In an era of increasing concern about the prevalence of antibiotic-resistant illness, Case Western Reserve researchers have identified a promising new pathway to disabling disease: blocking bacteria's access to iron in the body.
The scientists showed how bacterial siderophore, a small molecule, captures iron from two abundant supply sources to fan bacterial growth — as well as how the body launches a chemical counterassault against this infection process. Their findings appear in a recent edition of The Journal of Experimental Medicine.
"Bacterial siderophore will be an important target for therapeutics one day because it can be modified to prevent bacteria from acquiring iron, but at the same time, it's possible to preserve host access to iron," said senior author Laxminarayana Devireddy, DVM, PhD, assistant professor of pathology, Case Comprehensive Cancer Center.
Investigators knew from the outset that bacterial siderophore captures iron from the host mammal and transforms it so that bacteria can absorb and metabolize the mineral. In this investigation, Devireddy and his colleagues discovered that human mitochondria, which very closely resemble bacteria, possess their own iron-acquisition machinery — mitochondrial siderophore. Mammalian mitochondria are membrane-encased subunits within cells that generate most of the cell's energy, and like their bacteria counterparts, mammalian mitochondria have their own siderophore mechanism that seeks out, captures and delivers iron for utilization.
At the test tube level, investigators found that bacteria can feed on iron supplied by bacterial siderophore and mitochondrial siderophore. From this glut of iron, bacteria proliferate and make the host mammal very ill with an infection.
"It's like bacteria can use their own iron-capture machinery or the host's. It just doesn't matter," Devireddy said. "They are very good at utilizing siderophore from both bacterial and mammalian siderophore sources. That means that bacteria get the most iron."
Case Western Reserve researchers also demonstrated that the absence of mitochondrial siderophore in a mammal can enhance its ability to resist infection. When investigators exposed mice deficient for mitochondrial siderophore to systemic infection by E. coli, the animals resisted infection. The reason? E. coli bacteria had less iron to access from mitochondrial siderophore-deficient mice.
Additionally, mammals are not entirely defenseless from a bacteria raid on mitochondrial siderophore iron supplies. In another phase of their investigation, scientists found that normal mice secrete the protein lipocalin 24p3, which isolates bacterial siderophore and suppresses synthesis of mammalian siderophore.
"The action of lipocalin significantly reduced the mortality of the mice from the E. coli infection, and some mice actually recovered," Devireddy said. "That kind of delay in bacterial proliferation gave the immune system time to identify and then neutralize the microbe."
These findings highlight the potential of developing effective therapeutics to reverse bacterial infection.
"Any approach that would suppress either bacterial or mitochondrial siderophore and activate lipocalin-2 would likely slow infection, allowing the host's immune system to respond," Devireddy said. "Such novel approaches would also provide a much-needed alternative to treat those infections that have become antibiotics resistant."
In addition to Devireddy, investigators on this project were Zhuoming Liu, PhD (lead author), Scott Reba, Suheel Kumar Porwal, PhD, W. Henry Boom, MD, Robert B. Petersen, PhD, Roxana Rojas, MD, PhD, and Rajesh Viswanathan, PhD, all of Case Western Reserve University, and Wei-Dong Chen, PhD, National Cancer Institute of the National Institutes of Health (NIH). This work was supported by NIH R01DK081395, Case Western Reserve University startup funds to Devireddy, an American Cancer Society Research Scholar Award, and March of Dimes and American Society of Hematology career development awards.
About Case Comprehensive Cancer Center
Case Comprehensive Cancer Center is an NCI-designated Comprehensive Cancer Center located at Case Western Reserve University. The center, which has been continuously funded since 1987, integrates the cancer research activities of the largest biomedical research and health care institutions in Ohio – Case Western Reserve, University Hospitals (UH) Case Medical Center and the Cleveland Clinic. NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer. It is led by Stanton Gerson, MD, Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology, director of the National Center for Regenerative Medicine, Case Western Reserve, and director of the Seidman Cancer Center at UH Case Medical Center.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu
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