Aspergillus fumigatus Viability Drives Allergic Responses to Inhaled Conidia

Details

• Personal Author:
  Beezhold, Donald H. ; Croston TL ; Germolec DR ; Goldsmith WT ; Green, Brett J. ; Kashon ML ; Lemons, Angela R. ; Marshall NB ; Nayak, Ajay P.
• Description:
  Background: Aspergillus fumigatus induced allergic airway disease has been shown to involve conidial germination in vivo but the immunological mechanisms remain uncharacterized. Objective: A subchronic murine exposure model was used to examine the immunological mediators that are regulated in response to either culturable or non-culturable A. fumigatus conidia. Methods: Female B6C3F1/N mice were repeatedly dosed via inhalation with 1 x 105 viable or heat inactivated conidia (HIC), twice a week for 13 weeks (26 exposures). Control mice inhaled HEPA-filtered air. The influence of A. fumigatus conidial germination on the pulmonary immunopathological outcomes was evaluated by flow cytometry analysis of cellular infiltration in the airways, assessment of lung mRNA expression, and quantitative proteomics and histopathology of whole lung tissue. Results: Repeated inhalation of viable conidia, but not HIC, resulted in allergic inflammation marked by vascular remodeling, extensive eosinophilia, and accumulation of alternatively activated macrophages (AAMs) in the murine airways. More specifically, mice that inhaled viable conidia resulted in a mixed TH1 and TH2 (IL-13) cytokine response. Recruitment of eosinophils corresponded with increased Ccl11 transcripts. Furthermore, genes associated with M2 or alternatively activated macrophage polarization (e.g. Arg1, Chil3 and Retnla) were significantly upregulated in viable A. fumigatus exposed mice. In mice inhaling HIC, CD4+ T cells expressing IFN-gamma (TH1) dominated the lymphocytic infiltration. Quantitative proteomics of the lung revealed metabolic reprogramming accompanied by mitochondrial dysfunction and endoplasmic reticulum stress stimulated by oxidative stress from repetitive microbial insult. Conclusion: Our studies demonstrate that A. fumigatus conidial viability in vivo is critical to the immunopathological presentation of chronic fungal allergic disease. [Description provided by NIOSH]
• Subjects:
  Blood Fungi Hypersensitivity Immune System Laboratories Lung Macrophages Occupational Health Respiratory System Safety
• Keywords:
  Allergic Reactions Allergy Author Keywords: Aspergillus Fumigatus Cytokines Gene Expression Germination Histopathology Immune Reaction Immunological Tests Inhalation Laboratory Animals Pulmonary Effects Viability

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• ISSN:
  1081-1206
• Document Type:
  Text
• Funding:
  Interagency Agreement
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  121
• Issue:
  2
• NIOSHTIC Number:
  nn:20051520
• Citation:
  Ann Allergy Asthma Immunol 2018 Aug; 121(2):200-210.e2
• Contact Point Address:
  Ajay P. Nayak, Ph.D., Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107
• Email:
  Ajay.Nayak@jefferson.edu
• Federal Fiscal Year:
  2018
• Peer Reviewed:
  True
• Source Full Name:
  Annals of Allergy, Asthma and Immunology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:00b5269b9dd1e1a77a97d8b6cdac8e279ab47a4923168a146eda52a8546b067b41abcd154f4b78e774ff4687c90f377a4f7d44a4aa516ce3f441fc9592572b82
• Download URL:
  https://stacks.cdc.gov/view/cdc/211426/cdc_211426_DS1.pdf
• File Type:
  [PDF - 4.04 MB ]