New research from the University of Pennsylvania shows that Yersinia pseudotuberculosis, a relative of the bacterial pathogen that causes plague, triggers the body’s immune system to form intestinal lesions called granulomas. – Teach daily

Yersinia Bacteria cause a wide variety of human and animal diseases, the most famous being the plague it causes Yersinia pestis. close, Yersinia pseudotuberculosisIt causes gastrointestinal disease and is less lethal but naturally infects both mice and humans, making it a useful model for studying its interactions with the immune system.

These two nurses, as well as a close third cousin, Y. enterocoliticawhich infect pigs and can cause food-borne illness if people eat infected meat, have several features in common, particularly their knack for interfering with the immune system’s ability to respond to infection.

Plague is blood-borne and transmitted by infected fleas. Infection with the other two is ingestion-dependent. However, the focus of much work in this field has been on interactions Yersinia With lymphoid tissue, not intestines. A new study on Y. pseudotuberculosis Led by a team from the College of Veterinary Medicine of Pennsylvania and published in Nature Microbiology He explains that, in response to infection, the host immune system forms small, obstructive lesions in the intestine called granulomas. It is the first time that these organized groups of immune cells have been found in the gut in response Yersinia infections.

The team went on to show that monocytes, a type of immune cell, maintain these granulomas. Without it, the granulomas deteriorated, allowing the mice to overcome them Yersinia.

“Our data reveal a previously unappreciated location where Yersinia “It can colonize and participate in the immune system,” says Igor Brodsky, senior author of the work and professor and chair of the department of pathology at the Veterinary University of Pennsylvania. These granulomas form in order to control bacterial infection in the intestine. And we have shown that if they are not formed or maintained, the bacteria are able to overcome immune system control and cause a larger systemic infection.”

Brodsky says the findings have implications for developing new therapies that boost the host immune system. A drug that harnesses the power of immune cells not just to keep Yersinia But, they say, overcoming its defenses can eliminate the pathogen completely.

New battlefield

Y. pestisAnd Y. pseudotuberculosisAnd Y. enterocolitica It shares an extreme ability to evade immune detection.

in the three Yersinia Infection, the defining characteristic is that it colonizes lymphoid tissue and is able to escape immune control and multiply, cause disease, and spread,” says Brodsky.

Previous studies have shown this Yersinia It prompted the formation of granulomas in the lymph nodes and spleen, but didn’t notice them in the intestines until Daniel Sorobetti, a research fellow in Brodsky’s group, took a closer look at the intestines of affected mice. Y. pseudotuberculosis.

“Because it’s an oral-acquired pathogen, we were interested in how the bacteria behaved in the gut,” says Brodsky. Daniel made the following preliminary observation Yersinia pseudotuberculosiinfection, there were microscopically visible lesions along the gut that had not 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. enterocoliticaformed within five days after infection.

A biopsy of intestinal tissue confirmed that the lesions were a type of granuloma known as a granuloma, made up 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 combat. bacteria and viruses.

Granulomas form in other diseases involving chronic infection, including tuberculosis Y. pseudotuberculosis its name. Somewhat paradoxically, these granulomas—while essential in controlling infection by sequestering the infectious agent—also maintain a host of pathogens within those walls.

The team wanted to understand how these granulomas were formed and maintained, working with mice that lacked monocytes as well as animals treated with antibodies that deplete monocytes. In animals that lack monocytes, “these granulomas, with their distinctive architecture, will not form,” Brodsky says.

Instead, more discolored and necrotic abscess developed, neutrophil activation failed, and the mice were less able to control the invading bacteria. These animals experienced higher levels of bacteria in their gut and succumbed to infection.

foundations of the future

The researchers believe that monocytes are responsible for recruiting neutrophils to the site of infection and thus triggering granuloma formation, which helps control bacteria. The researchers believe that this leading role for monocytes may exist outside the intestine.

“We hypothesize that this is a general role for monocytes in other tissues as well,” says Brodsky.

But the discoveries also point to the gut as a major site of interaction between the immune system and Yersinia.

“Prior to this study, we knew that Peyer’s patches are the primary site where the body interacts with the external environment through the mucous tissue of the intestine,” says Brodsky. Peyer’s patches are small areas of lymphoid tissue in the gut that regulate the microbiome and ward off infection.

In future work, Brodsky and colleagues hope to continue piecing together the mechanism by which monocytes and neutrophils contain bacteria, an effort they are pursuing in collaboration with Sunny Shin’s lab in the Department of Microbiology at the Perelman College of Medicine.

A deeper understanding of the molecular pathways that regulate the immune response could one day offer avenues in host-targeted immunotherapies, through which a drug could tip the scales in favor of the host immune system, unleashing its ability to completely eradicate bacteria rather than simply containing them in granulomas.

“These therapies have caused an explosion of excitement in the cancer field,” says Brodsky, “the idea of ​​reactivating the immune system. Conceptually, we could also think about how to coax the immune system into activation to attack pathogens in these chronic conditions. infection as well.

Igor E. Brodsky is the Robert R. Marshak Professor and Chair of the Department of Pathology at the University of Pennsylvania School of Veterinary Medicine.

Rina Matsuda is a doctoral student in Brodsky’s lab at the Penn College of Veterinary Medicine.

Daniel Sorobetti is a research fellow in Brodsky’s lab at the Penn College of Veterinary Medicine.

Brodsky, Matsuda, and Sorobtia co-authored the study with Stefan T. Peterson of Penn Vet University, and James B. . Brodsky is considered a major author, and Matsuda and Surobeti were among the first.

The study was supported by the National Institutes of Health (grants AI128530, AI1139102A1, DK123528, AI160741-01, AI141393-2, and AI164655), Burroughs Wellcome Fund, Blanesflower Postdoctoral Scholarships, Swedish Association for Medical Research, Sweden American Foundation J Award Sigfrid Edström, Mark Foundation and National Science Foundation GRFP Award.

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