Joshua J. Obar, PhD
Associate Professor of Microbiology and Immunology
Microbiology and Immunology
Dartmouth College, Ph.D., 2006
Ohio Wesleyan University, B.A., 2001
Molecular and Cellular Biology Graduate Programs
Hinman Box 7556
1 Medical Center Drive
Lebanon NH 03756
Office: 650W Borwell Building
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.
MAVS Expression in Alveolar Macrophages Is Essential for Host Resistance against Aspergillus fumigatus.
Host Lung Environment Limits Aspergillus fumigatus Germination through an SskA-Dependent Signaling Response.
Editorial overview: Niche-specific and species-specific host-fungal interactions - how do they impact human health?
The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Aspergillus fumigatus Airway Infection.
Aspergillus fumigatus Strain-Specific Conidia Lung Persistence Causes an Allergic Broncho-Pulmonary Aspergillosis-Like Disease Phenotype.
MDA5 Is an Essential Sensor of a Pathogen-Associated Molecular Pattern Associated with Vitality That Is Necessary for Host Resistance against Aspergillus fumigatus.
Sensing the threat posed by Aspergillus infection.
Editorial: Host and Pathogen Determinants of Allergic and Invasive Fungal Diseases.
Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner.
Secondary Bacterial Pneumonia by Staphylococcus aureus Following Influenza A Infection Is SaeR/S Dependent.