Browsing by Subject "Aspergillosis"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Co-recognition of β-glucan and chitin and programming of adaptive immunity to Aspergillus fumigatus
    (Frontiers Media S.A., 2015-04-21) Amarsaikhan, Nansalmaa; Templeton, Steven P.; Department of Microbiology and Immunology, IU School of Medicine
    The prevalence of fungal infections has increased concurrently with increases in immune suppressive therapies and susceptible individuals. Opportunistic fungal pathogens such as Aspergillus fumigatus may exhibit invasive growth and dissemination resulting in a high mortality rate. Herein, we discuss how immune sensing of germination directs innate immune responses and programs adaptive responses that could promote or impair immune protection during periods of heightened susceptibility. In infected individuals, Th1 responses are the most protective, while Th2 responses lead to poor disease outcomes. In particular, the roles of β-glucan and chitin co-recognition in shaping Th1- and Th2-type immunity to fungal infection are explored. We discuss how fungal responses to environmental stresses could result in decreased immune protection from infection, particularly in response to anti-fungal drugs that target β-glucan synthesis. Furthermore, we consider how experimental modulation of host-pathogen interactions might elucidate the mechanisms of protective and detrimental immunity and the potential of current and future studies to promote the development of improved treatments for patients that respond poorly to existing therapies.
  • Thumbnail Image
    Item
    Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection
    (American Society for Microbiology (ASM), 2014-08) O'Dea, Evan M.; Amarsaikhan, Nansalmaa; Li, Hongtao; Downey, Joshua; Steele, Emery; Van Dyken, Steven J.; Locksley, Richard M.; Templeton, Steven P.; Department of Microbiology & Immunology, IU School of Medicine
    In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitin-expressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293. CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of Af5517-aspirated mice displayed decreased gamma interferon secretion and increased interleukin-4 transcription. In addition, repeated aspirations of Af5517 induced lung transcription of the Th2-associated chemokines CCL11 (eotaxin-1) and CCL22 (macrophage-derived chemokine). Eosinophil recruitment in response to conidial aspiration was correlated with the level of chitin exposure during germination and was decreased by constitutive lung chitinase expression. Moreover, eosinophil-deficient mice subjected to multiple aspirations of Af5517 prior to neutrophil depletion and infection exhibited decreased morbidity and fungal burden compared to the levels of morbidity and fungal burden found in wild-type mice. These results suggest that exposure of chitin in germinating conidia promotes eosinophil recruitment and ultimately induces Th2-skewed immune responses after repeated aspiration. Furthermore, our results suggest that eosinophils should be examined as a potential therapeutic target in patients that mount poorly protective Th2 responses to A. fumigatus infection.
  • Thumbnail Image
    Item
    Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis
    (JoVE, 2018-03-09) Stolz, Dylan J.; Sands, Ethan M.; Amarsaikhan, Nansalmaa; Tsoggerel, Angar; Templeton, Steven P.; Microbiology and Immunology, School of Medicine
    The quantification of lung fungal burden is critical for the determination of the relative levels of immune protection and fungal virulence in mouse models of pulmonary fungal infection. Although multiple methods are used to assess fungal burden, quantitative polymerase chain reaction (qPCR) of fungal DNA has emerged as a technique with several advantages over previous culture-based methods. Currently, a comprehensive assessment of lung pathology, leukocyte recruitment, fungal burden, and gene expression in mice with invasive aspergillosis (IA) necessitates the use of a significant number of experimental and control animals. Here the quantification of lung histological staining to determine fungal burden using a reduced number of animals was examined in detail. Lung sections were stained to identify fungal structures with Gomori's modified methanamine silver (GMS) staining. Images were taken from the GMS-stained sections from 4 discrete fields of each formalin-fixed paraffin-embedded lung. The GMS stained areas within each image were quantified using an image analysis program, and from this quantification, the mean percentage of stained area was determined for each sample. Using this strategy, eosinophil-deficient mice exhibited decreased fungal burden and disease with caspofungin therapy, while wild-type mice with IA did not improve with caspofungin. Similarly, fungal burden in mice lacking γδ T cells were also improved by caspofungin, as measured by qPCR and GMS quantification. GMS quantification is therefore introduced as a method for the determination of relative lung fungal burden that may ultimately reduce the quantity of experimental animals required for comprehensive studies of invasive aspergillosis