Uncovering cellular stress signal triggered by Salmonella

Like people, cells get stressed too, and researchers want to understand how.

In a new paper published in Infection and Immunity, researchers from the O’Riordan lab looked for causes of stress for cells infected with Salmonella.

“Stress at its core is a decision making tool,” said Zachary Powers, PhD, who defended his dissertation in June 2026.

“It allows us to read environmental cues and respond effectively. Stress can happen at a single cellular level as well; [for example] when bacteria invade a cell, this may be sensed by the cell as stress.”

For this study, Powers studied Salmonella enterica serovar Typhi, a bacterium that, when contracted, can lead to typhoid fever, a potentially devastating systemic infection.

The team found that the bacteria camp out inside the cell and rapidly break down one specific amino acid, asparagine.

In addition to being a protein building block, asparagine is a molecule that signals to the cell that it should grow.

When asparagine is degraded, the cell deploys a stress response program.

“The core finding of the research is that it's Salmonella Typhi degrading host asparagine that is triggering cellular stress,” Powers said.

You might recognize when you’re stressed by a pounding heart or sweaty hands. Cells have a different mechanism using a sensor, the kinase GCN2.

The researchers deleted the gcn2 gene from cells and observed how the cells interacted with Salmonella.

They found that the cells lacking GCN2 were worse at their innate immune functions and that, after 24 hours, more of the bacteria survived in the cells.

Cells being able to sense stress promotes their ability to fight off an infection.

“The most impactful finding is that immune cells sense when invading bacteria deplete nutrients and can use this information to aid in controlling Salmonella enterica Typhi infection,” said Mary O'Riordan, Ph.D., Professor of Microbiology & Immunology and principal investigator on the study.

This research may have broader implications beyond infection.

Asparagine is used by some cancer cells, signaling to the cancer that it should grow.

In clinical settings, recombinant bacterial asparaginases can be used to reduce the amount of asparagine present, inhibiting cell growth.

“Zach showed tremendous creativity and determination in taking this project from his original observation, that Salmonella enterica Typhi triggered nutrient sensing pathway, to identifying the key host nutrient sensor and the bacterial factor that triggers this sensor,” O’Riordan said.

Additional authors: Michael J. McFadden, Gi Young Lee, Tracey Schultz, Luiza A. Castro Jorge, Daniel F. Edwards III, Simon Sanchez-Paiva, Jonathan Z. Sexton, Katherine R. Spindler, Jeongmin Song

Paper cited: “Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages,” Infection & Immunity. DOI: 10.1128/iai.00178-26

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