Stream of funding spurs advances in human health:
Arizona State University Biodesign Institute researchers have received three significant new grants, advancing knowledge of digestive proteins in the human gut, toxic exposure to fungi during childhood and long-term vaccine effectiveness.
The power of proteins
Abishek Shrivastava is a researcher with the Biodesign Center for Fundamental and Applied Microbiomics and an assistant professor in ASU’s School of Life Sciences. His interdisciplinary research combines biology, physics and computer science to probe fundamental questions concerning the microbiome. This rapidly expanding field concerns the billions of bacterial and other nonhuman cells in the body and their essential roles in health and disease. Shrivastava is the recipient of a new $1.96 million Maximizing Investors’ Research Award from the National Institutes of Health (NIH) National Institute for General Medical Science (NIGMS).
The NIGMS program is designed to stimulate scientific breakthroughs by providing five-year grants, which afford investigators the stability and flexibility needed to significantly enhance their research productivity. The program also helps distribute funding more widely among the nation’s highly talented and promising investigators.
“Genomics research has shown that changes in the diversity of the gut microbiome correlates with the progression of multiple diseases,” Shrivastava says. “Why is the microbiome essential to our health? What mechanisms govern communication between microbes and our gut? This award will help our lab answer these questions. In the future, the products of our research can be used to design bioengineered therapeutics.”
Although essential microbes in the gut are known to provide innumerable health benefits, the mechanisms by which they convert the nutrients required for growth, metabolism and activity to beneficial products in the body are poorly understood. The prestigious and highly competitive NIH award will help Shrivastava pursue studies of the various metabolites generated by the gut microbiome.
Several gut microbes use specialized protein secretion machinery to secrete enzymes that break down dietary fiber. This results in the creation of beneficial metabolites through fermentation, which help the human body fight against diseases such as Type 2 diabetes, obesity and dementia.
Gut microbes also secrete a class of protein-degrading enzymes that impact human immunity. The Shrivastava lab will study a newly discovered machinery known as the bacterial Type 9 Secretion System, which enables important gut microbes to secrete proteins that form beneficial metabolites. The research employs a multidisciplinary approach, including genetics, biophysics, biochemistry and animal models, to uncover how the secretome of gut microbes influences health.
Effect of toxins on childhood growth
Rosa Krajmalnik-Brown directs the newly established Biodesign Center for Health Through Microbiomes and is a professor with the School of Sustainable Engineering and the Built Environment. Her new $2.6 million, five-year grant is from the NIH National Institute of Environmental Health Sciences.
The project explores aflatoxin, a carcinogen produced by Aspergillus flavus and A. parasiticus, pathogenic fungi that grow on maize. The research will evaluate the effect of aflatoxin exposure on growth in children, determining whether aflatoxin effects are mediated by the gut microbiome and inflammation.
“I am very excited about this project because it brings together an amazing team and topics I am passionate about, including food quality, environmental exposure, biotransformation’s of organic chemicals, gut microbiomes and child development,” Krajmalnik-Brown says. “I am looking forward to bringing this expertise together to help children in less privileged countries.”
The multidisciplinary approach involves expertise in epidemiology, pediatrics, toxicology, environmental engineering, human microbiome and bioreactors. The research will investigate children exposed via diet to aflatoxins, ages 6–9 months and 24–27 months, providing evidence that could lead to significant investments in aflatoxin remediation efforts by organizations such as the CDC, USAID and other international public health organizations focused on improving global child health.
Given the widespread occurrence of stunting and other nutritional disorders in countries where maize is a staple food, the impact of aflatoxin exposure on childhood growth is a critical issue to examine. Although previous research has suggested a link between aflatoxin exposure and human growth, most of these studies have not accounted for seasonal variations in aflatoxin exposure, food preparation and growth.
The project will study the temporal changes in diet, aflatoxin exposure and growth in a prospective cohort of children from rural Guatemala, a country with one of the highest rates of child stunting and aflatoxin exposure globally.
By studying the impact of aflatoxin exposure on growth and the potential role of the gut microbiome in mediating these effects, the new research holds the potential to inform new public health strategies for reducing aflatoxin exposure and promote microbiome-directed treatments, advancing our understanding of the physiological mechanisms underlying aflatoxin-mediated growth restriction.
The study involves an international research team, including the Maya Health Alliance, Brigham and Women’s Hospital, Harvard Medical School Department of Global Health and Social Medicine and Centro de Investigaciones en Nutricion y Salud (CIENSA).
How long are vaccines effective?
Vel Murugan has received a $2.5 million grant from the Defense Advanced Research Projects Agency to study the longevity of protection provided by vaccines against infectious disease.
Murugan is the associate research director of the Biodesign Virginia G. Piper Center for Personalized Diagnostics and the Biodesign Clinical Testing Laboratory, as well as the Health Solutions Ambassador for the College of Health Solutions at ASU.
The new project aims to develop an algorithm to evaluate vaccine effectiveness over time, with unrivalled accuracy.
“This is a collaborative project between my laboratory and Professor Nevil Sign at the University of Maryland. This project will significantly improve our understanding of the mechanism behind the longevity of vaccine effectiveness,” Murugan says. “This will pave the way for us to design better, longer-lasting vaccines for infectious diseases, cancer and many more modalities.”
In the wake of the SARS CoV-2 pandemic and the ongoing threat of serious global infectious disease, understanding the durability of vaccine protection is of critical importance. Nevertheless, existing methods that aim to track the waning of vaccine effectiveness over time have struggled with a number of shortcomings.
Although the concept of immune memory is well established, at present, the most dependable method to determine if a vaccine can establish long-lasting immunity lasting 10 or more years is to simply wait and observe the vaccine recipient. Despite numerous in-depth studies using multiple parameters, no accurate algorithm exists to predict the longevity of immune memory.
The project will examine immune memory formation in a class of cells known as lymphocytes, a type of white blood cell that plays a crucial role in the immune system. Lymphocytes are responsible for recognizing and responding to invasive foreign substances, such as bacteria and viruses. The researchers hypothesize that vaccines bearing long-term effectiveness leave a signature on lymphocyte cells that can be detected and analyzed shortly after vaccination. This is believed to be the case regardless of the specific infectious pathogen under study.
The approach investigates effective, widely used, FDA-licensed vaccines to see whether they activate identifiable immune pathways that are distinct from ineffective vaccines. This “pathogen-agnostic” approach can help identify vaccine components likely to be the most effective over an extended period.
The project examines six CDC-recommended vaccines: Pertussis, Yellow Fever, Rubella, Polio, Measles and HPV, comparing effective versus ineffective versions of these vaccines in animal models. Phase 2 of the study will test the effectiveness of the new algorithm on SARS-CoV-2-vaccinated individuals.