Penn Vet’s Center for Host-Microbial Interactions, a unique venture for any veterinary school, is designed to facilitate collaborative projects that leverage cutting-edge tools to study the intersection of microbes and disease. In doing so, researchers will gain insight into how bacteria, parasites, viruses, and other organisms interact with their animal and human hosts in ways that either maintain health or lead to disease.
The Center is currently funding five pilot projects, with a second round of proposals currently being reviewed for funding. In addition to these pilots, the Center provides ongoing support and training for Penn Vet faculty and their labs to carry out analyses of the complex datasets generated by genomic approaches.
Canine atopic dermatitis as a model for human dermatology
Canine atopic dermatitis is a common allergic skin condition that is similar to human atopic dermatitis. Veterinarians at Penn Vet’s Ryan Hospital treat dogs that present with typical symptoms such as itching and then progress to scabs, hair loss, and secondary bacterial infections that can often be resistant to antibiotic treatments. Penn Vet faculty Dr. Charles Bradley, Dr. Elizabeth Mauldin, Dr. Dan Morris, and Dr. Shelley Rankin are collaborating with Dr. Elizabeth Grice of the Perelman School of Medicine to examine the ecosystem of bacteria on the dogs’ skin and monitor changes in the microbiome of each dog during treatment. The goal is to understand the role of resident microbial organisms in resistance to infection, the onset of infection, and the development of antimicrobial resistance once infection occurs.
Very little is known about the dog microbiome. Since dogs develop spontaneous and complex diseases, much like humans, -- and since they share much of our environment -- they serve as ideal models for understanding how both animals and humans can suddenly go from being healthy one day to dealing with a chronic or recurring disease the next day.
The rumen microbiome in health and productivity of dairy cows
Dr. Dipti Pitta sees a direct connection between the gastrointestinal microbiome in cattle and the animal’s ability to process food, thrive, and produce milk and meat – a critical part of the global food supply. As a ruminant, the cow’s digestive tract offers a rich source of information pertinent to the study of microbial environments. Dairy cows are more prone to metabolic problems immediately after calving, as the animal has to adapt quickly from a non-lactating to lactating phase. The “dry” cow’s nutritional needs are much less demanding than those producing milk, so lactating cows are generally fed a much higher energy diet than dry cows. Dr. Pitta is studying the effect of changes in diet and metabolism that occur during the transition from dry to lactation period on the microbial populations, as these are the mechanisms that drive the fermentation processes to release substrates required for producing milk.
The impact of maternal stress on cognitive development of offspring: a microbial link?
Dr. Tracy Bale is examining the relationship between early prenatal stress, the mother’s vaginal microbiome, and her offspring’s brain development. Dr. Bale believes that, because a baby’s gut is first colonized by bacteria from the mother’s vagina at birth, perhaps differences are produced in the population of microbes by a mother’s stress, and can lead to changes in a baby’s own gut microbiome. This altered microbial community could then lead to differences in how important nutrients are absorbed in the offspring’s body, leading to differences in how the baby’s brain develops.
Communication at the interface of intestinal stem cells and commensal microbes
Prior research conducted by Dr. Christopher Lengner has shed light on the idea that most cases of colorectal cancer may originate from a mutation in a stem cell that leads to unregulated growth. Yet other research has indicated that chronic inflammation, inspired by an immune response to gut bacteria, may also play a leading role in increasing cancer risk. The goal of Dr. Lengner’s latest research project is to reconcile these two ideas.
This project will involve experimentally manipulating expression of the protein Msi, which Dr. Lengner’s lab has previously found to bind directly to RNA molecules that are involved in regulating immune responses. Dr. Lengner and his colleagues will track the response of the microbial communities as Msi levels are either turned up or down. What they find may lead to the pursuit of other questions, such as how tumor development progresses in the presence or absence of various microbial communities.
Other CHMI research
Canine IBD and the gut microbiome
This project, led by PennVet researcher Dr. Dan Beiting, and Internal medicine clinician Dr. Mark Rondeau. Inflammatory bowel disease (IBD) is a debilitating disease characterized by inflammation and disruption of normal gut function. Like people, dogs spontaneously develop IBD, which can result in chronic weight loss, vomiting and diarrhea. One hallmark of IBD in both dogs and humans is variation in how different patients, or even the same patient over time, respond to treatment. In this research project we explore the notion that the ‘good’ bacteria living in the gut, the so-called ‘microbiome’, may influence not only the course of IBD, but also the response to treatment.
To examine the relationship between the microbiome, gut inflammation and response to treatment, Beiting and Rondeau leverage canine chronic enteropathy (CCE), a model of spontaneous inflammatory intestinal disease, to identify changes in the microbiome following three distinct treatments: alteration of diet, antibiotic treatment, and immune-suppression with corticosteroids. While such clinical trials would be challenging and expensive to carry out in humans, they are relatively inexpensive and can be more rigorously controlled in dogs, providing important insight into host-microbial interactions during intestinal disease. Information gleaned from this study could lead to the design of diagnostic tests that profile good bacteria in the gut of sick animals to help guide treatment options. Alternatively, this study may aid in the design of probiotic treatments for IBD.
Pita DW, Kumar S, Vecchiarelli B, Shirley DJ, Bittinger K, Baker LD, Ferguson JD, Thomsen N. Temporal dynamics in the ruminal microbiome of dairy cows during the transition period. Journal of Animal Science 2014 Jul.
Misic AM, Gardner SE, Grice EA. The wound microbiome: Modern Approaches to examining the role of microorganisms in impaired chronic wound healing. Advances in Wound Care 2014 Jul.
Novais FO, Carvalho LP, Passos S, Roos DS, Carvalho EM, Scott P, Beiting DP. Genomic Profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology. Journal of Investigative Dermatology. 2014 Jul 18.
Beiting DP, Peixoto L, Akopyants NS, Beverley SM, Wherry EJ, Christian DA, Hunter CA, Brodsky IE, Roos DS. Differential Induction of TLR3-dependent Innate Immune Signaling by Closely Related Parasite Species. PLoS One 9(2): Feb 5, 2014
Novais FO, Nguyen BT, Beiting DP, Carvalho LP, Glennie ND, Passos S, Carvalho EM, Scott P. Human Classical Monocytes Control the Intracellular Stage of Leishmania braziliensis by Reactive Oxygen Species. Journal of Infectious Diseases; Jan 7, 2014
Novais FO, Carvalho LP, Graff JW, Beiting DP, Ruthel G, Roos DS, Betts MR, Goldschmidt MH, Wilson ME, de Oliveira, Scott P.. Cytotoxic T cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis. PLOS Pathogens 9: 2013.
Beiting DP. Protozoan Parasites and Type I Interferon: A Cold Case Reopended (Review). 2014. manuscript in press.
Hall, AO, DP Beiting, C Tato, B John, G Oldenhove, CG Lombana, GH Pritchard, JS Silver, N Bouladoux, JS Stumhofer, TH Harris, J Grainger, EDT Wojno, S Wagage, DS Roos, P Scott, L A Turka, S Cherry, SL Reiner, D Cua, Y Belkaid, MM Elloso, and CA Hunter. 2012. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37: 511–523.
Grants & Awards
Tracy Bale (PI) - R21/R33 MH104184-01 - Maternal stress and the vaginal microbiome: impacts on brain development
Description: Dr. Bale has developed mouse models relevant to neurodevelopment disorders to study the interaction of genes and the environment, assessing epigenetic mechanisms involved in sex-specific programming of the brain. In her microbiome project, she uses the prenatal stress model to ascertain the mechanisms involved in how the maternal vaginal microbiome contributes to offspring neurodevelopment reprogramming.
Role of CHMI in the project: Help in design, execution and analysis of microbiome, transcriptome and metabolomics experiments. Develop strategies for integrating and interrogating the diverse datasets generated in this project.
Sunny Shin (PI) and Igor Brodsky (Co-PI) - Insitute for Immunology pilot grant program - Defining novel regulators of inflammasome activation with forward genetics
Description: Microbial infection or cellular stress can induce assembly of multiprotein complexes termed inflammasomes that mediate an innate immune inflammatory response involving activation of caspase-1. Caspase-1 is required for secretion of IL-1 family cytokines and an inflammatory cell death termed pyroptosis. Inflammasome-dependent pyroptosis and cytokine release contribute to control of pathogen infection, but are also linked to pathological inflammation during many inflammatory and autoimmune disorders. Caspase-1-mediated pyroptosis is morphologically distinct from the classical pathway of apoptotic cell death and does not engage executioner caspases or other apoptotic cellular machinery. A key unanswered question is how caspase-1 activation is regulated and mediates cell death. In this IFI Pilot Grant application we propose to utilize CRISPR-Cas9-based genome-wide genetic screening in human cells to identify essential regulators of caspase-1-dependent pyroptosis. While many of the immune sensors that regulate inflammasome activation have been described, upstream regulators as well as downstream targets of caspase-1 that mediate pyroptosis are not known. Completing this genome-wide CRISPR-Cas9 screen for genes whose loss confers resistance to caspase-1-dependent pyroptosis is likely to reveal novel regulators of caspase-1-mediated effector functions that may serve as targets for regulating inflammatory responses.
Role of CHMI in the project : Analysis of high-throughput sequencing data to identify novel genes from this genome-wide screen
Chris Hunter (PI) - RO1 AI110201-01 - IL27 and Treg cells
Description: Dr. Hunter has found that a molecule produced by immune cells, called interleukin-27 (IL27), drives the development of a specific population of immune cells, termed regulatory T cells (‘Tregs’ for short). These Tregs are crucial for suppressing inflammation and putting the brakes on our immune system. Without IL27 or Tregs, animals develop an uncontrolled immune response during infections, and damage their own tissues. Dr. Hunter will use this grant to explore the ways in with IL27 achieves this important effect, potentially leading to new therapies for regulating autoimmune disease.
Role of CHMI in the project: Use of genome-wide transcriptional profiling of Tregs to identify the cellular pathways and functions controlled by IL27
Dan Beiting and Mark Rondeau (Co-PIs) - award from Royal Canin to study the impact of therapeutic diets on the the microbiome of dogs undergoing treatment for canine chronic enteritis, and inflammatory bowel disease.
Hope and Robert Sheft made a generous gift of $250,000 to the CHMI to help fund a competitive grant program open to interdisplinary teams from across Penn who will harness the power of genomics to study the intersection of microbes and disease.
Dan Beiting (PI) - Provost Interdisciplinary Seminar Fund award to host the 2014 Symposium on Microbial Communities in Health and Disease. This event is hosted jointly by PennVet, the School of Medicine and the School of Arts and Sciences.