19With relatively few known specific transcription factors to control the abundance of specific 20 mRNAs, Plasmodium parasites also regulate the stability and turnover of transcripts to provide 21 more comprehensive gene regulation. Plasmodium transmission stages impose translational 22 38 39 3 AUTHOR SUMMARY 40 Malaria is a disease caused by Plasmodium parasites, which are transmitted during an 41 infectious blood meal by anopheline mosquitoes. Transmission of the sexual stages of the 42 parasite to mosquitoes requires the proper regulation of specific mRNAs. While much work has 43 been done to characterize regulation of mRNAs in female gametocytes, little has been done to 44 assess this regulation in male gametocytes. Here, we demonstrate that PyCCR4-1, a member of 45 the CAF1/CCR4/NOT RNA metabolic complex, acts upon transcripts both directly and indirectly 46 in both male and female parasites, and results in a reduction of male gametocytemia. In 47
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic and multiple vaccines have been developed and authorized for human use. While these vaccines reduce disease severity, they do not prevent infection allowing SARS-CoV-2 to continue to spread and evolve. To confer protection against infection and limit transmission, vaccines must be developed that induce mucosal immunity in the respiratory tract. Therefore, we performed proof-of-principle pre-clinical vaccine and challenge studies with a virus-particle mimicking intranasal vaccine against SARS-CoV-2. The vaccine candidate consisted of the self-assembling 60-subunit I3-01 protein scaffold covalently decorated with the SARS-CoV-2 receptor binding domain (RBD) using the SpyCatcher-SpyTag system. We verified the intended antigen display features by reconstructing the I3-01 scaffold to 3.4A using cryo-EM, and established RBD decoration through both SDS-PAGE and negative stain TEM. Using this RBD grafted SpyCage scaffold (RBD+SpyCage), we performed two vaccination studies in Syrian hamsters using an intranasal prime and boost vaccine regiment followed by SARS-CoV-2 challenge. The initial study focused on assessing the immunogenicity of RBD+SpyCage, which indicated that vaccination of hamsters induced a non-neutralizing antibody response that enhanced viral clearance but did not prevent infection. In an expanded study, we demonstrated that covalent bonding of RBD to the scaffold was required to induce an antibody response. Consistent with the initial study, animals vaccinated with RBD+SpyCage more rapidly cleared SARS-CoV-2 from both the upper and lower respiratory tract, whereas admixtures of SpyCage and RBD, or either component alone did not. These findings demonstrate the intranasal SpyCage vaccine platform can induce protection against SARS-CoV-2 and, with additional modifications to improve immunogenicity, is a versatile and adaptable system for the development of intranasal vaccines targeting respiratory pathogens.
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