Soman Abraham

Overview:

The Abraham laboratory is interested in developing innovative approaches for curbing microbial infections through the study of the molecular interactions occurring between pathogenic bacteria and prominent immune and epithelial cells. We believe that there is a significant amount of crosstalk occurring between bacteria and host cells during infection and that the outcome of this interaction dictates both how quickly the infection is cleared and the severity of the pathology associated with the infection. We also believe that through deciphering this crosstalk we should be able to selectively promote certain beneficial interactions while abrogating the harmful ones.

There are two major research areas being pursued in this laboratory. The first involves elucidating the role of mast cells in modulating immune responses to microbes.  Our studies have revealed that mast cells play a key sentinel role and upon bacterial or viral infection, modulate both innate and adaptive immune responses through the release of immunomodulatory molecules borne in granules. Our current investigations are centered on elucidating the molecular and cellular aspects of how mast cells mediate their immunomodulatory role. We are also examining several mast cell-targeted strategies to boost immunity to infections as well as reduce any pathological consequences of infection.

The second area of research investigates cross-talk between distinct infectious agents such as Uropathogenic E. coli, Salmonella typhimurium and Yersinia pestis and the immune system. We have recognized that different pathogens possess distinct mechanisms to evade or coopt one or more immune cells to establish infection. We have also unraveled novel intracellular innate host defense activities including expulsion of whole bacteria from infected epithelial cells, a feat mediated by immune recognition molecules and the cellular trafficking system.

Cumulatively, our studies should facilitate the design of innovative strategies to combat pathogens that selectively potentiate the host’s immune response without evoking some of its harmful side effects.

Positions:

Grace Kerby Distinguished Professor of Pathology

Pathology
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor in Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1976

Ahmadu Bello University (Nigeria)

M.S. 1978

Ahmadu Bello University (Nigeria)

Ph.D. 1981

Newcastle University

Postdoctoral Fellowship

University of Tennessee at Knoxville

Assistant Professor, Medicine

University of Tennessee at Knoxville

Assistant Professor of Pathology, Microbiology And Immunology

University of Tennessee at Knoxville

Associate Clinical Director, Microbiology/Serology

Washington University in St. Louis

Assistant Professor, Molecular Microbiology

Washington University in St. Louis

Clinical Director, Serology

Washington University in St. Louis

Grants:

Aberrant remodeling of bladder following infection

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Combatting Bladder Cancer by Inducing Epithelial Turnover

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Novel Adjuvants and Carriers for Opiod Vaccines

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Adjuvant Discovery Program (Option #2)

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Adjuvant Discovery Program (Option #3)

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections.

Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.
Authors
Wu, J; Hayes, BW; Phoenix, C; Macias, GS; Miao, Y; Choi, HW; Hughes, FM; Todd Purves, J; Lee Reinhardt, R; Abraham, SN
MLA Citation
Wu, Jianxuan, et al. “A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections.Nature Immunology, vol. 21, no. 6, June 2020, pp. 671–83. Epmc, doi:10.1038/s41590-020-0688-3.
URI
https://scholars.duke.edu/individual/pub1441447
PMID
32424366
Source
epmc
Published In
Nature Immunology
Volume
21
Published Date
Start Page
671
End Page
683
DOI
10.1038/s41590-020-0688-3

A humanized mouse model to study mast cells mediated cutaneous adverse drug reactions.

Recently a G-protein-coupled receptor, MAS Related GPR Family Member X2 (MRGPRX2), was identified as a specific receptor on human mast cells responsible for IgE independent adverse drug reactions (ADR). Although a murine homologue, Mrgprb2, has been identified for this receptor, its affinity for many ADR-causing drugs is poor making it difficult to undertake in vivo studies to examine mechanisms of ADR and to develop therapeutic strategies. Here, we have created humanized mice capable of generating MRGPRX2-expressing human MCs allowing for the study of MRGPRX2 MCs-mediated ADR in vitro as well as in vivo. Humanized mice were generated by hydrodynamic-injection of plasmids expressing human GM-CSF and IL-3 into NOD-scid IL2R-γ-/- strain of mice that had been transplanted with human hematopoietic stem cells. These GM/IL-3 humice expressed high numbers of tissue human MCs but the MRGPRX2 receptor expressed in MCs were limited to few body sites including the skin. Importantly, large numbers of MRGPRX2-expressing human MCs could be cultured from the bone marrow of GM/IL-3 humice revealing these mice to be an important source of human MCs for in vitro studies of MRGPRX2-related MCs activities. When GM/IL-3 humice were exposed to known ADR causing contrast agents (meglumine and gadobutrol), the humice were found to experience anaphylaxis analogous to the clinical situation. Thus, GM/IL-3 humice represent a valuable model for investigating in vivo interactions of ADR-causing drugs and human MCs and their sequelae, and these mice are also a source of human MRGPRX2-expressing MCs for in vitro studies.
Authors
Mencarelli, A; Gunawan, M; Yong, KSM; Bist, P; Tan, WWS; Tan, SY; Liu, M; Huang, EK; Fan, Y; Chan, JKY; Choi, HW; Abraham, SN; Chen, Q
MLA Citation
Mencarelli, Andrea, et al. “A humanized mouse model to study mast cells mediated cutaneous adverse drug reactions.J Leukoc Biol, vol. 107, no. 5, May 2020, pp. 797–807. Pubmed, doi:10.1002/JLB.3MA1219-210RR.
URI
https://scholars.duke.edu/individual/pub1426905
PMID
31922289
Source
pubmed
Published In
J Leukoc Biol
Volume
107
Published Date
Start Page
797
End Page
807
DOI
10.1002/JLB.3MA1219-210RR

Introducing a novel experimental model of bladder transplantation in mice.

Bladder dysfunction is a common clinical problem attributed to various conditions such as posterior urethral valves, neurogenic bladder, ureteral ectopy, or bladder exstrophy. Currently, the main therapeutic option for these dysfunctions is neobladder reconstruction with gastrointestinal tract segments. However, the latter was associated with significant long-term complications. To provide a new candidate of possible surgical solution for bladder dysfunction, we propose a novel orthotropic mouse bladder transplantation model. The donor bladder with abdominal aorta and inferior vena cava was isolated and orthotopically sutured to the recipient, whose bladder above the ureteral opening level was removed. The recipient mice showed more than 80% 6-month survival rate and comparable body weight to control mice. At both 1 month and 6 months posttransplant, the urine voiding behavior of recipient mice and control mice was monitored by cystometry. We found that the recipient mice displayed similar bladder pressure and urine secretion ability compared to control mice especially at 6 months posttransplant. Similarity of bladder structure between recipient and control mice was confirmed by histology. As a proof of principle, we tested our model in an allogeneic setting. Early acute rejection was noted after day 5 that was histologically more profound by day 10 posttransplant. These results indicate that the mouse bladder transplant is able to provide normal bladder function.
Authors
Wang, J; Wu, J; Moris, D; Hayes, B; Abraham, SN; Cendales, LC
MLA Citation
Wang, Jun, et al. “Introducing a novel experimental model of bladder transplantation in mice.American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Apr. 2020. Epmc, doi:10.1111/ajt.15912.
URI
https://scholars.duke.edu/individual/pub1437338
PMID
32282990
Source
epmc
Published In
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Published Date
DOI
10.1111/ajt.15912

Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury.

Platelet responses have been associated with end-organ injury and mortality following complex insults such as cardiac surgery, but how platelets contribute to these pathologies remains unclear. Our studies originated from the observation of microvascular platelet retention in a rat cardiac surgery model. Ensuing work supported the proximity of platelet aggregates with perivascular mast cells (MCs) and demonstrated that platelet activation triggered systemic MC activation. We then identified platelet activating factor (PAF) as the platelet-derived mediator stimulating MCs and, using chimeric animals with platelets defective in PAF generation or MCs lacking PAF receptor, defined the role of this platelet-MC interaction for vascular leakage, shock, and tissue inflammation. In application of these findings, we demonstrated that inhibition of platelet activation in modeled cardiac surgery blunted MC-dependent inflammation and tissue injury. Together, our work identifies a previously undefined mechanism of inflammatory augmentation, in which platelets trigger local and systemic responses through activation of perivascular MCs.
Authors
Karhausen, J; Choi, HW; Maddipati, KR; Mathew, JP; Ma, Q; Boulaftali, Y; Lee, RH; Bergmeier, W; Abraham, SN
MLA Citation
Karhausen, Jörn, et al. “Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury.Sci Adv, vol. 6, no. 12, Mar. 2020, p. eaay6314. Pubmed, doi:10.1126/sciadv.aay6314.
URI
https://scholars.duke.edu/individual/pub1435663
PMID
32206714
Source
pubmed
Published In
Science Advances
Volume
6
Published Date
Start Page
eaay6314
DOI
10.1126/sciadv.aay6314

Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy.

Cocaine is one of the most potent and addictive psychostimulants known and there are no available pharmacotherapies to treat cocaine addiction. Here we describe a novel cocaine vaccine employing the mucosal adjuvant and mast cell-activating oligopeptide, mastoparan-7 (M7), to achieve optimal IgA antibody responses in mucosal secretions and effective induction of humoral immunity using a short immunization protocol. This formulation, using a hapten-carrier system to deliver cocaine as antigen, also reduced cocaine penetration of the blood brain barrier and protected mice from its psychoactive effects by reducing cocaine-induced locomotion. Surprisingly, the magnitude of cocaine-specific antibody titers induced by each adjuvant was not the major determinant of functional protection from cocaine challenge. A side-by-side comparison of the two haptens, cocaine and its analog GNC demonstrated that cocaine haptenation resulted in superior functional protection when used in combination with the novel mucosal adjuvant, M7. These results provide a new potential strategy for combatting cocaine addiction through mucosal vaccination.
Authors
St John, AL; Choi, HW; Walker, QD; Blough, B; Kuhn, CM; Abraham, SN; Staats, HF
MLA Citation
St John, Ashley L., et al. “Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy.Npj Vaccines, vol. 5, 2020, p. 12. Pubmed, doi:10.1038/s41541-020-0161-1.
URI
https://scholars.duke.edu/individual/pub1429605
PMID
32047657
Source
pubmed
Published In
Npj Vaccines
Volume
5
Published Date
Start Page
12
DOI
10.1038/s41541-020-0161-1