How Typhoid Fever Triggers Severe Neurological Symptoms

About 15% of patients with typhoid fever develop serious neurological complications, including delirium and seizures, that are collectively described as acute encephalopathy. Until now, however, scientists have not clearly understood the mechanisms behind these life-threatening neurological effects.

A new Yale study published May 8 in the journal Nature Microbiology provides critical insights into how typhoid fever leads to encephalopathy. Researchers found that typhoid toxin, a key virulence factor only produced by the bacterium Salmonella Typhi, does not directly damage brain cells, as previously thought. Instead, it targets the endothelial cells lining the blood-brain barrier (BBB), causing significant barrier disruption and subsequent brain pathology.

The findings will inform treatment of this life-threatening infection, which annually afflicts about 12 million people and causes about 200,000 deaths, mostly in the world’s poorest countries.

“Our findings shift the focus of typhoid fever neurological complications from direct neuronal injury to vascular damage of the blood-brain-barrier,” said senior author Jorge Galán, the Lucille P. Markey Professor of Microbial Pathogenesis and professor of cell biology at the Yale School of Medicine. “This discovery is critical for guiding therapeutic approaches to one of typhoid fever’s most serious manifestations.”

Typhoid fever, caused by Salmonella Typhi, is one of the oldest documented human diseases. Most commonly spread by contaminated food or water, it is characterized by high fever, headaches, nausea, and, in some cases, potentially deadly neurological complications.

The Galán laboratory previously identified typhoid toxin as responsible for many of the disease’s symptoms. Unique among bacterial toxins, typhoid toxin specifically binds to human cells that display certain sugar modifications (Neu5Ac glycans) on their surfaces, a feature absent in most other mammals. 

Initially, the team hypothesized that typhoid toxin directly attacked neurons, but mouse models contradicted this idea, as injecting the toxin directly into the brain produced no neurological symptoms. Additionally, mice genetically modified to protect neurons from toxin binding still developed neurological symptoms.

“This was an unexpected and striking result,’’ Galán noted.

Instead, researchers discovered that typhoid toxin severely damages the endothelial cells lining the BBB, a crucial protective barrier separating the bloodstream from the brain. This damage triggered inflammation, edema, and neurological dysfunction in mice models. Crucially, mice engineered to protect endothelial cells from toxin binding showed no neurological symptoms.

The team demonstrated that treatment with the corticosteroid dexamethasone effectively mitigated toxin-induced damage of the BBB and reduced brain inflammation and edema. 

“Our findings strongly support the clinical use of corticosteroids in severe typhoid fever cases, providing a clear rationale for therapies targeting inflammation and BBB integrity,” Galán said. 

Heng Zhao, an associate research scientist in the Galán laboratory, is the lead author of the study. This research was conducted through a collaboration between the Galán laboratory and the laboratory of Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine and professor of neuroscience and of obstetrics, gynecology, and reproductive sciences at the Yale School of Medicine. It was supported by grants from the National Institutes of Health.