In the November 17, 2021 issue of Science Translational Medicine, Sajid et al. reported an mRNA vaccine encoding a tick salivary protein.
Normally, the bite of a host is not detectable due to the unique components of tick-secreted saliva. Tick bites in I9ISP-immunized guinea pigs, on the other hand, cause considerable erythema or pruritus within a relatively short amount of time, allowing for rapid detection and removal of the tick. Similarly, this phenomena is likely to occur in humans, as they are more likely to remove ticks as soon as erythema or itching appears, considerably limiting the potential for transmission of Burkholderia sp. Thus, immunization of humans with I9ISP may help prevent Lyme disease if it is administered.
When ticks feed on human blood, they secrete saliva, which contains hundreds of active proteins and lipids, including coagulation inhibitors, metalloproteinases, vasodilators, and complement inhibitors, in order to get past the host's immune defenses. Tick salivary molecules reduce host immune reactions, inflammation, pain, blood clotting, and vasoconstriction, allowing ticks to feed on host blood and transmit diseases for extended periods. The compositional complexity of tick-secreted salivary proteins makes any vaccination using a single recombinant antigen to mimic acquired resistance very difficult.
By targeting salivary proteins released by ticks, Sajid et al. developed an mRNA vaccine against ticks. The vaccine is made up of nucleoside-modified mRNAs that are encapsulated in lipid nanoparticles. The researchers mixed mRNAs of 19 proteins from the saliva of the black-legged tick (Ixodes scapularis) as targets. 19ISP (19 Ixodes salivary proteins) is the name of the "cocktail" mRNA vaccine.
Based on existing studies, the researchers evaluated 19 proteins expressed in the salivary glands of the black-legged tick, the majority of which were produced upon the bite. The researchers started by looking at the antigenicity of the antibodies' component proteins. The ELISA results revealed that at least 10 of the 19 antigens were immunoreactive, implying possible antibody production.
After confirming that the 19ISP vaccine elicited a particular antibody response in vitro, the researchers wanted to see if 19ISP-vaccinated guinea pigs would establish an acquired immunological response in vivo. So they put ticks on the backs of guinea pigs and discovered that considerable erythema or erythema occurred around the bite site 18 hours after the tick bite, peaked within 24 hours, and lasted throughout the tick bite. In guinea pigs vaccinated with a control vaccine containing luciferase mRNA, however, no such reaction was detected.
In addition to the erythema, the researchers examined the time the ticks stayed on the hosts, feeding, and changes in body weight after feeding. Ticks shed from 19ISP-immunized hosts substantially earlier than the control group, and most of the ticks were found to be underfed and weighed significantly less than those that had not received 19ISP immunization. In addition, guinea pigs inoculated with 19ISP were considerably less susceptible to Burkholderia sp. infection.
These results suggest that the 19ISP vaccine makes guinea pigs immune to acquired resistance to tick bites. The presence of erythema can alert the host to detect tick invasion in time to remove it and prevent further transmission of Burkholderia sp.
The researchers used transcriptome differential analysis to further understand the immune response related to 19ISP immunization and host protection. In 19ISP-vaccinated guinea pigs, differences in humoral and cellular immune responses linked with acquired tick resistance were found. 2 weeks after the guinea pigs were vaccinated with 19ISP, the researchers isolated and retrieved RNA from whole blood of immunized and non-immunized guinea pigs for transcriptome study.
A total of 125 differentially expressed genes were discovered using PCA (principal component analysis) and cluster analysis. In the 19ISP immunization group, 113 inflammation-related genes were up-regulated and 12 genes were down-regulated as compared to the control group. The researchers performed KEGG enrichment analysis to confirm the signaling pathways in response to 19ISP vaccination. Many immune-related signaling pathways, such as T cell and B cell signaling pathways, chemokine signaling pathways, and natural killer cell signaling pathways, were found among the top 20 ranked signaling pathways.
These findings imply that 19ISP mRNA vaccine can successfully stimulate the host's immune system.
To further understand some of the cell-mediated immune responses induced by 19ISP vaccination, two weeks after vaccination, investigators isolated peripheral blood mononuclear cells (PBMCs) from vaccinated and unvaccinated 19ISP guinea pigs, as PBMCs are stimulated by tick-secreted saliva to undergo relevant immune changes. Activation of T and B cells following vaccination typically induces elevated expression of a number of cytokines and chemokines, including IFN-γ, TNF-α, CXCL10, IL-2, IL-4 and IL-8, which the investigators found to be significantly upregulated in 19ISP-vaccinated guinea pigs.
These results suggest that inoculation with 19ISP can indeed enhance the immune response to tick invasion in guinea pigs by increasing a number of cell-mediated immune responses.
Researchers isolated peripheral blood mononuclear cells (PBMCs) from vaccinated and unvaccinated 19ISP guinea pigs two weeks after vaccination to better understand some of the cell-mediated immune responses induced by 19ISP vaccination, as PBMCs are stimulated by tick-secreted saliva to undergo relevant immune changes. Activation of T and B cells in response to vaccination normally results in increased expression of a number of cytokines and chemokines, including IFN-, TNF-, CXCL10, IL-2, IL-4, and IL-8, all of which were shown to be considerably upregulated in 19ISP-vaccinated guinea pigs.
These findings imply that inoculating guinea pigs with 19ISP can improve their immune response to tick invasion by enhancing a variety of cell-mediated immune responses.
Overall, vaccination with 19ISP mRNA resulted in an acquired anti-tick immune response in the host, as well as the protection of Burkholderia sp. infection transmitted by ticks. Future research could look into whether similar vaccine preparation strategies could be applied to other tick-borne pathogens such Mycobacterium avium (B. microti), Mycoplasma phagocytophilum (A. phagocytophilum), and Powassan virus.
RNA is a hydrophilic, negatively charged macromolecule, and its ability to autonomously transmembrane is limited.
Therefore, how to efficiently deliver mRNA to the cytoplasm and play a corresponding role is one of the key issues that limit the application of RNA therapy.
An ideal delivery system can carry mRNA through the cytoplasmic membrane without being degraded by RNase, and can allow mRNA to be released into the cytoplasm for translation after entering the cell.
In recent years, a variety of strategies have been used for mRNA delivery, and most of these methods are inspired by siRNA and plasmid DNA delivery technologies.
Therefore, how to specifically deliver mRNA to target cells is currently a difficult problem.Extracellular barriermRNA molecules are very easily degraded by enzymes, so they need to be protected from RNA hydrolase (RNAse) in extracellular serum during systemic administration to ensure that mRNA can reach target cells smoothly.Inner body escapeWhen reaching the target cell, the vector carrying mRNA enters the cytoplasm through endocytosis, which is also the most common way for the vector to enter the cell.
In endosomal vesicles, mRNA can be detected by Toll-like receptors (TLRs) and sent for degradation, so endosomal escape is essential for mRNA to reach the ribosome.Intracellular immunityWhen foreign mRNA is delivered to the cytoplasm, it can be recognized by TLR3 and TLR7/8, or by activating retinoic acid-induced gene I-like receptors in the cytoplasm, thereby activating the natural immune system.
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