MSGID: 1:317/3 640ff873   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
       * RELATED_TERMS   
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             Stem_cell_treatments o Bubonic_plague o Periodontal_disease   
             o COPD o Yellow_fever   
      
   ==========================================================================   
   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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