Abstract
Cholera toxin (CT) induces severe diarrhea in humans but acts as an adjuvant to enhance immune responses to vaccines when administered orally. Nasally administered CT also acts as an adjuvant, but CT and CT derivatives, including the B subunit of CT (CTB), are taken up from the olfactory epithelium and transported to the olfactory bulbs and therefore may be toxic to the central nervous system. To assess the toxicity, we investigated whether nasally administered CT or CT derivatives impair the olfactory system. In mice, nasal administration of CT, but not CTB or a non-toxic CT derivative, reduced the expression of olfactory marker protein (OMP) in the olfactory epithelium and olfactory bulbs and impaired odor responses, as determined with behavioral tests and optical imaging. Thus, nasally administered CT, like orally administered CT, is toxic and damages the olfactory system in mice. However, CTB and a non-toxic CT derivative, do not damage the olfactory system. The optical imaging we used here will be useful for assessing the safety of nasal vaccines and adjuvants during their development for human use and CT can be used as a positive control in this test.
Highlights
The delivery routes and adjuvants used for vaccination are important for the development of protective immune responses against mucosal pathogens
olfactory marker protein (OMP) expression did not change in the olfactory epithelium (OE) or in the glomeruli at the dorsal and lateral surfaces of olfactory bulbs (OBs) over the 72-h period after nasal administration of 30 μg CTB, CTB was transported from the OE to the OBs (Fig 1A and 1C)
These results suggest that nasal administration of 30 μg cholera toxin (CT) but not CTB impaired the OE at 72 h and the OBs at 72 h
Summary
The delivery routes and adjuvants used for vaccination are important for the development of protective immune responses against mucosal pathogens. Nasal administration is one of the most effective routes for the induction of antigen-specific protective immunity in both the systemic and mucosal compartments. Because most vaccines are insufficient to induce antigenspecific responses in both the systemic and mucosal immune systems when antigen is administered alone, adjuvant is required to enhance the immune responses. Co-administration of a biologically active mucosal adjuvant, such as cholera toxin (CT) or heat-labile enterotoxin (LT), whose sequence is 80% homologous to that of CT, can overcome the limited response of PLOS ONE | DOI:10.1371/journal.pone.0139368. Co-administration of a biologically active mucosal adjuvant, such as cholera toxin (CT) or heat-labile enterotoxin (LT), whose sequence is 80% homologous to that of CT, can overcome the limited response of PLOS ONE | DOI:10.1371/journal.pone.0139368 September 30, 2015
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