De'Broski R. Herbert, PhD

• De'Broski R. Herbert, PhD
  Penn Presidential Professor of Immunology
  Co-director of Admissions Immunology Graduate Group
  Director of International Affairs and Outreach
  Institute for Infection and Zoonotic Disease (IIZD)
  University of Pennsylvania, PennVet
• Lab: 215-746-5740
• Office: 314-454-1091
• Email: debroski@vet.upenn.edu
• Web: drherbertlab.org

Focus

The over-arching goal of my research program is to use parasitic organisms as a guide to investigate basic mechanisms of host immunity, inflammation and wound healing. I have been continuously NIH-R01 funded by the National Institutes of Health (NIH) since 2007 and have authored 61 manuscripts published in journals that include: Science, Science Immunology, Nature Medicine, Nature Communications, Immunity, JEM, PNAS, PLoS Pathogens, and the Journal of Immunology. Most of this work has focused on the immune response to parasitic helminths, organisms that are the likely evolutionary driving force for Type 2 immunity. Helminths are a major cause of disease in impoverished populations (~2-3 billion people) and biomedical research focused on parasitic helminths has been a fertile ground for scientific discovery.

Helminths such as hookworms pose a formidable challenge to the host immune system regarding their large size, morphological complexity and the host tissue niches they occupy. While infectious larval stages can cause tremendous damage to host tissues as they invade and migrate, the hematophagous nature of adult stages can cause persistent injury during feeding. Surprisingly, most helminth species can survive for years, even decades in their hosts due to a variety of mechanisms including those that suppress and evade host immunity. Given this complex biology, research projects based in my lab (and most collaborative work) focus on the mechanisms that initiate Type 2 responses, those that drive tissue repair, and requirements for host protective immunity at the sites where worms invade and reside (e.g., skin, respiratory tract, and intestine). Given the widely held notion that allergic inflammation is due to maladaptive Type 2 responses that initially evolved to deal with helminths, our work has broad relevance to both infectious and non-infectious disease.

MIST Research

This MIST program stems from our long-standing interest in the alarmin cytokine interleukin 33 (IL-33), an IL-1 family cytokine that serves pleiotropic roles in mammalian health and disease. While IL-33 can drive can Type 2 immunity through the expansion of group 2 innate lymphoid cells (ILC2), TH2 cells, and eosinophils, it is now clear that IL-33 also augments the functions of TH1, TH17 and Foxp3+ T regulatory cells (Treg). While it is clear that mucosal antigen presenting cells (APC) release a myriad of soluble factors (e.g. cytokines, growth factors, metabolites) that provide instructive signals for lymphocyte adaptation to tissue-specific microenvironments through cognate APC-T interactions, the mechanisms responsible for delivery from APC to T cells in the mucosa or regional lymph nodes to instruct inflammatory or tolerogenic programs remain unknown. Our recent work demonstrates that the enigmatic pore-forming protein named Perforin-2 is necessary for conventional dendritic cells (cDC) to deliver IL-33 to ST2+GATA3+Treg. Strikingly, humans with the Type 2 inflammatory disease chronic rhinosinusitis with nasal polyps (CRSwNP) have mucosal DC cluster that co-express Perforin-2 and the cDC2 lineage-defining transcription factor interferon regulatory factor 4 (IRF4). Our overarching aim is to uncover the mechanisms of this release and the diversity of contexts where this mechanism is biologically important. Thus, our project is built upon exciting data that cDC can focally deliver at the APC-T cell interface through a mechanism dependent upon the transmembrane pore-forming protein Perforin-2.

Current Grant Support

R01	PI 20%	08/06/2021- 07/31/2025
NIH Myeloid derived IL-33 controls Treg responses during parasite infection

PP-U01	PI 20%	08/20/2021 -05/31/2026
NIH Perforin 2 controls unconventional cytokine release from mucosal APC

R01	Co-investigator 5%	05/01/2020 - 04/30/2024
NIH A Cul5 E3 ubiquitin ligase complex that prevents TH2/TH17 differentiation and allergic asthma HL153539

R01	Co-investigator 5%	06/01/2020-05/31/2025
NIH Solitary chemosensory / tuft cells in lung regeneration and inflammation HL153539

R01	PI 20%	01/17/2017 – 12/31/2022
NIH Physiological roles of schistosome TRP ion channels with atypical pharmacology

Merit Review	Co-investigator 5%	01/01/2021 – 12/31/2023
VA COVID-19: Elucidating the Role of the Nasal Epithelium in SARS-CoV-2 Infection, Transmission, and Prevention

Publications

De'Broski R. Herbert PhD

The Secretome of Adult Murine Hookworms Is Shaped by Host Expression of STAT6. Ferguson AA, Rossi HL, Herbert DR. Parasite Immunol. 2024 Jul;46(7):e13056. doi: 10.1111/pim.13056.PMID: 39073185

Hookworms dynamically respond to loss of Type 2 immune pressure. Ferguson AA, Inclan-Rico JM, Lu D, Bobardt SD, Hung L, Gouil Q, Baker L, Ritchie ME, Jex AR, Schwarz EM, Rossi HL, Nair MG, Dillman AR, Herbert DR. PLoS Pathog. 2023 Dec 11;19(12):e1011797. doi: 10.1371/journal.ppat.1011797. eCollection 2023 Dec.PMID: 38079450

A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection. Ethgen LM, Pastore C, Lin C, Reed DR, Hung LY, Douglas B, Sinker D, Herbert DR, Belle NM.Mucosal Immunol. 2024 Apr;17(2):238-256. doi: 10.1016/j.mucimm.2024.02.003. Epub 2024 Feb 8.PMID: 38336020

Every cell is an immune cell; contributions of non-hematopoietic cells to anti-helminth immunity. Inclan-Rico JM, Rossi HL, Herbert DR. Mucosal Immunol. 2022 May 10. doi: 10.1038/s41385-022-00518-7. Online ahead of print. PMID: 35538230

Trefoil Factor Family: A Troika for Lung Repair and Regeneration. Rossi HL, Ortiz-Carpena JF, Tucker D, Vaughan AE, Mangalmurti NS, Cohen NA, Herbert DR. Am J Respir Cell Mol Biol. 2021 Nov 16. doi: 10.1165/rcmb.2021-0373TR. PMID: 34784491

Neuroimmune regulatory networks of the airway mucosa in allergic inflammatory disease. Jean EE, Good O, Rico JMI, Rossi HL, Herbert DR. J Leukoc Biol. 2021 Apr 15. doi: 10.1002/JLB.3RU0121-023R. Online ahead of print. PMID: 33857344

Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma. Sell EA, Ortiz-Carpena JF, Herbert DR, Cohen NA. Ann Allergy Asthma Immunol. 2021 Feb;126(2):143-151. doi: 10.1016/j.anai.2020.10.011. Epub 2020 Oct 26. PMID: 33122124

Oncolytic Myxoma virus infects and damages the tegument of the human parasitic flatworm Schistosoma mansoni. Rahman MM, McFadden G, Ruthel G, Herbert DR, Freedman BD, Greenberg RM, Bais S. Exp Parasitol. 2022 May 19;239:108263. doi: 10.1016/j.exppara.2022.108263. Online ahead of print. PMID: 35598646

Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the decline of host vaccine responses. Musaigwa F, Kamdem SD, Mpotje T, Mosala P, Abdel Aziz N, Herbert DR, Brombacher F, Nono JK. PLoS Pathog. 2022 Feb 14;18(2):e1010327. doi: 10.1371/journal.ppat.1010327. eCollection 2022 Feb. PMID: 35157732

Schistosome TRPML channels play a role in neuromuscular activity and tegumental integrity. Bais S, Norwillo A, Ruthel G, Herbert DR, Freedman BD, Greenberg RM. Biochimie. 2022 Jan 3;194:108-117. doi: 10.1016/j.biochi.2021.12.018 PMID: 34990770

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host. Adewale B, Heintz JR, Pastore CF, Rossi HL, Hung LY, Rahman N, Bethony J, Diemert D, Babatunde JA, Herbert DR. PLoS Negl Trop Dis. 2021 Oct 18;15(10):e0009550. doi: 10.1371/journal.pntd.0009550. eCollection 2021 Oct. PMID: 34662329

Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations. Douglas B, Wei Y, Li X, Ferguson A, Hung LY, Pastore C, Kurtz JR, McLachlan JB, Nolan TJ, Lok J, Herbert DR. PLoS Pathog. 2021 Jul 8;17(7):e1009709. doi: 10.1371/journal.ppat.1009709. eCollection 2021 Jul. PMID: 34237106

LINGO3 regulates mucosal tissue regeneration and promotes TFF2 dependent recovery from colitis. Zullo KM, Douglas B, Maloney NM, Ji Y, Wei Y, Herbine K, Cohen R, Pastore C, Cramer Z, Wang X, Wei W, Somsouk M, Hung LY, Lengner C, Kohanski MH, Cohen NA, Herbert DR. Scand J Gastroenterol. 2021 Jul;56(7):791-805. doi: 10.1080/00365521.2021.1917650. Epub 2021 May 3. PMID: 33941035

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae. Damen MSMA, Stankiewicz TE, Park SH, Helsley RN, Chan CC, Moreno-Fernandez ME, Doll JR, Szabo S, Herbert DR, Softic S, Divanovic S. Int J Obes (Lond). 2021 Nov;45(11):2377-2387. doi: 10.1038/s41366-021-00902-6. Epub 2021 Jul 23. PMID: 34302121

Myeloid-derived interleukin-33 limits the severity of dextran sulfate sodium (DSS)-induced colitis. Hung LY, Pastore CF, Douglas B, Herbert DR. Am J Pathol. 2020 Nov 24:S0002-9440(20)30505-8. doi: 10.1016/j.ajpath.2020.11.004. PMID: 33245913

Cellular context of IL-33 expression dictates impact on anti-helminth immunity. Hung LY, Tanaka Y, Herbine K, Pastore C, Singh B, Ferguson A, Vora N, Douglas B, Zullo K, Behrens EM, Li Hui Tan T, Kohanski MA, Bryce P, Lin C, Kambayashi T, Reed DR, Brown BL, Cohen NA, Herbert DR. Sci Immunol. 2020 Nov 13;5(53):eabc6259. doi: 10.1126/sciimmunol.abc6259. PMID: 33188058

Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma. Sell EA, Ortiz-Carpena JF, Herbert DR, Cohen NA. Ann Allergy Asthma Immunol. 2020 Oct 26:S1081-1206(20)31144-3. doi: 10.1016/j.anai.2020.10.011. PMID: 33122124 Review

R-spondin 2 mediates neutrophil egress into the alveolar space through increased lung permeability. Jackson, S.R., Costa, M.F.D.M., Pastore, C.F., Zhao, G., Weiner, A.I., Adams, S., Palashikar, G., Quansah, K., Hankenson, K., Herbert, DR, Vaughan, A.E. BMC Res Notes. 2020 Feb 4;13(1):54. doi: 10.1186/s13104-020-4930-8. PMID: 32019591

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