Research in our lab focuses on understanding how nematode infections in humans and animals can be controlled. A recombinant fusion antigen vaccine was developed to prevent infection with Onchocerca volvulus. Comprehensive studies have described the mechanism of the protective immune response induced by the vaccine. The NSG mouse model has advanced Dirofilaria immitis research by accelerating the development of diagnostics and therapy. Infection of NSG mice with Strongyloides stercoralis has enabled us to study the progression of lethal hyperinfection and to discover new treatments for this disease.
Abraham Research
Name:
David Abraham, PhD
Position:
Professor, Department of Microbiology & Immunology
Organization:
Sidney Kimmel Medical College
Bluemle Life Sciences Building
233 South 10th Street, Suite 530
Philadelphia, PA 19107
Email:
David.Abraham@jefferson.edu
Contact Number(s):
Research Projects
Development of a vaccine against Onchocerca volvulus, the causative agent of river blindness
We have developed a vaccine against the nematode Onchocerca volvulus, the etiologic agent of river blindness, which is characterized by infectious blindness, skin disease, and chronic disability. Our research focused on identifying the optimal formulation of a recombinant vaccine to protect humans against infection O. volvulus. We tested multiple adjuvant and antigen combinations to identify the vaccine formulation with consistent efficacy and durability in a mouse model. Immunization of non-human primates with the vaccine demonstrated that all tested formulations were immunogenic and safe, and non-human primate serum could passively transfer protective immunity to naïve mice. The mechanism underlying the vaccine-induced protective immune response was identified, with an emphasis on antibodies, cytokines, and cell interactions. In addition, Collaborative Cross mice were used to test the Onchocerca vaccine in genetically diverse mice to assess its efficacy in heterogeneous populations, as would be seen in humans in endemic regions.
Dirofilaria immitis infection of NSG mice – development, diagnostics, and therapy
Efforts to control dog heartworm, Dirofilaria immitis infections, are challenged by increasing drug resistance and inadequate early detection methods. Our laboratory has developed a mouse model using NSG mice to study canine heartworm infections. The parasite develops into adult male and female worms in the hearts of NSG mice, mirroring the infection dynamics of the natural canine host. D. immitis-specific microRNAs were identified in the plasma of infected mice, which mirrored those detected in D. immitis-infected dogs.
The NSG mouse model has also been shown to be valuable for the evaluation of chemotherapies against D. immitis. NSG mice were infected with D. immitis isolates that were either drug-susceptible or drug-resistant; the susceptible isolate was killed by the drug ivermectin, whereas the resistant isolate survived. The focus of our research on heartworm is: (1) identifying correlations between canine and mouse control of D. immitis infection, (2) critical analysis of D. immitis development, and (3) development of novel drugs and diagnostics for D. immits infections of dogs and potentially filarial infection of humans.
Mechanism and therapy of hyperinfection by Strongyloides stercoralis
Humans infected with Strongyloides stercoralis routinely maintain long-term chronic infections, which may evolve into fatal hyperinfection if the patient is treated with steroids or is co-infected with HTLV-1. Our research has focused on determining the mechanisms and therapies for hyperinfection caused by this infection. We have reported that NSG mice are susceptible to the complete life cycle of S. stercoralis and will develop hyperinfection when exposed to steroids, like in humans. Research was also directed at determining the mechanism of steroid-induced hyperinfection and describing the interaction between S. stercoralis and HTLV-1 in humanized mice. Finally, we have discovered that treating mice, with potentially lethal S. stercoralis hyperinfection, with dafachronic acid significantly reduced the worm burden, thus opening the possibility of a new treatment for this devastating human disease.