In a study of ethnically diverse people from Cameroon, the presence of a parasite infection was closely linked to the make-up of the gastrointestinal microbiome, according to a research team led by Penn scientists
Parasite infections are a constant presence for many people who live in tropical regions, particularly in less industrialized areas. These often chronic conditions are at best unpleasant; more seriously, children with parasite diseases that cause diarrhea can die of malnutrition or dehydration.
In Genome Biology, a study led by University of Pennsylvania scientists investigated the links between parasite infection and the gut microbiome. Using genetic methods to characterize the gastrointestinal microbiome of 575 ethnically diverse Cameroonian people representing populations from nine villages with meaningful differences in lifestyle, the researchers discovered that the presence of parasites was strongly associated with the overall composition of the microbiome.
“We found that we could look at someone’s microbiome and use it to predict whether someone had a gastrointestinal parasite infection,” says Meagan Rubel, who completed her doctorate degree at Penn and is now a postdoc at the University of California, San Diego. “Whether or not it was parasites changing the microbiome or something in the resident microbiota of a person that made them more susceptible to infection, we can’t say, but the association was strong.”
Rubel led the study in collaboration with Penn’s Sarah Tishkoff, a Penn Integrates Knowledge Professor in the Perelman School of Medicine and School of Arts and Sciences, and Frederic Bushman, a microbiologist in the medical school. In addition to the microbiome and parasites, the research also examined markers of immune function, dairy digestion, and pathogen infection, a rich dataset.
The investigation entailed six months of field work, collecting fecal and blood samples from Mbororo Fulani pastoralists, cattle herders with a diet high in meat and dairy; Baka and Bagyeli rainforest hunter-gatherers, who practice a limited amount of farming but also forage for meat and plant-based foods; and Bantu-speaking agropastoralists, who both grow crops and raise livestock. As a comparison group, the study included data from two groups of people living in urban areas of the United States, with a diet heavier in animal fats, proteins, and processed foods.
In the field, the researchers tested for malaria and a number of other pathogens that infect both the blood and gastrointestinal system.
Of the 575 people tested in Cameroon, the researchers found nearly 40% were infected with more than one parasite before receiving an antiparasitic treatment, with hunter-gatherers, on average, most likely to be co-infected with multiple parasites. In particular, the team found that four soil-transmitted gut parasites tended to co-occur at a rate much higher than chance: Ascaris lumbricoides, Necator americanus, Trichuris trichiura, and Strongyloides stercoralis, or ANTS.
“Gut parasites are a global public health concern,” says Rubel. “And you tend to see several of these parasites together in resource-poor settings where people may not have access to clinical care, piped water, and soap, so there’s more opportunity for them to be transmitted.”
Back in the lab at Penn, the researchers used genomic sequencing tools to take a snapshot of the participants’ gut microbiomes. The composition of the microbiome, they found, could accurately predict a person’s country (U.S. or Cameroon) and lifestyle (urban, pastoralist, agropastoralist, or hunter-gatherer). But after these two variables, the presence of ANTS parasites could be predicted with greater accuracy by the microbiome structure than any other variable the research team studied. Taken together, the microbiome could predict the presence of these four gut parasites with roughly 80% accuracy.
Infection with these parasites also led to upticks in immune system activation, specifically turning on pathways that promote inflammatory responses. Parasite infection was also associated with a greater likelihood of having bacteria from the order Bacteroidales, which are known to play a role in influencing digestion and immune system function.
In a second part of the study, the Penn-led team assessed the relationship between the gut microbiome and milk consumption in the Fulani pastoralist population. Earlier work by Tishkoff and colleagues illuminated how genetic mutations enabling lactose digestion arose in pastoralist communities in Africa, selected through evolution because of the important nutritional benefits of consuming dairy. In looking at the Fulani’s microbiomes, they also tended to have an abundance of bacterial genes capable of breaking down galactose, a component of lactose, and fats, compared to other groups. “This enrichment of genes could help you extract more nutrition from the food you eat,” Rubel says.
The researchers believe their findings, the largest-ever study on the link between gut microbiome composition and parasite infection from sub-Saharan Africa, can open new possibilities for future work. “The kinds of microbiome markers we found could be useful to predict the type of pathogens you have, or to shed light on the interplay between the microbiome and the immune system,” says Rubel.
Eventually, she adds, more research could even illuminate strategies for purposefully modulating the microbiome to reduce the risk of a parasite infection or minimize the harm it causes to the body.
This research was supported in part by the Lewis and Clark Fund, University of Pennsylvania, Leakey Foundation, Wenner-Gren Foundation, National Institutes of Health (grants AI007532-18, DK104339-01, GM113657-01, GM134957-01, HL113252, HL137063, HL098957, HL087115, and HL115354), National Science Foundation (grants 1540432 and 1317217), American Diabetes Association, Penn Center for AIDS Research, and PennCHOP Microbiome Program.
Rubel, Bushman, and Tishkoff’s coauthors on the paper were Penn Medicine’s Arwa Abbas, Louis J. Taylor, and Andrew Connell; the Children’s Hospital of Philadelphia’s Ceylan Tanes and Kyle Bittinger; the Johns Hopkins Cameroon Program’s Valantine N. Ndze; the Yaoundé Central Hospital’s Julius Y. Fonsah and Alfred K. Njamnshi; the University of Yaoundé’s Eric Ngwang and Charles Fokunang; and the Mbalmayo District Hospital’s André Essiane.
Frederic Bushman is the William Maul Measey Professor in Microbiology in the Perelman School of Medicine at Penn.
Meagan Rubel earned her Ph.D. from Penn and is now a postdoctoral researcher at the University of California, San Diego.
Sarah Tishkoff is the David and Lyn Silfen University Professor and a Penn Integrates Knowledge Professor at Penn, with appointments in the Department of Genetics in the Perelman School of Medicine and the Department of Biology in the School of Arts & Sciences.
UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
Irvine, CA – June 12, 2020 – A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
The study, published today in Nature Communications, titled, “Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots,” reveals how the genomic instability induced by the protein APOBEC3A offers a previously unknown vulnerability in cancer cells.
Each day, in human cells, tens of thousands of DNA damage events occur. In cancer cells, the expression of the protein APOBEC3A is one of the most common sources of DNA damage and mutations. While the mutations caused by these particular proteins in cancer cells contribute to tumor evolution, they also cause breaks in the DNA, which offer a vulnerability.
“Targeting cancer cells with high levels of APOBEC3A protein activities and disrupting, at the same time, the DNA damage response necessary to repair damages caused by APOBEC3A, could be key to more effective cancer therapies,” said Remi Buisson, PhD, senior investigator and an assistant professor in the Department of Biological Chemistry at the UCI School of Medicine. “However, to exploit the vulnerability of the cancer cells, it is critical to first quantitatively measure the protein’s activity in tumors.”
To understand the role of APOBEC3A in tumor evolution and to target the APOBEC3A -induced vulnerabilities, the researchers developed an assay to measure the RNA-editing activity of APOBEC3A in cancer cells. Because APOBEC3A is difficult to quantify in tumors, developing a highly sensitive assay for measuring activity was critical. Using hotspot RNA mutations, identified from APOBEC3A-positive tumors, the team developed an assay using droplet digital PCR and demonstrated its applicability to clinical samples from cancer patients.
“Our study presents a new strategy to follow the dysregulation of APOBEC3A in tumors, providing opportunities to investigate the role of APOBEC3A in tumor evolution and to target the APOBEC3A-induced vulnerability in therapy,” said Buisson. “We anticipate that the RNA mutation-based APOBEC3A assay will significantly advance our understanding of the function of the protein in tumorigenesis and allow us to more effectively exploit the vulnerabilities it creates in cancer therapy.”
This study was funded in part by the National Institutes of Health, a California Breast Cancer Research Program grant and an MPN Research Foundation Challenge grant.
About the UCI School of Medicine
Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.
Damon Runyon Cancer Research Foundation awards $3.2 million to top clinical investigators
The Damon Runyon Cancer Research Foundation has named four new Damon Runyon Clinical Investigators. The recipients of this prestigious three-year award are outstanding early career physician-scientists conducting patient-oriented cancer research at major research centers under the mentorship of the nation’s leading scientists and clinicians. Each will receive $600,000 to support innovative research with the potential to impact cancer diagnosis, prevention and treatment. In addition, Damon Runyon will repay an awardee’s medical school debt up to $100,000.
The Foundation also awarded Continuation Grants to two Damon Runyon Clinical Investigators for an additional two years of funding, totaling $400,000 each. The Continuation Grants are designed to support Clinical Investigators who are approaching the end of their original awards and need extra time to work on a promising avenue of research or a clinical trial. This program is possible through the generous support of the William K. Bowes, Jr. Foundation.
“The quality of research proposed by our new Clinical Investigators is exceptionally strong. We are thrilled to be funding brave and bold physician-scientists who are taking risks to experimentally address the most important questions in cancer research and then translate them into improving patients’ lives,” says Yung S. Lie, PhD, Damon Runyon President and Chief Executive Officer. “We are helping to launch the careers of tomorrow’s brightest cancer researchers.”
The Clinical Investigator Award program was designed to help address the shortage of physicians capable of translating scientific discovery into new breakthroughs for cancer patients. Through partnerships with industry sponsors and its Accelerating Cancer Cures initiative, the Damon Runyon Cancer Research Foundation has committed over $72 million to support the careers of 108 physician-scientists across the United States since 2000.
2020 Clinical Investigators
Todd A. Aguilera, MD, PhD, with mentors Robert D. Timmerman, MD, and Yang-Xin Fu, MD, PhD, at The University of Texas Southwestern Medical Center, Dallas
There is a critical need for new therapeutic approaches to treat advanced stage rectal cancer, which has increased incidence in younger people and poor prognosis. Working with a multidisciplinary team, Dr. Aguilera is leading a randomized clinical trial that combines an anti-CD40 agonist immunotherapy with radiation and chemotherapy for locally advanced rectal cancer. The drug aims to activate the protein CD40 on dendritic cells which plays a critical role in generating T-cell immunity. As part of the study, Dr. Aguilera is investigating the factors that influence a patient’s immune response to this combination treatment with the goal of optimizing therapy for difficult gastrointestinal cancers. If the proposed treatment is successful, it could become a new therapeutic standard that lowers the risk of metastasis, improves survival, shortens the treatment course and potentially avoids the need for surgery.
Anusha Kalbasi, MD, with mentors Antoni Ribas, MD, PhD, and Christine Brown, PhD, at University of California, Los Angeles
Immune checkpoint inhibitors, a standard of care for metastatic melanoma, release the brakes on a patient’s T cells, so they can attack a tumor. Some patients, however, relapse when resistance to treatment occurs. Dr. Kalbasi will lead a clinical trial to test a new immunotherapy treatment approach for patients with this deadly skin cancer, who did not respond to standard therapies. He will identify patients whose melanoma tumor cells express a protein called IL13Ra2. He will then collect the patient’s immune T cells, engineer them to identify tumor cells that express the protein and reinfuse the T cells to kill tumor cells inside the patient. In contrast to immune checkpoint inhibitors that require regular intravenous doses, these engineered chimeric antigen receptor (CAR) T cells are a one-time treatment that theoretically protect the body for life. This clinical trial may also offer insights on how CAR T therapy overcomes tumor resistance mechanisms to treat patients with metastatic melanoma.
Birgit Knoechel, MD, PhD, with mentors Kimberly Stegmaier, MD, and Catherine J. Wu, MD, at Dana-Farber Cancer Institute, Boston
Cancer cells harboring many genetic changes in their DNA often express novel proteins called neoantigens that activate the immune system to recognize and attack the tumor. Based on this mechanism, researchers are developing novel treatments to stimulate the immune system’s response against a tumor, but this approach may not work for pediatric cancers that carry few genetic mutations. Dr. Knoechel’s research is investigating alternative ways neoantigens can be generated, such as splicing or epigenetic changes, which occur frequently in leukemia and pediatric cancers. She is focusing on T-cell acute lymphoblastic leukemia (T-ALL), an aggressive blood malignancy in children and young adults that frequently stops responding to treatment causing relapse. Her research aims to identify mechanisms of immune “exhaustion” when T-cells stop fighting a tumor, define neoantigens generated by non-genetic mechanisms, and develop novel strategies to target non-genetic neoantigen expression. This research may lead to novel immunotherapy strategies for pediatric tumors.
Yvonne M. Mowery, MD, PhD, with mentor David G. Kirsch, MD, PhD, at Duke University, Durham
Head and neck cancers usually begin in the squamous cells that line the mucosal surfaces inside the mouth, nose and throat. Even with aggressive treatment including surgery, radiation therapy and chemotherapy, these tumors often recur with poor prognosis. Dr. Mowery will use patient samples and mouse models to investigate why these cancers are resistant to radiation treatment and to test new therapeutic approaches to improve outcomes for patients. She will also conduct a Phase 1 clinical trial to evaluate the effectiveness of using a combination of a radiation sensitizer (a drug that makes cancer cells more vulnerable to radiation therapy), radiation therapy and immunotherapy to treat patients with recurrent head and neck cancer.
In addition, the Committee recommended funding two Continuation Grants:
Vinod P. Balachandran, MD, Memorial Sloan Kettering Cancer Center, New York
“Recombinant interleukin-33 immunotherapy for pancreatic cancer” with mentors Steven D. Leach, MD, and Jedd D. Wolchok, MD, PhD
Piro Lito, MD, PhD, Memorial Sloan Kettering Cancer Center, New York
“Modeling responses to targeted ERK signaling inhibition at the single-cell level” with mentors Neal X. Rosen, MD, PhD, and Charles M. Rudin, MD, PhD
DAMON RUNYON CANCER RESEARCH FOUNDATION
To accelerate breakthroughs, the Damon Runyon Cancer Research Foundation provides today’s best young scientists with funding to pursue innovative research. The Foundation has gained worldwide prominence in cancer research by identifying outstanding researchers and physician-scientists. Twelve scientists supported by the Foundation have received the Nobel Prize, and others are heads of cancer centers and leaders of renowned research programs. Each of its award programs is extremely competitive, with less than 10% of applications funded. Since its founding in 1946, the Foundation has invested over $375 million and funded more than 3,750 young scientists. Last year, we committed nearly $22 million in new awards to brilliant young investigators.
100% of all donations to the Foundation are used to support scientific research. Administrative and fundraising costs are paid with revenue from the Damon Runyon Broadway Tickets Service and our endowment.
For more information visit damonrunyon.org
Director, Communications and Marketing
Protecting bays from ocean acidification
UD research shows that submerged vegetation helps to offset Chesapeake Bay acidification
For many years, the world’s oceans have suffered from absorbing human-made carbon dioxide from the atmosphere, which has led to the decreasing pH of saltwater, known as ocean acidification, and threatened the health of marine organisms and ecosystems. While this process has been well documented, the acidification process is complicated and poorly understood in coastal waters.
For example, the main stem of Chesapeake Bay, the largest estuary in the east coast, has suffered from low oxygen and acidification for years in its bottom waters. Unlike ocean waters, acidification in estuaries like Chesapeake Bay is driven by both fossil fuel-derived carbon dioxide as well as carbon dioxide released from the intense decomposition of algae spurred by nutrient inputs from surrounding land. Although scientists are improving their understanding of the causes of acidification, the ways in which coastal waters like Chesapeake Bay fight back and resist acidification are less known.
One possible way the Chesapeake Bay is combating ocean acidification comes in the form of an already present ally: submerged aquatic vegetation (SAV). While there was a bay-wide decline of SAV from the 1960s through the 1980s, restoring these once-abundant SAV beds has been a primary outcome of efforts to reduce loads of nutrients and sediments to the estuary and SAV cover has increased by 300 percent from 1984 to 2015.
One of the largest recovered SAV beds lies in an area of the bay known as the Susquehanna Flats — a broad, tidal freshwater region located near the mouth of the Susquehanna River at the head of the bay.
The University of Delaware’s Wei-Jun Cai was part of a research group that recently conducted a study of the bay, including in the Susquehanna Flats, in order to understand how the Chesapeake Bay uses a defense mechanism against acidification – known as buffering – to help reduce carbon dioxide and acidification in its waters during the summer time.
The research team included researchers from Xiamen University in China, St. Mary’s College, Oregon State University and the University of Maryland Center for Environmental Science’s Chesapeake Biological and Horn Point Laboratories.
They found that strong photosynthesis by the plants in SAV beds at the head of the bay and in other shallow, nearshore waters can remove nutrient pollution in the bay, can generate very high pH, and elevate the carbonate mineral saturation state, which facilitates the formation of calcium carbonate minerals. When these calcium carbonate particles and other biologically produced carbonate shells are transported downstream, they enter acidic subsurface waters where they dissolve.
This dissolution of the carbonate minerals helps to “buffer” the water against pH decreases or even support pH increases. “Just like people take Tums to neutralize the acids that cause heartburn, the idea is that SAV beds send carbonate minerals to the lower Bay to neutralize acids there,” said Jeremy Testa of the University of Maryland Center for Environmental Sciences and a co-author of the study.
The research was recently published in Nature Geoscience. The first author, Jianzhong Su, was a UD-Xiamen University Dual Degree doctoral student and had Cai as an adviser.
Calcium carbonate dissolution
In previous work, Cai, the Mary A.S. Lighthipe Professor in the School of Marine Science and Policy in UD’s College of Earth, Ocean and Environment, showed there was a lot of calcium carbonate dissolution in the subsurface water of the lower bay but they didn’t know where that carbonate was coming from.
“This paper shows unique evidence that the carbonate comes from these submerged aquatic vegetation beds,” said Cai. “Shallow waters in the upstream heads and nearshore areas can have a vast amount of submerged aquatic vegetation.”
In these areas during summer time, sunlight combines with nutrients to allow dense SAV beds to initiate high rates of photosynthesis that causes the pH in the water to increase, meaning the water is less acidic.
Because the pH is so high, the researchers were able to collect and measure the carbonate particles on the surface of the leaves, which they could scrape and analyze. Co-authors Chaoying Ni, professor in UD’s Department of Materials Science and Engineering and Director of the W.M. Keck Center for Advanced Microscopy and Microanalysis, and Yichen Yao, who was a master’s level student in materials engineering, did the mineral analysis.
“The lab did an image for us and showed the carbonate in these sediments and the sediment on the leaves, the particles, their concentration was a lot higher than the bottom sediment,” said Cai.
Theoretical carbon formations
When the researchers went to a shallow area upstream of the Susquehanna Flats, they also found the carbonate, which led them to their theory that the carbonate forms in one location, particularly, in the SAV bed of the Susquehanna Flats, and then it’s transported to the lower bay.
“We know there is a lot of carbonate dissolution in the lower bay, and we know the upper bay is where the carbonate is formed. So in the paper, we hypothesize that it’s that formation in the SAV bed that gets transported downstream and dissolves and we reproduce this downstream transport with a numerical model,” said Cai. “This carbonate that is transported from upstream actually acted as a way to resist, to buffer the pH of the system.”
There are important ecological ramifications of this finding in that coastal nutrient management and reduction not only help to fight against low oxygen stress but also acidification stress to the environments and organisms that live there via the resurgence of submerged vegetation.
Cai said that while their preliminary results are encouraging, the next steps are to determine if the carbonate particles are really transported by the currents and tides to the lower bay and if so, how fast and under what conditions this happens. He wants to go back to the Bay to nail down the missing link between where the carbonate forms and where it dissolves.
“This is a very interesting thing,” Cai said. “People talk about ocean acidification and very rarely talk about what resists it, what can buffer the system against ocean acidification. So that’s what we want to find.”
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