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Joshua J. Obar, PhD

Title(s):
Associate Professor of Microbiology and Immunology

Department(s):
Microbiology and Immunology

Education:
Dartmouth College, Ph.D., 2006
Ohio Wesleyan University, B.A., 2001

Programs:
Immunology Program
Molecular and Cellular Biology Graduate Programs

Websites:
http://geiselmed.dartmouth.edu/obar/

Contact Information:

Hinman Box 7556
1 Medical Center Drive
Lebanon NH 03756

Office: 650W Borwell Building
Phone: 603-650-6858
Email: Joshua.J.Obar@Dartmouth.edu


Professional Interests:

The goal of our laboratory is to understand the immune response against microbial infections. The immune system is critical in protecting the host against microbial infections, but an uncontrolled immune response can also be detrimental to the host. Our laboratory is currently focused on understanding how the immune system balances clearing a pathogen without inducing too much tissue immunopathology.

Pulmonary Immune Response to Aspergillus fumigatus

Typically, the respiratory immune system clears hundreds of Aspergillus conidia daily, but in immunocompromised individuals Aspergillus conidia can germinate in the lungs leading to the development of invasive aspergillosis. Currently, our knowledge of how Aspergillus fumigatus germination and growth is controlled in the respiratory tract is limited. Phagocytic alveolar macrophages and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia; subsequently, neutrophils and macrophages are sequentially recruited to the respiratory tract to control fungal growth and germination. But how neutrophils and macrophages are recruited to and activated in the respiratory tract after inhalation of A. fumigatus conidia remains ill defined. Early after instillation of A. fumigatus conidia expression of LTB4, IL-1a, and IL-1b is induced in the lungs. Interestingly, our preliminary studies demonstrate that while IL-1R1- deficient mice were highly susceptible to A. fumigatus, ASC-deficient mice were only mildly susceptible to A. fumigatus infection. Thus, it appears our data reveal important non-redundant roles for the IL-1a and IL-1b in controlling A. fumigatus infection in the lung. Our laboratory is currently using gene knockout mice, adoptive cell transfer, bone marrow chimeras, and therapeutic administration of cytokines and chemokines to explore the role of IL-1 cytokine in regulating immunity to A. fumigatus. These studies will expand our understanding of how A. fumigatus conidia are typically controlled in immunocompetent mammals. With this detailed understanding of the sequel of events necessary for leukocyte recruitment and activation to prevent invasive aspergillosis we can better understand how steroid or chemotherapeutic treatment alters anti-Aspergillus immunity to allow fungal growth and disease and also therapeutically manipulate these pathways to benefit patients with invasive aspergillosis.

Role of Pulmonary Mast Cells in Influenza Virus Pathology.

Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections. Not only do IAV-induced illnesses have a significant economic impact, but there are also ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought be the result of significant immunopathology. It is well defined that IAV strains vary in the severity of lung disease they induce. Thus, the long-term goal of our laboratory is to understand the fine balance between protection and host damage caused by immune responses to IAV infection. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. However, the role of the mast cell has been under explored during respiratory viral infection. Importantly, our data demonstrate that mast cells are critical for initiating the inflammatory immunopathology induced by influenza virus in a virus strain-specific manner; however, mast cells did not play a critical role in the clearance of IAV from the respiratory tract. Furthermore, others have reported that during IAV infection of humans significantly elevated levels of histamine can be detected coincident with IAV induced symptoms. Thus, mast cells are likely to participate in the immune response to IAV infection, but what their role is has not been elucidated. Thus the goal of is project is to elucidate the molecular mechanisms responsible for mast cell activation, recruitment, and activity during IAV infection. Importantly, we hope to elucidate the factor(s) which mast cells produce that drives pathological lung damage and systemic disease in hopes of discovering novel therapeutic targets. These studies will offer novel insights into the mechanisms of mast cell activation and function during respiratory viral infection and could help us understand why certain human populations (i.e. asthmatic individuals) develop more severe IAV-induced disease.


Selected Publications:

 

Secondary Bacterial Pneumonia by Staphylococcus aureus Following Influenza A Infection Is SaeR/S Dependent.
Borgogna TR, Hisey B, Heitmann E, Obar JJ, Meissner N, Voyich JM
J Infect Dis. 2018 Jul 24;218(5):809-813. doi: 10.1093/infdis/jiy210.
PMID: 29668950

Host-Derived Leukotriene B<sub>4</sub> Is Critical for Resistance against Invasive Pulmonary Aspergillosis.
Caffrey-Carr AK, Hilmer KM, Kowalski CH, Shepardson KM, Temple RM, Cramer RA, Obar JJ
Front Immunol. 2017;8:1984. doi: 10.3389/fimmu.2017.01984. Epub 2018 Jan 11.
PMID: 29375586

Type III interferon is a critical regulator of innate antifungal immunity.
Espinosa V, Dutta O, McElrath C, Du P, Chang YJ, Cicciarelli B, Pitler A, Whitehead I, Obar JJ, Durbin JE, Kotenko SV, Rivera A
Sci Immunol. 2017 Oct 6;2(16) pii: eaan5357. doi: 10.1126/sciimmunol.aan5357.
PMID: 28986419

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates.
Caffrey-Carr AK, Kowalski CH, Beattie SR, Blaseg NA, Upshaw CR, Thammahong A, Lust HE, Tang YW, Hohl TM, Cramer RA, Obar JJ
Infect Immun. 2017 Dec;85(12) pii: e00661-17. doi: 10.1128/IAI.00661-17. Epub 2017 Nov 17.
PMID: 28947643

<i>Aspergillus fumigatus</i> Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity.
Thammahong A, Caffrey-Card AK, Dhingra S, Obar JJ, Cramer RA
MBio. 2017 Apr 25;8(2) pii: e00056-17. doi: 10.1128/mBio.00056-17. Epub 2017 Apr 25.
PMID: 28442603

Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression.
Beattie SR, Mark KMK, Thammahong A, Ries LNA, Dhingra S, Caffrey-Carr AK, Cheng C, Black CC, Bowyer P, Bromley MJ, Obar JJ, Goldman GH, Cramer RA
PLoS Pathog. 2017 Apr;13(4):e1006340. doi: 10.1371/journal.ppat.1006340. Epub 2017 Apr 19.
PMID: 28423062

Heterogeneity among Isolates Reveals that Fitness in Low Oxygen Correlates with Aspergillus fumigatus Virulence.
Kowalski CH, Beattie SR, Fuller KK, McGurk EA, Tang YW, Hohl TM, Obar JJ, Cramer RA Jr
MBio. 2016 Sep 20;7(5) pii: e01515-16. doi: 10.1128/mBio.01515-16. Epub 2016 Sep 20.
PMID: 27651366

Alarmin(g) the innate immune system to invasive fungal infections.
Caffrey AK, Obar JJ
Curr Opin Microbiol. 2016 Aug;32:135-143. doi: 10.1016/j.mib.2016.06.002. Epub 2016 Jun 27.
PMID: 27351354

New advances in invasive aspergillosis immunobiology leading the way towards personalized therapeutic approaches.
Obar JJ, Hohl TM, Cramer RA
Cytokine. 2016 Aug;84:63-73. doi: 10.1016/j.cyto.2016.05.015. Epub 2016 May 30.
PMID: 27253487

Editorial: Vγ9Vδ2 T cells: triple costimulation goes the distance.
Sheridan BS, Obar JJ
J Leukoc Biol. 2016 Apr;99(4):515-7. doi: 10.1189/jlb.1CE1115-522R.
PMID: 27034461

View more publications on PubMed