Pharmaceutics
·
2021
·Vol. 13
·期 10
·1582
·
IF 6.321
Zhengqing Yu,Yujia Lu,Wandi Cao,Muhammad Tahir Aleem,Junlong Liu,Jianxun Luo,Ruofeng Yan,Lixin Xu,Xiaokai Song,Xiangrui Li
The pathogen of toxoplasmosis,Toxoplasma gondii(T. gondii), is a zoonotic protozoon that can affect the health of warm-blooded animals including humans. Up to now, an effective vaccine with completely protection is still inaccessible. In this study, the DNA vaccine encodingT. gondiihistone deacetylase SIR2 (pVAX1-SIR2) was constructed. To enhance the efficacy, chitosan and poly (d,l-lactic-co-glycolic)-acid (PLGA) were employed to design nanospheres loaded with the DNA vaccine, denoted as pVAX1-SIR2/CS and pVAX1-SIR2/PLGA nanospheres. The pVAX1-SIR2 plasmids were transfected into HEK 293-T cells, and the expression was evaluated by a laser scanning confocal microscopy. Then, the immune protections of pVAX1-SIR2 plasmid, pVAX1-SIR2/CS nanospheres, and pVAX1-SIR2/PLGA nanospheres were evaluated in a laboratory animal model. The in vivo findings indicated that pVAX1-SIR2/CS and pVAX1-SIR2/PLGA nanospheres could generate a mixed Th1/Th2 immune response, as indicated by the regulated production of antibodies and cytokines, the enhanced maturation and major histocompatibility complex (MHC) expression of dendritic cells (DCs), the induced splenocyte proliferation, and the increased percentages of CD4+and CD8+T lymphocytes. Furthermore, this enhanced immunity could obviously reduce the parasite burden in immunized animals through a lethal dose ofT. gondiiRH strain challenge. All these results propose that pVAX1-SIR2 plasmids entrapped in chitosan or PLGA nanospheres could be the promising vaccines against acuteT. gondiiinfections and deserve further investigations.Keywords:Toxoplasma gondii;histone deacetylase;SIR2;chitosan;PLGA;immune protection
研究领域:
免疫学
·
寄生虫学
·
疫苗学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Dongmei Tang,Yijun Chen,Hao Chen,Tingting Jia,Qiang Chen,Yamei Yu
In response to the persistent exposure to phage infection, bacteria have evolved diverse antiviral defense mechanisms. In this study, we report a bacterial two-component defense system consisting of a Sir2 NADase and a HerA helicase. Cryo-electron microscopy reveals that Sir2 and HerA assemble into a ∼1 MDa supramolecular octadecamer. Unexpectedly, this complex exhibits various enzymatic activities, including ATPase, NADase, helicase, and nuclease, which work together in a sophisticated manner to fulfill the antiphage function. Therefore, we name this defense system "Nezha" after a divine warrior in Chinese mythology who employs multiple weapons to defeat enemies. Our findings demonstrate that Nezha could sense phage infections, self-activate to arrest cell growth, eliminate phage genomes, and subsequently deactivate to allow for cell recovery. Collectively, Nezha represents a paradigm of sophisticated and multifaceted strategies bacteria use to defend against viral infections.
研究领域:
微生物学
·
分子生物学
·
结构生物学
·
病毒学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2024
·
IF 16.6
Liao Fumeng,Yu Guimei,Zhang Chendi,Liu Zhikun,Li Xuzichao,He Qiuqiu,Yin Hang,Liu Xiang,Li Zhuang,Zhang Heng
Recently, a novel two-gene bacterial defense system against phages, encoding a SIR2 NADase and a HerA ATPase/helicase, has been identified. However, the molecular mechanism of the bacterial SIR2–HerA immune system remains unclear. Here, we determine the cryo-EM structures of SIR2, HerA and their complex from Paenibacillus sp. 453MF in different functional states. The SIR2 proteins oligomerize into a dodecameric ring-shaped structure consisting of two layers of interlocked hexamers, in which each subunit exhibits an auto-inhibited conformation. Distinct from the canonical AAA+ proteins, HerA hexamer alone in this antiphage system adopts a split spiral arrangement, which is stabilized by a unique C-terminal extension. SIR2 and HerA proteins assemble into a ∼1.1 MDa torch-shaped complex to fight against phage infection. Importantly, disruption of the interactions between SIR2 and HerA largely abolishes the antiphage activity. Interestingly, binding alters the oligomer state of SIR2, switching from a dodecamer to a tetradecamer state. The formation of the SIR2–HerA binary complex activates NADase and nuclease activities in SIR2 and ATPase and helicase activities in HerA. Together, our study not only provides a structural basis for the functional communications between SIR2 and HerA proteins, but also unravels a novel concerted antiviral mechanism through NAD+ degradation, ATP hydrolysis, and DNA cleavage.
研究领域:
微生物学
·
结构生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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