Engman Laboratory

of Tropical Parasitology and Heart Disease

Department of Pathology, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois

Research in the Engman Laboratory

Our laboratory is engaged in two different lines of investigation: (I) organelle biogenesis in trypanosomes, and (II) pathogenesis and treatment of inflammatory heart diseases. Students in our lab pursue graduate study toward the Doctor of Philosophy Degree, typically through the IGP Chicago Campus Graduate Program, but also through the IBiS Evanston Campus Graduate Program and the Neuroscience Graduate Program, by special arrangement. Several students have conducted research in partial fulfillment of the Masters of Science Degree in Biotechnology.

Organelle Biogenesis in Trypanosomes

Trypanosomes are single-celled protozoans that cause human illnesses such as sleeping sickness and Chagas' disease. These hemoflagellate parasites have complex life cycles involving both insect and mammalian hosts. The African trypanosome, Trypanosoma brucei, is transmitted to humans and animals through the bite of the tsetse fly, and replicates in the host bloodstream until it is taken up by another fly, where the life cycle is completed. T. brucei evades the host immune response by changing its glycoprotein surface coat, a process called antigenic variation. By contrast, the American trypanosome, Trypanosoma cruzi, is transmitted by reduviid bugs and does not remain in the bloodstream after infection. Rather, T. cruzi invades mammalian cells and differentiates into an intracellular form that replicates within the host cell cytoplasm. Transitions between the insect vector and the mammalian host and between mammalian extracellular and intracellular environments are accompanied by complex morphologic and biochemical changes affecting virtually every part of the parasite cell. We are particularly interested in the biogenesis of the mitochondria and flagella in these unique eukaryotic organisms, since these organelles are essential for cell survival as well as potential targets for the development of novel drugs for treating trypanosomiasis. We use a combination of genetic and cell biologic approaches to study organelle biogenesis in trypanosomes.

Pathogenesis and Treatment of Inflammatory Heart Disease

An estimated 20 million Latin Americans are infected with T. cruzi and approximately 30 percent suffer from Chagas' disease. Disease normally does not develop in T. cruzi infected humans until decades after infection, and the heart is most commonly affected. Chagas' heart disease is characterized by mononuclear cell infiltration and fibrosis, which occur in the absence of detectable parasites. We are testing the hypothesis that immune responses directed toward both parasite antigens and heart antigens (i.e., autoimmunity) contribute to pathogenesis and have developed a mouse model of infection that exhibits both features. Mice develop a severe myocarditis 3-4 weeks after infection that possesses many of the aspects of the human disease. Furthermore, these mice have strong parasite-specific and heart-specific humoral and cellular immunity and it is our goal to determine the relative importance of these responses in cardiac inflammation. To facilitate this work, we have developed a purely autoimmune model of myocarditis, induced by immunization of mice with purified cardiac myosin. These mice develop a myocarditis 3-4 weeks after immunization that is more severe than that seen in the T. cruzi infected mice. The overall objectives of our studies are are (i) to elucidate the mechanisms by which parasite infection leads to cardiac inflammation and fibrosis, (ii) to determine the mechanisms by which T cells sensitized peripherally to a heart-specific antigen cause inflammatory heart disease and (iii) to develop novel, immunomodulatory therapies for the treatment of myocarditis in an antigen-specific manner.

These hematophagous triatomines release parasite-laden feces during or after a blood meal. Parasites are introduced into the vertebrate host if this material contaminates the bite wound or a mucous membrane. These bugs are typically found in rural areas in South and Central America and even in the southern half of the United States.

These forms of the trypanosome are found in the insect vector, the noninfective epimastigote in the midgut and the infective trypomastigote in the hindgut. These eukaryotic cells have complex life cycles and, within the vertebrate host, invade a wide variety of nucleated cells and replicate in the host cell cytoplasm.

Trypanosoma brucei causes African trypanosomiasis (or sleeping sickness) in humans and animals in Africa. There are 3 sub-species of T.brucei; T.b.brucei, T.b.gambiense and T.b.rhodesiense. It features a unique and notable variable surface glycoprotein (VSG) coat which is instrumental in avoiding the host's immune system while infecting the host bloodstream (pictures above)

Tsetse flies are large blood feeding flies from Africa. Crudely similar to other large flies, such as the housefly, they can be distinguished by two easily observed anatomic traits. Tsetse flies fold their wings completely when they are at rest so that one wing lies directly atop the other over the abdomen. They also have a long proboscis which extends directly forward and is attached by a distinct bulb to the bottom of their head.

The human disease occurs in two stages: the acute stage shortly after the infection, and the chronic stage that may develop over 10 years. In the acute phase, a local skin nodule called a chagoma can appear at the site of inoculation. When the inoculation site is a conjunctival mucous membrane, the patient may develop unilateral periorbital edema, conjunctivitis, and preauricular lymphadenitis. These symptoms are collectively as Romaņa's sign.