Martin Kriegel, MD, PhD
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Research Summary
The Kriegel lab has moved to Münster, Germany (University of Münster), where the following research is being continued besides ongoing collaborations with investigators at Yale:
The gut microbiota, the collection of trillions of commensals colonizing the gastrointestinal tract, does not elicit a pathologic immune response in healthy hosts even though immune cells are constantly in contact with microbial antigens at the mucosal surfaces. This phenomenon is partly due to the fact that the human gut microbiota and immune system have co-evolved for millennia with the host. Diet and environmental influences that have shaped these processes in the past are very different in today’s societies. Recent changes in the gut microbial community composition are thought to contribute to metabolic and immune-mediated diseases. An emerging theme in autoimmunity research is that outgrowth of detrimental commensals (“pathobionts”) or loss of beneficial commensals (“symbionts”) unleashes the autoimmune process in a genetically susceptible host by various mechanisms. While evidence exists for this paradigm in some mouse models, the proof in human autoimmune diseases is still outstanding. A major aim of this laboratory is to characterize the gastrointestinal microbiome of both mice and humans with systemic autoimmune diseases, and to potentially prove causal relations with humanized gnotobiotic animals. The ultimate goal is to develop novel biomarkers and therapeutic strategies for human autoimmune diseases.
Extensive Research Description
The Kriegel lab has moved to Münster, Germany (University of Münster), where the following research is being continued besides ongoing collaborations with investigators at Yale:
We are broadly interested in the role of commensal organisms in the development of autoimmunity. A major question in the lab is whether an autoimmune-prone host that is persistently colonized with cross-reactive commensals, develops chronic autoimmunity via molecular mimicry. We address this hypothesis using the antiphospholipid syndrome as a model disease since the structure and antigenic epitopes are well characterized for the major autoantigen and infectious triggers have been implicated in the pathogenesis. We are also exploring whether prokaryotic commensal protein orthologs can trigger autoreactivity in systemic lupus erythematosus. We study both human samples in vitro and autoimmune murine models in vivo.
In this context, we have characterized the commensal- and autoepitope-specific CD4+ T and B cell responses using synthetic peptides, recombinant fusion proteins as well as protein extracts from cultured anaerobic commensal candidates. We are further applying 16S rRNA-based realtime PCR and next-generation sequencing approaches in order to identify novel candidates. The mouse models we use include the lupus-prone (NZWxBXSB)F1 hybrid and Toll-like receptor 7 transgenic mice. We simultaneously study two knock-out mouse models of autoimmunity that we have crossed to the lupus-prone strains. We plan to merge both human and mouse studies in humanized, gnotobiotic animals that are colonized with human microbiota.
Another research avenue is the effect of genetic variants of the host immune system on the composition and function of the gut microbiome. We are exploring a particular autoimmunity-predisposing single nucleotide polymorphism and its impact on gut microbial community structures. Similar approaches as above will be employed to dissect the host-microbe interactions under the influence of genetic variants.
A third interest in the lab is the impact of dietary components on the autoimmune gut microbiome. We are actively pursuing studies that address the potential protective effects of certain diets in lupus- and antiphospholipid syndrome-prone mouse models. We aim to elucidate the contribution of the gut microbiota and differentiate it from direct host effects. These efforts should lead to the development of more selective therapeutic avenues that are targeting specifically the gut microbiota.
Lastly, we are studying endogenous retroviruses and their interactions with the gut microbiota in systemic autoimmunity. We use RT-PCR-based strategies to detect and quantify endogenous retroviruses in various contexts and couple these studies with microbiome research detailed above.
In summary, the overarching goal of our research is to discover causal factors within the gut microbiomes of autoimmune-prone individuals, to better understand gut microbial interactions with the host and environmental components, and to manipulate gut microbial communities as a novel therapeutic approach in autoimmunity.
Coauthors
Research Interests
Bacteria; Immune Tolerance; Immune System Diseases; Lymphocyte Activation; Autoimmunity; Immunity, Mucosal; Host-Pathogen Interactions
Public Health Interests
Biomarkers; Cancer; Evolution; Genetics, Genomics, Epigenetics; Immunology; Infectious Diseases; Microbial Ecology; Nutrition
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Selected Publications
- Within-host evolution of a gut pathobiont facilitates liver translocationYang Y, Nguyen M, Khetrapal V, Sonnert ND, Martin AL, Chen H, Kriegel MA, Palm NW. Within-host evolution of a gut pathobiont facilitates liver translocation Nature 2022, 607: 563-570. PMID: 35831502, PMCID: PMC9308686, DOI: 10.1038/s41586-022-04949-x.
- Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger AutoimmunityRuff WE, Dehner C, Kim WJ, Pagovich O, Aguiar CL, Yu AT, Roth AS, Vieira SM, Kriegel C, Adeniyi O, Mulla MJ, Abrahams VM, Kwok WW, Nussinov R, Erkan D, Goodman AL, Kriegel MA. Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity Cell Host & Microbe 2019, 26: 100-113.e8. PMID: 31227334, PMCID: PMC8194364, DOI: 10.1016/j.chom.2019.05.003.
- A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic AutoimmunityZegarra-Ruiz DF, Beidaq A, Iñiguez AJ, Di Ricco M, Vieira S, Ruff WE, Mubiru D, Fine RL, Sterpka J, Greiling TM, Dehner C, Kriegel MA. A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity Cell Host & Microbe 2018, 25: 113-127.e6. PMID: 30581114, PMCID: PMC6377154, DOI: 10.1016/j.chom.2018.11.009.
- Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupusGreiling TM, Dehner C, Chen X, Hughes K, Iñiguez AJ, Boccitto M, Ruiz DZ, Renfroe SC, Vieira SM, Ruff WE, Sim S, Kriegel C, Glanternik J, Chen X, Girardi M, Degnan P, Costenbader KH, Goodman AL, Wolin SL, Kriegel MA. Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus Science Translational Medicine 2018, 10 PMID: 29593104, PMCID: PMC5918293, DOI: 10.1126/scitranslmed.aan2306.
- Translocation of a gut pathobiont drives autoimmunity in mice and humansVieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA. Translocation of a gut pathobiont drives autoimmunity in mice and humans Science 2018, 359: 1156-1161. PMID: 29590047, PMCID: PMC5959731, DOI: 10.1126/science.aar7201.
- Subdoligranulum chews up joints: how a gut pathobiont can instigate arthritisKriegel M. Subdoligranulum chews up joints: how a gut pathobiont can instigate arthritis Trends In Immunology 2022, 44: 4-6. PMID: 36494272, DOI: 10.1016/j.it.2022.11.006.
- Evolving concepts of host–pathobiont interactions in autoimmunityPereira M, Kriegel M. Evolving concepts of host–pathobiont interactions in autoimmunity Current Opinion In Immunology 2022, 80: 102265. PMID: 36444784, DOI: 10.1016/j.coi.2022.102265.
- Structural host immune-microbiota interactionsBrito IL, Kriegel MA. Structural host immune-microbiota interactions Current Opinion In Structural Biology 2022, 76: 102445. PMID: 36063760, DOI: 10.1016/j.sbi.2022.102445.
- Malignant T Cell Activation by a Bacillus Species Isolated from Cutaneous T-Cell Lymphoma LesionsDehner CA, Ruff WE, Greiling T, Pereira MS, Redanz S, McNiff J, Girardi M, Kriegel MA. Malignant T Cell Activation by a Bacillus Species Isolated from Cutaneous T-Cell Lymphoma Lesions JID Innovations 2021, 2: 100084. PMID: 35199089, PMCID: PMC8844718, DOI: 10.1016/j.xjidi.2021.100084.
- 1504 The influence of dietary resistant starch content on the gut microbiota of patients with systemic lupus erythematosus and antiphospholipid syndromeKulyk I, Pereira M, Redanz S, Ruff W, Greiling T, Dehner C, Pagovich O, Ruiz D, Aguiar C, Erkan D, Kriegel M. 1504 The influence of dietary resistant starch content on the gut microbiota of patients with systemic lupus erythematosus and antiphospholipid syndrome Lupus Science & Medicine 2021, 8: a63-a64. DOI: 10.1136/lupus-2021-lupus21century.87.
- Development of a New International Antiphospholipid Syndrome Classification Criteria Phase I/II Report: Generation and Reduction of Candidate CriteriaBarbhaiya M, Zuily S, Ahmadzadeh Y, Amigo M, Avcin T, Bertolaccini M, Branch D, Jesus G, Devreese K, Frances C, Garcia D, Guillemin F, Levine S, Levy R, Lockshin M, Ortel T, Seshan S, Tektonidou M, Wahl D, Willis R, Naden R, Costenbader K, Erkan D, Agmon‐Levin N, Aguilar C, Alba P, Alpan O, Ambrozic A, Amoura Z, Andrade D, Andrade L, Appenzeller S, Esen B, Atsumi T, Berkun Y, Cabral A, Canaud G, Cervera R, Chen P, Chighizola C, Cimaz R, Cohen H, Costedoat‐Chalumeau N, Crowther M, Cuadrado M, de Groot P, de Moerloose P, Derksen R, Diz‐Kucukkaya R, Dörner T, Fortin P, Giannakopoulos B, Gómez‐Puerta J, Gonzalez E, Inanc M, Kenet G, Khamashta M, Kriegel M, Krilis S, Laskin C, Massicotte P, McCarty G, Meroni P, Mikdashi J, Myones B, Pengo V, Petri M, Roubey R, Sammaritano L, Sanna G, Sciascia S, Signorelli F, Soybilgic A, Tincani A, Woller S, Yelnik C. Development of a New International Antiphospholipid Syndrome Classification Criteria Phase I/II Report: Generation and Reduction of Candidate Criteria Arthritis Care & Research 2021, 73: 1490-1501. PMID: 33253499, PMCID: PMC8966711, DOI: 10.1002/acr.24520.
- Chapter 25 Microbiota influences on systemic lupus erythematosus and Sjögren’s syndromeGreiling T, Vieira S, Kriegel M. Chapter 25 Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome 2021, 211-221. DOI: 10.1016/b978-0-12-814551-7.00025-8.
- Chapter 9 Immunopathogenesis: the role of mucosal and skin microbiota in SLEGreiling T, Kriegel M. Chapter 9 Immunopathogenesis: the role of mucosal and skin microbiota in SLE 2021, 117-130. DOI: 10.1016/b978-0-12-820583-9.00012-9.
- Host–microbiota interactions in immune-mediated diseasesRuff WE, Greiling TM, Kriegel MA. Host–microbiota interactions in immune-mediated diseases Nature Reviews Microbiology 2020, 18: 521-538. PMID: 32457482, DOI: 10.1038/s41579-020-0367-2.
- Autoimmune host–microbiota interactions at barrier sites and beyondRuff WE, Kriegel MA. Autoimmune host–microbiota interactions at barrier sites and beyond Trends In Molecular Medicine 2015, 21: 233-244. PMID: 25771098, PMCID: PMC5918312, DOI: 10.1016/j.molmed.2015.02.006.
- Diet, microbiota and autoimmune diseasesVieira S, Pagovich O, Kriegel M. Diet, microbiota and autoimmune diseases Lupus 2014, 23: 518-526. PMID: 24763536, PMCID: PMC4009622, DOI: 10.1177/0961203313501401.
- Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c+ CD11b+ dendritic cellsKriegel MA, Rathinam C, Flavell RA. Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c+ CD11b+ dendritic cells Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 3457-3462. PMID: 22328150, PMCID: PMC3295274, DOI: 10.1073/pnas.1115308109.
- Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic miceKriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 11548-11553. PMID: 21709219, PMCID: PMC3136249, DOI: 10.1073/pnas.1108924108.
- E3 ubiquitin ligase GRAIL controls primary T cell activation and oral toleranceKriegel MA, Rathinam C, Flavell RA. E3 ubiquitin ligase GRAIL controls primary T cell activation and oral tolerance Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 16770-16775. PMID: 19805371, PMCID: PMC2757842, DOI: 10.1073/pnas.0908957106.
- Defective Suppressor Function of Human CD4+ CD25+ Regulatory T Cells in Autoimmune Polyglandular Syndrome Type IIKriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective Suppressor Function of Human CD4+ CD25+ Regulatory T Cells in Autoimmune Polyglandular Syndrome Type II Journal Of Experimental Medicine 2004, 199: 1285-1291. PMID: 15117972, PMCID: PMC2211900, DOI: 10.1084/jem.20032158.