Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 175, Issue 6, Pages 2489-2500Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.090530
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Funding
- NHLBI NIH HHS [R01-HL63670, R01 HL065912, R01 HL051082, R01-HL65912, R01-HL51082] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL051082, R01HL063670, R01HL065912] Funding Source: NIH RePORTER
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The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. in contrast, the IL-4/13(-/-) mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activation of macrophages. The development of a robust Th1/Th17 response and classical activation of macrophages resulted in significant containment of H99 in the lungs of IL-4/13-/- mice compared with unopposed growth of H99 in the lungs of wild-type mice. However, IL-4/13(-/-) mice showed only 1-week longer survival compared with wild-type mice. The comparison of brain and spleen cryptococcal loads at weeks 2, 3, and 4 postinfection revealed that the systemic dissemination in IL-4/13(-/-) mice occurred with an approximate 1-week delay but subsequently progressed with similar rate as in the wild-type mice. Furthermore, wild-type and IL-4/13(-/-) mice developed equivalently severe meningitis/encephalitis at the time of death. These data indicate that the Th2 immune bias is a crucial mechanism for pulmonary virulence of H99, whereas other mechanisms are largely responsible for its central nervous system tropism and systemic dissemination. (Am J Pathol 175:2489-2500: DOI: 10.2353/ajpath.2009.090530)
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