New research from the University of Pennsylvania demonstrates that
Yersinia pseudotuberculosis, a relative of the bacterial pathogen that causes plague, triggers the body's immune system to form lesions in the intestines called granulomas.

Date:
March 13, 2023
Source:
University of Pennsylvania
Summary:
Researchers sheds light on a face-off in the intestines between the
immune system and a bacterial pathogen whose family members cause
gastrointestinal disease and the plague. The team's insights may
extend to other chronic infections and could inform the development
of immunotherapies capable of fully extinguishing such diseases.


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FULL STORY ========================================================================== Yersiniabacteria cause a variety of human and animal diseases, the
most notorious being the plague, caused by Yersinia pestis. A relative, Yersinia pseudotuberculosis, causes gastrointestinal illness and is less
deadly but naturally infects both mice and humans, making it a useful
model for studying its interactions with the immune system.


========================================================================== These two pathogens, as well as a third close cousin, Y. enterocolitica,
which affects swine and can cause food-borne illness if people consume
infected meat, have many traits in common, particularly their knack for interfering with the immune system's ability to respond to infection.

The plague pathogen is blood-borne and transmitted by infected
fleas. Infection with the other two depends on ingestion. Yet the
focus of much of the work in the field had been on interactions of
Yersiniawith lymphoid tissues, rather than the intestine. A new study
of Y. pseudotuberculosisled by a team from Penn's School of Veterinary
Medicine and published in Nature Microbiology demonstrates that, in
response to infection, the host immune system forms small, walled-off
lesions in the intestines called granulomas. It's the first time these organized collections of immune cells have been found in the intestines
in response to Yersiniainfections.

The team went on to show that monocytes, a type of immune cell, sustain
these granulomas. Without them, the granulomas deteriorated, allowing
the mice to be overtaken by Yersinia.

"Our data reveal a previously unappreciated site where Yersiniacan
colonize and the immune system is engaged," says Igor Brodsky, senior
author on the work and a professor and chair of pathobiology at Penn
Vet. "These granulomas form in order to control the bacterial infection
in the intestines. And we show that if they don't form or fail to
be maintained, the bacteria are able to overcome the control of the
immune system and cause greater systemic infection." The findings have implications for developing new therapies that leverage the host immune
system, Brodsky says. A drug that harnessed the power of immune cells to
not only keep Yersinia in check but to overcome its defenses, they say,
could potentially eliminate the pathogen altogether.

A novel battlefield Y. pestis, Y. pseudotuberculosis, and
Y. enterocoliticashare a keen ability to evade immune detection.

"In all three Yersinia infections, a hallmark is that they colonize
lymphoid tissues and are able to escape immune control and replicate,
cause disease, and spread," Brodsky says.

Earlier studies had shown that Yersinia prompted the formation of
granulomas in the lymph nodes and spleen but had never observed them in
the intestines until Daniel Sorobetea, a research fellow in Brodsky's
group, took a closer look at the intestines of mice infected with
Y. pseudotuberculosis.

"Because it's an orally acquired pathogen, we were interested in how
the bacteria behaved in the intestines," Brodsky says. "Daniel made
this initial observation that, following Yersinia pseudotuberculosis
infection, there were macroscopically visible lesions all along the length
of the gut that had never been described before." The research team,
including Sorobetea and later Rina Matsuda, a doctoral student in the
lab, saw that these same lesions were present when mice were infected
with Y. enterocolitica, forming within five days after an infection.

A biopsy of the intestinal tissues confirmed that the lesions were a
type of granuloma, known as a pyogranuloma, composed of a variety of
immune cells, including monocytes and neutrophils, another type of white
blood cell that is part of the body's front line in fighting bacteria
and viruses.

Granulomas form in other diseases that involve chronic infection,
including tuberculosis, for which Y. pseudotuberculosis is named. Somewhat paradoxically, these granulomas -- while key in controlling infection
by walling off the infectious agent -- also sustain a population of the pathogen within those walls.

The team wanted to understand how these granulomas were both formed
and maintained, working with mice lacking monocytes as well as animals
treated with an antibody that depletes monocytes. In the animals lacking monocytes "these granulomas, with their distinct architecture, wouldn't
form," Brodsky says.

Instead, a more disorganized and necrotic abscess developed, neutrophils
failed to be activated, and the mice were less able to control the
invading bacteria.

These animals experienced higher levels of bacteria in their intestines
and succumbed to their infections.

Groundwork for the future The researchers believe the monocytes are
responsible for recruiting neutrophils to the site of infection and
thus launching the formation of the granuloma, helping to control the
bacteria. This leading role for monocytes may exist beyond the intestines,
the researchers believe.

"We hypothesize that it's a general role for the monocytes in other
tissues as well," Brodsky says.

But the discoveries also point to the intestines as a key site of
engagement between the immune system and Yersinia.

"Previous to this study we knew of Peyer's patches to be the primary
site where the body interacts with the outside environment through the
mucosal tissue of the intestines," says Brodsky. Peyer's patches are
small areas of lymphoid tissue present in the intestines that serve to
regulate the microbiome and fend off infection.

In future work, Brodsky and colleagues hope to continue to piece together
the mechanism by which monocytes and neutrophils contain the bacteria,
an effort they're pursing in collaboration with Sunny Shin's lab in the Perelman School of Medicine's microbiology department.

A deeper understanding of the molecular pathways that regulate this immune response could one day offer inroads into host-directed immune therapies,
by which a drug could tip the scales in favor of the host immune system, unleashing its might to fully eradicate the bacteria rather than simply corralling them in granulomas.

"These therapies have caused an explosion of excitement in the
cancer field," Brodsky says, "the idea of reinvigorating the immune
system. Conceptually we can also think about how to coax the immune
system to be reinvigorated to attack pathogens in these settings of
chronic infection as well." Igor E. Brodsky is the Robert R. Marshak
Professor and chair of the Department of Pathobiology at the University
of Pennsylvania School of Veterinary Medicine.

Rina Matsuda is a doctoral student in the Brodsky Laboratory at Penn's
School of Veterinary Medicine.

Daniel Sorobetea is a research fellow in the Brodsky Laboratory at Penn's School of Veterinary Medicine.

Brodsky, Matsuda, and Sorobetea coauthored the study with Penn Vet's
Stefan T.

Peterson, James P. Grayczyk, Indira Rao, Elise Krespan, Matthew Lanza,
Charles- Antoine Assenmacher, Daniel P. Beiting, and Enrico Radaelli and University Hospital Regensburg's Matthias Mack. Brodsky is senior author,
and Matsuda and Sorobetea were co-first authors.

The study was supported by the National Institutes of Health (grants
AI128530, AI1139102A1, DK123528, AI160741-01, AI141393-2, and AI164655), Burroughs Wellcome Fund, Foundation Blanceflor Postdoctoral Scholarship, Swedish Society for Medical Research, Sweden-America Foundation J. Sigfrid Edstro"m Award, Mark Foundation, and National Science Foundation GRFP
Award.

* RELATED_TOPICS
o Health_&_Medicine
# Immune_System # Medical_Topics # Lymphoma #
Infectious_Diseases
o Plants_&_Animals
# Bacteria # Veterinary_Medicine # Mice # Microbiology
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========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Original written by Katherine Unger Baillie. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Daniel Sorobetea, Rina Matsuda, Stefan T. Peterson, James
P. Grayczyk,
Indira Rao, Elise Krespan, Matthew Lanza, Charles-Antoine
Assenmacher, Matthias Mack, Daniel P. Beiting, Enrico Radaelli,
Igor E. Brodsky.

Inflammatory monocytes promote granuloma control of Yersinia
infection.

Nature Microbiology, 2023; DOI: 10.1038/s41564-023-01338-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/03/230313162737.htm

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