Eosinophils are recruited in response to chitin exposure and enhance Th2-mediated immune pathology in Aspergillus fumigatus infection.
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.
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA.
Evan M
EM
O'Dea
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA.
Nansalmaa
N
Amarsaikhan
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA.
Hongtao
H
Li
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA.
Joshua
J
Downey
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA.
Emery
E
Steele
Department of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Microbiology/Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.
Steven J
SJ
Van Dyken
Department of Medicine, University of California, San Francisco, San Francisco, California, USA Department of Microbiology/Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.
Richard M
RM
Locksley
Department of Microbiology and Immunology, Indiana University School of Medicine-Terre Haute, Terre Haute, Indiana, USA sptemple@iupui.edu.
Steven P
SP
Templeton
D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002686:Chitin / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D002686:Chitin