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Hepatocytes

H-IPSE internalized by just a limited range of cells

Hepatocytes

A team led by Children’s National Hospital found that H-IPSE is internalized by just a limited range of cells, including hepatocytes.

Schistosoma mansoni is a parasite that hides out in snails, breaks free into waterways, and then infects humans, spending much of its life inside blood vessels, laying eggs and jeopardizing public health when those eggs are excreted in urine or feces. As parasitic diseases go, the ailment it causes, Schistosomiasis, is second only to malaria in global impact, according to the Centers for Disease Control and Prevention.

In order to elude the human host’s defenses, S. mansoni uses self-defense tactics that researchers are trying to better understand in order to outmaneuver the parasite. A research team led by Children’s National Hospital is trying to tease out the multiple steps that enable this parasite to reproduce and generate millions of eggs without killing its host.

The parasite’s eggs secrete a number of proteins, with IPSE as one of the most abundant, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. That protein binds immunoglobulin, which induces basophils and mast cells to release IL-4. After sequestering chemokines, H-IPSE infiltrates the cell nucleus (thus H-IPSE is called an infiltrin), modulating gene expression.

“H-IPSE tips the immune system balance, making it more likely to trigger a Th2 anti-inflammatory response,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author. “It downregulates pro-inflammatory pathways, but we wanted to know more about which specific human cells it targets.”

Using Trypan Blue, a stain that selectively colors certain cells bright blue, they solved the mystery, finding that H-IPSE is internalized by just a limited range of cells. What’s more, some cell types, like urothelial cells and hepatocytes (the liver’s chief functioning cells, which activate innate immunity), are more susceptible than neurons, endothelial cells or immature dendritic cells.

In addition to Dr. Hsieh, presentation co-authors include Olivia Lamanna, Evaristus Mbanefo and Kenji Ishida, all of Children’s National; Franco Falcone, of University of Nottingham; and Theodore Jardetzky and Luke Pennington, of Stanford University.

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

Schistosoma haematobium egg

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D.

Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.

Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.

In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”

S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.

“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”

Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.

In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.

Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.