Updated project metadata. Systemic infection with Cryptococcus neoformans, a dangerous and contagious pathogen found throughout the world, frequently results in lethal cryptococcal pneumonia and meningoencephalitis, and no effective treatments of cryptococcosis are available. Here, we describe Prm1, a novel regulator of virulence in C. neoformans. C. neoformans prm1 cells exhibit extreme sensitivity to various environmental stress conditions. Furthermore, prm1 cells show deficiencies in the biosynthesis of chitin, chitosan, and mannoprotein, which in turn result in impairment of cell wall integrity. Treatment of mice with heat-killed prm1 cells was found to facilitate the host immunological defence against infection with wild-type C. neoformans. Further investigation demonstrated that prm1 cells strongly promote pulmonary production of interferon- and Th1 responses, leading to activation of macrophage M1 differentiation and inhibition of M2 polarization. Therefore, our findings suggest that C. neoformans Prm1 may be a viable target for the development of anti-cryptococcosis medications and, cells lacking Prm1 represent a promising candidate for a vaccine.