Intranasal vaccination with TSdA+c-di-AMP triggers a mixed cytokine profile in the nasopharynx-associated lymphoid tissue together with local and systemic immunogenicity

PACINI MF.; BULFONI BALBI C.; DINATALE B.; GONZÁLEZ F.; PROCHETTO E.; DE HERNADEZ A.; CRIBB P.; FARRÉ C.; ESPARIZ M.; BLANCATO V.; MAGNI C.; MARCIPAR I.; PEREZ AR.

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2023

0001-706X

Trypanosoma cruzi, the agent of Chagas disease, can infect through conjunctive ororal mucosas. Therefore, the induction of mucosal immunity by vaccination is relevantnot only to trigger local protection but also to stimulate both humoral and cell-mediatedresponses in systemic sites to control parasite dissemination. In a previous study, wedemonstrated that a nasal vaccine based on a Trans-sialidase (TS) fragment plus themucosal STING agonist c-di-AMP, was highly immunogenic and elicited prophylacticcapacity. However, the immune profile induced by TS-based nasal vaccines at thenasopharyngeal-associated lymphoid tissue (NALT), the target site of nasalimmunization, remains unknown. Hence, we analyzed the NALT cytokine expressiongenerated by a TS-based vaccine plus c-di-AMP (TSdA+c-di-AMP) and theirassociation with mucosal and systemic immunogenicity. The vaccine was administeredintranasally, in 3 doses separated by 15 days each other. Control groups receivedTSdA, c-di-AMP, or the vehicle in a similar schedule. We demonstrated that femaleBALB/c mice immunized intranasally with TSdA+c-di-AMP boosted NALT expressionof IFN-γ and IL-6, as well as of IFN-β and TGF-β. TSdA+c-di-AMP increased TSdAspecificIgA secretion in the nasal passages and also in the distal intestinal mucosa.Moreover, T and B-lymphocytes from NALT-draining cervical lymph nodes and spleenshowed an intense proliferation after ex-vivo stimulation with TSdA. Intranasaladministration of TSdA+c-di-AMP provokes an enhancement of TSdA-specific IgG2aand IgG1 plasma antibodies, accompanied by an increase IgG2a/IgG1 ratio, indicativeof a Th1-biased profile. In addition, immune plasma derived from TSdA+c-di-AMPvaccinated mice exhibit in-vivo and ex-vivo protective capacity. Lastly, TSdA+c-di-AMPnasal vaccine also promotes intense footpad swelling after local TSdA challenge. Ourdata support that TSdA+c-di-AMP nasal vaccine triggers a NALT mixed pattern ofcytokines that were clearly associated with an evident mucosal and systemicimmunogenicity. These data are useful for further understanding the immuneresponses elicited by the NALT following intranasal immunization and the rationaldesign of TS-based vaccination strategies for prophylaxis against T. cruzi.