AUTHOR=Fa Zhenzong , Xu Jintao , Yi Jiu , Sang Junjun , Pan Weihua , Xie Qun , Yang Runping , Fang Wei , Liao Wanqing , Olszewski Michal A. 

TITLE=TNF-α-Producing Cryptococcus neoformans Exerts Protective Effects on Host Defenses in Murine Pulmonary Cryptococcosis

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01725

DOI=10.3389/fimmu.2019.01725

ISSN=1664-3224

ABSTRACT=<p>Tumor necrosis factor alpha (TNF-α) plays a critical role in the control of cryptococcal infection, and its insufficiency promotes cryptococcal persistence. To explore the therapeutic potential of TNF-α supplementation as a booster of host anti-cryptococcal responses, we engineered a <italic>C. neoformans</italic> strain expressing murine TNF-α. Using a murine model of pulmonary cryptococcosis, we demonstrated that TNF-α-producing <italic>C. neoformans</italic> strain enhances protective elements of host response including preferential T-cell accumulation and improved Th1/Th2 cytokine balance, diminished pulmonary eosinophilia and alternative activation of lung macrophages at the adaptive phase of infection compared to wild type strain-infected mice. Furthermore, TNF-α expression by <italic>C. neoformans</italic> enhanced the fungicidal activity of macrophages <italic>in vitro</italic>. Finally, mice infected with the TNF-α-producing <italic>C. neoformans</italic> strain showed improved fungal control and considerably prolonged survival compared to wild type strain-infected mice, but could not induce sterilizing immunity. Taken together, our results support that TNF-α expression by an engineered <italic>C. neoformans</italic> strain while insufficient to drive complete immune protection, strongly enhanced protective responses during primary cryptococcal infection.</p>