A trio of chemists at Indiana University Bloomington have created a new sensor to detect chemical changes in immune cells during the breakdown of pathogens. The work could potentially contribute to the early diagnosis and treatment of infectious diseases, such as tuberculosis, which avoid certain elements of the body’s immune response.
The results were reported on October 8 in Angewandte Chemie, a leading chemistry journal. The study was led by Yan Yu, an associate professor at IU Bloomington College of Arts and Sciences’ Department of Chemistry.
The particles in the study were designed to understand phagocytosis, the process by which immune cells take up and destroy pathogens in the body. During this important process, pathogens are absorbed into cellular spaces called phagosomes, which then “mature” through a complex sequence of chemical reactions and kill invasive disease.
“Many important cell functions, including phagocytosis, rely on the orchestration of complex chemical reactions, but measuring these different reactions in real time inside a living cell is extremely challenging,” Yu said. “This study shows that particles of the type designed in our laboratory are largely useful for understanding many types of complex chemical interactions in living cells.”
The particles used in the study are called Janus particles, named after the Roman god with two faces. The artificially constructed particles are so-called, as two sides of the same particle are “coated” with different chemical sensors. These sensors can act as detectors or “journalists” for various chemicals involved in the biological process being studied.
Yu’s laboratory has perfected a technique to pack these receptors very tightly together across the surface of a Janus particle, significantly increasing their efficiency as a study tool.
Yu’s previous research on Janus particles has provided new insights into the body’s ability to resist fungal infection as well as a new method of activating the body’s T cells, which are used to fight cancer, improve immunotherapy, fight viral infection and induce tolerance in autoimmune disease. The latter work is the subject of a patent application to the U.S. Patent and Trademark Office. She has also filed a preliminary patent on the recently reported discovery.
In the new study, the Yus team designed a Janus particle, the two sides of which consist of a 3-micrometer pH reporter and a 500-nanometer proteolysis reporter. As a result, the researchers were able to simultaneously measure two chemical processes involved in phagocytosis acidification and proteolysis within a single maturation phagosome in real time. They identified that phagosomes require an “acid lumen” to activate enzymes that digest pathogens encapsulated within, a critical step to prevent the pathogens from reproducing inside host immune cells.
They also showed that lipopolysaccharide, a sugar compound found in the outer wall membranes of many bacteria, can affect acidification and proteolysis in phagosomes.
Understanding these processes is especially important in bacterial infections that avoid the body’s immune response by hijacking one or more events in the phagosoding process, which counteracts the protective function of the phagosome. These diseases include tuberculosis, which is the world’s leading killer of infectious diseases that claim about 1.5 million lives annually.
“The Janus particles created in this study act as a sensor to detect these chemical changes inside immune cells during pathogen degradation,” Yu said. “But more broadly, the work demonstrates the feasibility of Janus particles as a general tool for monitoring multiple responses in a cell – as well as highlighting their potential for the detection and diagnosis of infectious diseases.”
The other authors on the study are Seonik Lee and Zihan Zhan, both graduate research assistants in Yu’s laboratory at IU Bloomington. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health.