A new target for nitric oxide has been revealed in studies of how it inhibits the growth of Salmonella. This bacterium is a common cause of food-poisoning.
"Nitric oxide is naturally produced in the nose and the gut and other tissues in the body to ward off infection," explained the senior author of the paper, Dr. Ferric Fang. He is a University of Washington (UW) professor of laboratory medicine, microbiology and medicine.
Nitric oxide – not to be confused with nitrous oxide, the laughing gas in dentists' offices – is similar to the preservatives in hotdogs, Fang said. Reactive nitrogen species, like nitric oxide, make brown meat an appetizing pink. They also weed out microorganisms that spoil food or cause food poisoning.
Fang's lab has made several important discoveries on ways mammals exploit the biochemical properties of nitric oxide to defend themselves from germs. Nitric oxide, a key actor in the body's innate immune defenses, apprehends a rogue's gallery of disease-causing organisms.
The newest results underscore that nitric oxide's antimicrobial actions are due to its interference with the metabolism, or energy production, of pathogens.
"Nitric oxide imposes substantial metabolic restrictions on bacteria," the researchers noted. Fang explained that its reactions with numerous metabolic targets accounts for the broad-spectrum nature of its success. It keeps many types of disease-causing bacteria at bay. It also prevents an overgrowth of the body's many helpful bacteria.
The latest report on the versatility of nitric oxide in arming hosts against pathogens is published in the July 21 issue of Cell Host & Microbe. Dr. Anthony R. Richardson, who is now at the University of North Carolina at Chapel Hill, led the research while he was a postdoctoral fellow in the Fang lab.
Fang's team looked at the multi-pronged action of nitric oxide on Salmonella enterica serovar Typhimurium. This type of Salmonella can contaminate food and is similar to the bacteria that cause typhoid fever.
Nitric oxide and related chemicals put Salmonella into a difficult situation called nitrosative stress. When exposed to nitric oxide, Salmonella is unable to make two essential amino acids, methionine and lysine.
Without these, Salmonella cannot grow.
"This is bad news for the bacteria, but not for the host," Fang said. "Nitric oxide doesn't damage the host that produces it."
The ability to withstand nitrosative stress makes some forms of bacteria more virulent than milder types that can't handle it.
Richardson and his colleagues found that nitric oxide and its cousins throw a monkey wrench into several points in the Krebs cycle, also known as the tricarboxylic acid cycle. This cycle is the second stage in cellular respiration, when fuel is broken down to release energy for cell growth and division.
The researchers outlined how multiple interruptions in this cycle create a series of biochemical consequences that starve Salmonella of methionine and lysine. Nitric oxide also blocks certain regulatory genes that otherwise would give Salmonella an alternate chemical route out of its distress.
"Collectively, this work demonstrates that nitric oxide imposes substantial metabolic restrictions on bacteria," the authors concluded.
In a commentary on these findings, Dr. Stephen Spiro of the Department of Molecular and Cell Biology at the University of Texas at Dallas wrote that the work "focuses renewed interest in central metabolic pathways as nitric oxide targets."
"More generally," he noted, "this study provides an excellent illustration that a proper understanding of host-pathogen interactions and the development of therapeutic interventions require a detailed knowledge of pathogen metabolism."
Nitric oxide's targeting of the Krebs cycle is not unique to Salmonella. In learning how the body naturally controls the energy supplies and growth of varied disease-causing organisms, Fang said, scientists may be able to develop new broad-spectrum antimicrobials that mimic these effects, drugs that promote the body's own natural defenses against infection, or agents that overcome the ways virulent bacteria compensate when being starved of certain nutrients.
In addition to Richardson and Fang, the UW researchers on the study "Multiple Targets of Nitric Oxide of the Tricarboxylic Acid (TCA) Cycle of Salmonella enterica Serovar Typhimurium" were Elizabeth C. Payne, Noah Younger, Joyce E. Karlinsey, Vinai Thomas, Lynne Becker, William W. Navarre, Margaret E. Castor and Stephen J. Libby.
The research was supported by grants from the National Institutes of Health.
Leila Gray | EurekAlert!
During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases
First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences