title: Airway delivery of interferon-γ overexpressing macrophages confers resistance to Mycobacterium avium infection in SCID mice.
abstract: Mycobacterium avium (M. avium) causes significant pulmonary infection, especially in immunocompromised hosts. Alveolar macrophages (AMs) represent the first line of host defense against infection in the lung. Interferon gamma (IFN-γ) activation of AMs enhances in vitro killing of pathogens such as M. avium We hypothesized that airway delivery of AMs into the lungs of immunodeficient mice infected with M. avium will inhibit M. avium growth in the lung and that this macrophage function is in part IFN-γ dependent. In this study, normal BALB/c and BALB/c SCID mice received M. avium intratracheally while on mechanical ventilation. After 30 days, M. avium numbers increased in a concentration-dependent manner in SCID mice compared with normal BALB/c mice. Airway delivery of IFN-γ-activated BALB/c AMs or J774A.1 macrophages overexpressing IFN-γ into the lungs of SCID mice resulted in a significant decrease in M. avium growth (P < 0.01, both comparisons) and limited dissemination to other organs. In addition, airway delivery of IFN-γ activated AMs and macrophages overexpressing IFN-γ increased the levels of IFN-γ and TNF-α in SCID mice. A similar protective effect against M. avium infection using J774A.1 macrophages overexpressing IFN-γ was observed in IFN-γ knockout mice. These data suggest that administration of IFN-γ activated AMs or macrophages overexpressing IFN-γ may partially restore local alveolar host defense against infections like M. avium, even in the presence of ongoing systemic immunosuppression.
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio pasular@gmail.com rajamouli.pasula@va.gov.
authors.forename: Rajamouli
authors.initials: R
authors.lastname: Pasula
authors.affiliation: Research Service, VA Medical Center - Nebraska/Western Iowa, Omaha, Nebraska.|Department of Internal Medicine and Microbiology and Immunology, University of Nebraska Medical Center, Omaha, Nebraska.|Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Banurekha
authors.initials: B
authors.lastname: Kesavalu
authors.affiliation: Research Service, VA Medical Center - Nebraska/Western Iowa, Omaha, Nebraska.|Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Maher Y
authors.initials: MY
authors.lastname: Abdalla
authors.affiliation: College of Public Health, The Ohio State University, Columbus, Ohio.
authors.forename: William J
authors.initials: WJ
authors.lastname: Martin
mesh_terms: D000818:Animals; D007108:Immune Tolerance / Q000187:drug effects; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID / Q000276:immunology*; D009164:Mycobacterium Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009162:Mycobacterium avium / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: 
  M. avium
  ; Alveolar macrophages; immunosuppression; interferon gamma; reconstitution; ventilation