Immunization with a heat-killed prm1 deletion strain protects the host from Cryptococcus neoformans infection

Abstract

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 and vaccination of cryptococcosis are available. Here, we describe Prm1, a novel regulator of C. neoformans virulence . C. neoformans prm1Δ cells exhibit extreme sensitivity to various environmental stress conditions. Furthermore, prm1Δ cells show deficiencies in the biosynthesis of chitosan and mannoprotein, which in turn result in impairment of cell wall integrity. Treatment of mice with heat-killed prm1Δ cells was found to facilitate the host immunological defence against infection with wild-type C. neoformans . Further investigation demonstrated that prm1Δ cells strongly promote pulmonary production of interferon-γ, 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.

Immune evasion by Cryptococcus gattii in vaccinated mice coinfected with C. neoformans

“…Other groups have focused on cryptococcal deletion strains for vaccination. Elimination of F-box protein (Fbp1), sterylglucosidase (Sgl1), or plasma membrane proteolipid 3-related membrane protein 1 (Prm1) expression generated strains fbp1 Δ , sgl1 Δ, and prm1 Δ, respectively ( 14 – 16 ). While the precise mechanism of protection for these strains remains unclear, each induced a Th1 response following vaccination ( 14 – 16 ).…”

“…Elimination of F-box protein (Fbp1), sterylglucosidase (Sgl1), or plasma membrane proteolipid 3-related membrane protein 1 (Prm1) expression generated strains fbp1 Δ , sgl1 Δ, and prm1 Δ, respectively ( 14 – 16 ). While the precise mechanism of protection for these strains remains unclear, each induced a Th1 response following vaccination ( 14 – 16 ). We have also demonstrated the efficacy of an avirulent, cryptococcal mutant strain: Deletion of all three cryptococcal chitin deacetylase (Cda) genes yielded a chitosan-deficient strain of C. neoformans , cda1 Δ 2 Δ 3 Δ ( Cn-cda1 Δ 2 Δ 3 Δ) ( 17 ).…”