are better able to control parasite growth than WT mice and survive an otherwise lethal T. cruzi infection. Similar results were obtained with strains of T. cruzi differing in their virulence properties. While we have not investigated this thoroughly, it is tempting to speculate that type I IFNs (or lack ofsensitivity to this class of cytokines) may favor the establishment of chronic infection. Our data support a growing paradigm that sensitivity to type I IFNscan be detrimental to the host in a variety of non-viral pathogen infection models.


Ph.D., 1993, University of Western Ontario
Post-doc, 1993-1999, Yale University School of Medicine


Costales, J., Daily, J.P and Burleigh, B.A. 2009. Cytokine-dependent and –independent gene expression changes and cell cycle block revealed in Trypanosoma cruzi-infected host cells by comparative mRNA profiling. BMC Genomics, 10:252.

Chessler, A-D., Unnikrishnan, M, Daily, J.P., Bei, A.K. and B. A. Burleigh. 2009. Trypanosoma cruzi triggers an early Type I IFN response in vivo at the site of intradermal infection. J.Immunol.  182:2288-96.

Mott, G. A, Lenormand, G., Costales, J.E., Fredberg, J.J. and B. A. Burleigh. 2009. Modulation of host cell mechanics by Trypanosoma cruziJ. Cell Physiol. 218:315-22.

Chessler, A-D., Ferreira, L., Chang, T-H., Fitzgerald, K.A and B A. Burleigh. 2008. A novel IRF3-dependent pathway activated by trypanosomes triggers IFN? inmacrophages and fibroblasts.  J. Immunol. 181:7917-7924.

Petersen, C.A., Krumholz, K., Carmen, J., Sinai, A.P., and B.A. Burleigh.  2006. Trypanosoma cruzi infection and Nuclear Factor kappa B prevent apoptosis in cardiac cells.  Infect. Immun. 74:1580-7.

Petersen,C.A. and B.A Burleigh. 2005. Toll-like receptor 2 regulates IL-1b-dependent cardiomyocyte hypertrophy triggered by Trypanosoma cruzi. Infect. Immun. 73(10):6974-80.

Burleigh, B.A. 2005. Host cell signaling and Trypanosoma cruzi invasion: Do all roads lead to lysosomes? Science STKE, pe36.