SE Valley Times

Disease-causing microbes have evolved sophisticated strategies for invading the body, flourishing in often hostile environments, and evading immune defenses. In a new study, Professor Cheryl Nickerson, her Arizona State University colleagues, and collaborators at the University of Cincinnati and NASA Johnson Space Center delve into the physical forces guiding this behavior in a multidrug-resistant strain of salmonella, a bacterial pathogen. Their insights may accelerate the design of new therapies to address life-threatening bacterial infections such as sepsis.

The study, which appears in the journal Gut Microbes, investigates how pathogens like salmonella change their disease characteristics under fluid shear conditions like those they encounter in our bodies during infection. Fluid shear is the mechanical force caused by fluid flow, such as along the walls of blood vessels or over the surfaces of cells in the intestine. Fluid shear can influence how bacteria behave and interact with host cells during infection in ways that are not predicted when these organisms are grown under traditional laboratory conditions.

For example, fluid shear can affect the ability of bacteria like salmonella to adhere to and invade host tissues, which can play a crucial role in the development and progression of disease. Despite their importance, the effects of physical dynamics, including fluid shear on cell behavior, remain largely unexplored.

The researchers used mathematical modeling and laboratory investigations of bacterial cultures to study how the genes and disease-causing traits of multidrug-resistant salmonella typhimurium change under different physiological fluid shear environments. The conditions produced in the laboratory experiments mimic the transition of bacteria during their journey from the intestinal tract to the bloodstream, causing often fatal blood infections known as sepsis.

“The serious health risk of blood-borne infections has been exacerbated by the rapidly increasing rate of antimicrobial resistance in pathogens, creating a 'perfect storm' that has significantly increased morbidity and mortality worldwide,” according to Nickerson, a professor with the Biodesign Center for Fundamental and Applied Microbiomics and the School of Life Sciences at ASU.

There are more than 2,600 different types of salmonella. While these bacteria are notorious for producing food-borne illnesses, only a subset are known to cause infections in humans, which they do with impressive frequency.

Salmonella is one of the leading causes of gastrointestinal diseases worldwide. According to the World Health Organization (WHO), nontyphoidal salmonella infections result in nearly 94 million cases of gastroenteritis and approximately 155,000 deaths annually. In the United States alone, the Centers for Disease Control and Prevention (CDC) estimates that salmonella causes about 1.35 million infections, 26,500 hospitalizations and 420 deaths every year.

Salmonella typhimurium ST313 strain D23580, investigated in this study, has been linked to highly invasive infections in sub-Saharan Africa and elsewhere. Unlike other S. typhimurium strains that primarily cause gastroenteritis, D23580 often leads to severe and fatal systemic infections including those in the bloodstream. This dangerous strain is also resistant to many antibiotic drug treatments contributing to higher morbidity and mortality rates.

S. typhimurium ST313 infections are more likely to cause invasive disease than classic gastrointestinal disease-causing S. typhimurium strains leading to sepsis and severe illness especially in immunocompromised individuals such as those with HIV or malaria or young children.

Sepsis is a life-threatening response to infection caused by various bacteria viruses fungi and parasites. According to WHO there were approximately 49 million cases of sepsis in 2020 resulting in 11 million deaths accounting for about 20% of all global deaths​. This makes sepsis a significant global health issue even more deadly than some other major conditions like cancer and coronary disease.

Understanding biology epidemiology ST313 strains like D23580 critical developing targeted interventions improving diagnostic methods designing effective treatments vaccines combat infections.

"By integrating mathematical modeling microbiology biophysics this study advances understanding mechanical forces relevant encountered microbes infected host may influence infection outcomes including lead sepsis offers holistic approach study host-microbe systems biology,” says lead author Jiseon Yang.

Although sepsis third leading cause death worldwide little understanding mechanisms responsible deadly disease resulted lack efficacious therapeutic treatments due part studying sepsis-inducing pathogens traditional laboratory conditions fail replicate physiological fluid shear forces microbes normally encounter body transition infected tissues bloodstream rapid increase antimicrobial resistance bacterial pathogens presents real threat treatment sepsis reduces number treatments available patients

To explore fluid shear forces researchers used device called rotating wall vessel bioreactor culture S.typhimurium strain D23580 specialized bioreactor modified simulate broader range conditions microorganisms bacteria encounter body

Using approach researchers simulated quantitated different ranging low experienced intestinal tract high bloodstream

“In many ways health threat septic infections represents silent risk killed more people past two decades COVID-19 Accordingly specifically designed gain new insight mechanisms develop more effective therapeutic treatments” Nickerson says 

Research first demonstrate incremental changes alter stress responses survival immune cells called macrophages colonization human intestinal cells global gene expression any ST313 providing insight impact survive cause

Study represents milestone ongoing quest understand help guide regulate field colleagues helped lay foundation over two decades ago