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(searched for: doi:10.3389/fimmu.2021.745625)
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Shuangshuang Wang, Erchao Sun, Yuepeng Liu, Baoqi Yin, Xueqi Zhang, Mengling Li, Qi Huang, Chen Tan, Ping Qian, Venigalla B. Rao, et al.
Published: 16 June 2022
Abstract:
The interplay between defense and counter-defense systems of bacteria and phages is a major driver of evolution of both organisms, leading to their greatest genetic diversity. Bacterial restriction-modification (R-M) and CRISPR-Cas are two well-known defense systems that target phage DNAs through their nuclease activities, whereas phages have developed counter-defense systems through covalent modifications of their genomes. Recent studies have revealed many novel nuclease-containing antiphage systems, which leads to the question of what’s the role of phage genome modifications in countering these systems. Here, we scanned Escherichia coli genome sequences available in the NCBI databases and found abundant nuclease-containing defense systems, indicating that phage genomic DNA could be a major target for E. coli to restrict infection. From a collection of 816 E. coli strains, we cloned and validated 14 systems. Particularly, Gabija and type III Druantia systems have broad antiphage activities. Using wild-type phage T4 and its mutants, T4 (hmC) and T4 (C), which contain glucosyl-5-hydroxymethylcytosines, 5-hydroxymethylcytosines, and unmodified cytosines in the genomic DNA respectively, we revealed the complex roles of genomic modification of phage T4 in countering the nuclease-containing defense systems other than simply blocking the degradation of genomic DNA by nuclease.
Mengling Li, Cen Chen, Xialin Wang, Pengju Guo, Helong Feng, Xueqi Zhang, Wanpo Zhang, Changqin Gu, Jingen Zhu, Guoyuan Wen, et al.
Published: 14 June 2022
Abstract:
Mucosal vaccines that can induce local mucosal immune responses and combat the pathogens at entry sites are considered to be the most effective way to prevent infection. A universal platform that can be customized for development of mucosal vaccines against any given pathogen is therefore highly desired. Here, we demonstrate an efficient approach to develop nasal mucosal vaccines through genetic engineering of T4 phage to generate antigen-decorated nanoparticles. The antigen coding sequence was inserted into T4 genome in-frame at the C terminus of Soc (small outer capsid protein) using the CRISPR-Cas phage editing technology. During the propagation of recombinant T4 phages in E. coli, the Soc-antigen fusion proteins self-assemble on T4 capsids to form antigen-decorated nanoparticles that have intrinsic adjuvant activity and mucosal adhesive property. As a proof of concept, we showed that intranasal immunization with Flu viral M2e-decorated T4 nanoparticles efficiently induced local mucosal as well as systemic immune responses and provided complete protections against divergent influenza viruses in a mouse model. Potentially, our platform can be customized for any respiratory pathogen to rapidly generate mucosal vaccines against future emerging epidemics and pandemics.
Jingen Zhu, Swati Jain, Jian Sha, Himanshu Batra, Neeti Ananthaswamy, Paul B. Kilgore, Emily K. Hendrix, Yashoda M. Hosakote, Xiaorong Wu, Juan P. Olano, et al.
Published: 29 April 2022
Abstract:
SUMMARY: The authorized mRNA- and adenovirus-based SARS-CoV-2 vaccines are intramuscularly injected and effective in preventing COVID-19, but do not induce efficient mucosal immunity, or prevent viral transmission. We developed a bacteriophage T4-based, multicomponent, needle and adjuvant-free, mucosal vaccine by engineering spike trimers on capsid exterior and nucleocapsid protein in the interior. Intranasal administration of T4-COVID vaccine induced higher virus neutralization antibody titers against multiple variants, balanced Th1/Th2 antibody and cytokine responses, stronger CD4+ and CD8+ T cell immunity, and higher secretory IgA titers in sera and bronchoalveolar lavage with no effect on the gut microbiota, compared to vaccination of mice intramuscularly. The vaccine is stable at ambient temperature, induces apparent sterilizing immunity, and provides complete protection against original SARS-CoV-2 strain and its Delta variant with minimal lung histopathology. This mucosal vaccine is an excellent candidate for boosting immunity of immunized and/or as a second-generation vaccine for the unimmunized population.
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