Intestinal mucosa of a hamster infected with the yellow fever virus, showing ischemia and bacterial translocation, a mechanism by which bacteria and their products (marked in red by immunohistochemistry) pass from the intestinal lumen (blue arrows) to the intestinal mucosa (green arrows) and reach the bloodstream. The same mechanism of injury occurs in humans with fatal yellow fever (image: Amaro Nunes Duarte Neto/HC-FM-USP)
Published on 03/02/2026
By Elton Alisson | Agência FAPESP – Yellow fever is considered a hepatic disease because it primarily affects the liver. However, it also affects several other organs during its acute phase, including the kidneys, heart, brain, and lungs.
Researchers from the University of São Paulo (USP) in Brazil and the University of Wisconsin-Madison in the United States conducted a study that found hemorrhaging also occurs in the intestinal mucosa during the progression of severe cases of the disease, in which complications arise that can lead to death. This gastrointestinal damage allows bacteria inside the organ to enter the bloodstream and reach the liver, causing sepsis, a generalized systemic infection, which worsens the initial clinical condition caused by the virus.
The results of the study, supported by FAPESP, suggest that gastrointestinal damage is a key factor that differentiates fatal cases from treatable ones. These findings may also guide new treatment strategies focused on preventing bacterial sepsis. The results were published in the Journal of Infectious Diseases.
“We observed that low blood supply to the intestine, which we call mesenteric ischemia, ultimately leads to the passage of bacterial products from the organ – which has the highest concentration of human microbiota – into the blood of patients who have developed the most severe form of yellow fever,” Esper Kallás tells Agência FAPESP. Kallás is a professor at the USP Medical School (FM) and one of the authors of the study.
“This ends up causing an increase in neutrophils in the blood [a type of white blood cell that constitutes the first line of defense against bacteria and fungi],” explains the researcher, who is also the director of the Butantan Institute.
The enigma of neutrophils
The researcher and his collaborators at the Laboratory of Allergy and Clinical Immunopathology at FM-USP had previously observed that patients with yellow fever and increased neutrophil counts had higher mortality rates. The discovery, published in a previous article, intrigued the group because neutrophils are commonly associated with the immune response to bacterial infections, while yellow fever is a viral disease.
In 2020, they began a study with patients who had the most severe form of the disease to investigate the causes of this neutrophilia. “One hypothesis was that the inflammatory cascade itself could lead to neutrophilia. Another possibility was that it reflected bone marrow alterations induced by the virus, but that didn’t fit well,” says Kallás.
The most plausible hypothesis was that neutrophilia was caused by an inflammatory process triggered in the intestine due to ischemia. Bacteria could cross the intestinal barrier and enter the bloodstream, causing inflammation that worsens the condition and leads to death.
Biological marker
In order to identify potential biological markers associated with this bacterial translocation process, researcher Mateus Vailant Thomazella analyzed plasma samples from 90 severely ill patients admitted to the Hospital das Clínicas (a hospital complex administered by FM-USP) and the Emílio Ribas Institute of Infectious Diseases between 2018 and 2019. Twenty-seven of the patients died. Thomazella received a scholarship from FAPESP to conduct the analysis under the guidance of Kallás.
Scanning the blood plasma of deceased patients indicated that intestinal fatty acid-binding protein (I-FABP) plays an important role in disease prognosis, acting as a biomarker for intestinal damage. Plasma concentrations of I-FABP were significantly higher in fatal cases.
“I-FABP is a marker closely associated with damage to enterocytes, the cells that make up the intestinal mucosa. When damage occurs in this mucosa, the levels of this protein increase in the plasma,” Thomazella explains.
Autopsy observations
Amaro Nunes Duarte, a professor in the Department of Pathology at FM-USP, also observed damage to the intestinal mucosa. While conducting autopsies during the São Paulo epidemic (2018-2019), Duarte noticed hemorrhaging in the intestinal wall and ischemia of the splanchnic bed, the network of vessels that supplies the abdominal organs.
“Initially, these observations were treated as the pathologist’s anatomical impressions, but upon analyzing the slides, I found vascular damage in the intestines and stomach, characteristic of a lack of blood supply. Vascular damage to the gastrointestinal mucosa allows bacteria to pass from the intestinal lumen into the blood and liver, aggravating the initial damage caused by the yellow fever virus and leading to death,” Duarte explains.
To validate their findings, the USP researchers teamed up with Professor Adam Bailey of the University of Wisconsin-Madison, who developed an experimental model of hamsters infected with the virus. Analysis of the animal tissues revealed findings similar to those seen in humans, including hemorrhages and thrombi in the intestinal wall.
“The entry of bacteria into the animals’ blood showed that translocation is a progressive mechanism in the evolution of severe yellow fever,” says Duarte. The researchers now intend to analyze lung samples from patients who died to understand the effects of this translocation on the organ.
The article “Mesenteric ischemia and bacterial translocation precipitate the intoxication phase of yellow fever” can be read at academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiaf483/8261590.
Source: https://agencia.fapesp.br/57332
