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Schistosoma

Parasitic eggs trigger upregulation in genes associated with inflammation

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Schistosoma

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium.

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium. As the body reacts to millions of eggs laid by the blood flukes, people can develop fever, cough and abdominal pain, according to the Centers for Disease Control and Prevention. Schistosomiasis triggered by S. haematobium can also include hematuria, bladder calcification and bladder cancer.

Despite the prevalence of this disease, there are few experimental models specifically designed to study it, and some tried-and-true preclinical models don’t display the full array of symptoms seen in humans. It’s also unclear how S. haematobium eggs deposited in the host bladder modulate local tissue gene expression.

To better understand the interplay between the parasite and its human host, a team led by Children’s National Hospital injected 6,000 S. haematobium eggs into the bladder wall of seven-week-old experimental models.

After four days, they isolated RNA for analysis, comparing differences in gene expression in various treatment groups, including those that had received the egg injection and experimental models whose bladders were not exposed to surgical intervention.

Using the Database for Annotation, Visualization and Integrated Discovery (DAVID) – a tool that helps researchers understand the biological meaning of a long list of genes – the team identified commonalities with other pathways, including malaria, rheumatoid arthritis and the p53 signaling pathway, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. Some 325 genes were differentially expressed, including 34 genes in common with previous microarray data.

“Of particular importance, we found upregulation in genes associated with inflammation and fibrosis. We also now know that the body may send it strongest response on the first day it encounters a bolus of eggs,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National, and the research project’s senior author. “Next, we need to repeat these experiments and further narrow the list of candidate genes to key genes associated with immunomodulation and bladder cancer.”

In addition to Dr. Hsieh, presentation co-authors include Lead Author Kenji Ishida, Children’s National; Evaristus Mbanefo and Nirad Banskota, National Institutes of Health; James Cody, Vigene Biosciences; Loc Le, Texas Tech University; and Neil Young, University of Melbourne.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

Parasite collage

Which micro-organisms lurk within urine?

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Dr. Michael Hsieh's clay shield

Innovative urologist Michael Hsieh takes unbeaten path

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Dr. Michael Hsieh's clay shield

For an elementary school art project, Michael H. Hsieh, M.D., Ph.D., was instructed to fashion a coat of arms out of clay. In addition to panels for truth, justice and Taiwan, in the shield’s M.D. panel, a snake twists around a rod, like the staff for Asclepius, a Greek god associated with healing.

Children’s urologist Michael H. Hsieh, M.D., Ph.D., knew from age 10 that he would become a doctor. Proof is at his parents’ home. For an elementary school art project, students were instructed to fashion a coat of arms out of clay. In addition to panels for truth, justice and Taiwan, in the shield’s M.D. panel, a snake twists around a rod, like the staff for Asclepius, a Greek god associated with healing.

“I liked science. When I can use it to help patients, that is very rewarding,” says Dr. Hsieh, the first doctor in his family.

These days, Dr. Hsieh’s Twitter profile serves as a digital coat of arms, describing him as “tinker, tailor,” #UTI #biologist, epithelial #immunologist, helminthologist and #urologist.

Tinker/tailor is shorthand for the mystery drama, “Tinker Tailor Solider Spy,” he explains, adding that the “tinker” part also refers “to the fact that I am always questioning things, and science is about experimentation, trying to seek answers to questions.”

While still in medical school during a rotation Dr. Hsieh saw a bladder operation on a young child and thought it was “amazing.” That experience in part inspired Dr. Hsieh to become a urologist and bladder scientist. His training in immunology and study of the bladder naturally led him to study urinary tract infections and parasitic worms that affect the urinary tract. In addition, thanks to R01 funding from the National Institutes of Health (NIH), Dr. Hsieh is co-principal investigator with Axel Krieger, University of Maryland, and Jin U. Kang, Johns Hopkins, on a project to develop imaging robots for supervised autonomous surgery on soft tissue.

The $1 million in NIH funding pushes the boundaries on amazing by using multi-spectral imaging technology and improved techniques to reduce surgical complications.

Anastomosis is a technique used by surgeons to join one thing to another, whether it’s a vascular surgeon suturing blood vessels, an orthopedic surgeon joining muscles or a urologist stitching healthy parts of the urinary tract back together. Complications can set in if their stitching is too tight, prompting scar tissue to form, or too loose, letting fluid seep out.

“The human eye can see a narrow spectrum of electromagnetic radiation. These multi-spectral imaging cameras would see across greater set of wavelengths,” he says.

The project has three aims: figuring out the best way to place sutures using multi-spectral imaging, accurately tracking soft tissue as they model suturing and comparing the handicraft of a robot against anastomosis hand-sewn by surgeons.

“I like challenges, and I like new things. I am definitely not interested in doing permutations of other people’s work,” Dr. Hsieh explains. “I would much rather go on a path that hasn’t been tread. It is more difficult in some ways, but on a day-to-day basis, I know I am making a contribution.”

In another innovative research project, Dr. Hsieh leveraged a protein secreted by a parasitic worm, Schistosoma haematobium, that suppresses inflammation in hosts as a new therapeutic approach for chemotherapy-induced hemorrhagic cystitis, a form of inflammation of the bladder.

Watching his first surgery nearly 30 years ago, he had no idea robots might one day vie to take over some part of that complicated procedure, or that parasite proteins could be harnessed as drugs. However, he has a clear idea which innovations could be on the horizon for urology in the next three decades.

“My hope is 30 years from now, we will have a solid UTI vaccine and more non-antibiotic therapies. UTIs are the second-most common bacterial infection in childhood and, in severe cases, can contribute to kidney failure,” he says.

Globally, parasitic worms pose an ongoing challenge, affecting more than 1 billion worldwide – second only to malaria. People persistently infected by schistosome worms fail to reach their growth potential, struggle academically and lack sufficient energy for exercise or work.


“There is a feeling that the infection prevalence might be decreasing globally, but not as quickly as everyone hopes. In 30 years perhaps with more mass drug administration and additional drugs – including a vaccine – we’ll have it close to eliminated globally. It would become more like polio, casting a slim shadow with small pockets of infection here or there, rather than consigning millions to perpetual poverty.”

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

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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.