Nasal immunization with a L. lactis-derived trans-sialidase antigen plus c-di-AMP protects against acute oral T. cruzi infection

Pacini, María Florencia; González, Florencia Belén; Dinatale, Brenda; Balbi, Camila Bulfoni; Villar, Silvina Raquel; Farré, Cecilia; Lupi, Giuliana; Espariz, Martín; Blancato, Víctor Sebastián; Magni, Christian; Marcipar, Iván Sergio; Pérez, Ana Rosa

doi:10.1016/j.vaccine.2022.02.071

Cited by 10 publications

(6 citation statements)

References 73 publications

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“…Blood parasitemia, weight, health condition, and survival were periodically monitored. Parasites in blood were determined by counting 50 fields of a 22x22 coverslip from 5 μL of tail blood as previously published ( Pacini et al., 2022 ). The endpoint was established when the animals lost 25% of their weight or presented an evident deterioration of health condition.…”

Section: Methodsmentioning

confidence: 99%

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Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Biscari

Kaufman

Farré

et al. 2022

Front. Cell. Infect. Microbiol.

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Lipopolysaccharide (LPS) induces the activation of dendritic cells (DCs) throughout the engagement of toll-like receptor 4. LPS-activated DCs show increased capacity to process and present pathogen-derived antigens to activate naïve T cells. DCs-based vaccines have been successfully used to treat some cancer types, and lately transferred to the field of infectious diseases, in particular against HIV. However, there is no vaccine or DC therapy for any parasitic disease that is currently available. The immune response against Trypanosoma cruzi substantially relies on T cells, and both CD4+ and CD8+ T lymphocytes are required to control parasite growth. Here, we develop a vaccination strategy based on DCs derived from bone marrow, activated with LPS and loaded with TsKb20, an immunodominant epitope of the trans-sialidase family of proteins. We extensively characterized the CD8+ T cell response generated after immunization and compared three different readouts: a tetramer staining, ELISpot and Activation-Induced Marker (AIM) assays. To our knowledge, this work shows for the first time a proper set of T cell markers to evaluate specific CD8+ T cell responses in mice. We also show that our immunization scheme confers protection against T. cruzi, augmenting survival and reducing parasite burden in female but not male mice. We conclude that the immunization with LPS-activated DCs has the potential to prime significant CD8+ T cell responses in C57BL/6 mice independently of the sex, but this response will only be effective in female, possibly due to mice sexual dimorphisms in the response generated against T. cruzi.

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Section: Methodsmentioning

confidence: 99%

“…To evaluate and quantify the health status of the animals, a clinical score designed by our group was used, which assigns a certain score according to observable and progressive signs: piloerection, lack of movement, hunchback, ocular discharge and diarrhea, as described in ( Pacini et al., 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Biscari

Kaufman

Farré

et al. 2022

Front. Cell. Infect. Microbiol.

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“…We detected 38 studies that used TS proteins or part of them in vaccine formulations, among them 23 studies using TS‐GI proteins or their fragments as immunogens. The collected TS‐GI vaccine data are shown in Table 2 20–42 …”

Section: Resultsmentioning

confidence: 99%

The high identity of the Trypanosoma cruziGroup‐I of trans‐sialidases points them as promising vaccine immunogens

Pacini,

Perdomini,

Bulfoni Balbi

et al. 2023

Proteins

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Trans‐sialidase (TS) superfamily of proteins comprises eight subgroups, being the proteins of Group‐I (TS‐GI) promising immunogens in vaccine approaches against Trypanosoma cruzi. Strikingly, TS‐GI antigenic variability among parasite lineages and their influence on vaccine development has not been previously analyzed. Here, a search in GenBank detects 49 TS‐GI indexed sequences, whereas the main infecting human different parasite discrete typing units (DTU) are represented. In silico comparison among these sequences indicate that they share an identity above 92%. Moreover, the antigenic regions (T‐cell and B‐cell epitopes) are conserved in most sequences or present amino acid substitutions that scarcely may alter the antigenicity. Additionally, since the generic term TS is usually used to refer to different immunogens of this broad family, a further in silico analysis of the TS‐GI‐derived fragments tested in preclinical vaccines was done to determine the coverage and identity among them, showing that overall amino acid identity of vaccine immunogens is high, but the segment coverage varies widely. Accordingly, strong H‐2K, H‐2I, and B‐cell epitopes are dissimilarly represented among vaccine TS‐derived fragments depending on the extension of the TG‐GI sequence used. Moreover, bioinformatic analysis detected a set of 150 T‐cell strong epitopes among the DTU‐indexed sequences that strongly bind human HLA‐I supertypes. In all currently reported experimental vaccines based on TS‐GI fragments, mapping these 150 epitopes showed that they are moderately represented. However, despite vaccine epitopes do not present all the substitutions observed in the DTUs, these regions of the proteins are equally recognized by the same HLAs. Interestingly, the predictions regarding global and South American population coverage estimated in these 150 epitopes are similar to the estimations in experimental vaccines when the complete sequence of TS‐GI is used as an antigen. In silico prediction also shows that a number of these MHC‐I restricted T‐cell strong epitopes could be also cross‐recognized by HLA‐I supertypes and H‐2Kb or H‐2Kd backgrounds, indicating that these mice may be used to improve and facilitate the development of new TS‐based vaccines and suggesting an immunogenic and protective potential in humans. Further molecular docking analyses were performed to strengthen these results. Taken together, different strategies that would cover more or eventually fully of these T‐cell and also B‐cell epitopes to reach a high level of coverage are considered.

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“…If infection cannot be avoided, a prophylactic vaccine should induce a substantial decrease in parasite burden in tissues, which will eventually diminish morbidity and mortality rates. In recent years, special attention has been paid to the use of glycoantigens, chimeric antigens, novel adjuvants, and live platforms (Nogueira et al, 2013;Sanchez Alberti et al, 2017;Portillo et al, 2019;Bivona et al, 2020;Lokugamage et al, 2021;Rodrigues da Cunha et al, 2021;Cai et al, 2022;Pacini et al, 2022). Recently, Jha et al (2023) demonstrated that a parasite attenuated by the deletion of cyclophilin-19 completely prevents T. cruzi infection.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with parasite-specific TcTASV proteins combined with recombinant baculovirus as a delivery platform protects against acute and chronic Trypanosoma cruzi infection

Masip,

Caeiro,

Cosenza

et al. 2024

Front. Cell. Infect. Microbiol.

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Chagas’ is a neglected disease caused by the eukaryotic kinetoplastid parasite, Trypanosoma cruzi. Currently, approximately 8 million people are infected worldwide, most of whom are in the chronic phase of the disease, which involves cardiac, digestive, or neurologic manifestations. There is an urgent need for a vaccine because treatments are only effective in the initial phase of infection, which is generally underdiagnosed. The selection and combination of antigens, adjuvants, and delivery platforms for vaccine formulations should be designed to trigger mixed humoral and cellular immune responses, considering that T. cruzi has a complex life cycle with both intracellular and bloodstream circulating parasite stages in vertebrate hosts. Here, we report the effectiveness of vaccination with a T. cruzi-specific protein family (TcTASV), employing both recombinant proteins with aluminum hydroxide and a recombinant baculovirus displaying a TcTASV antigen at the capsid. Vaccination stimulated immunological responses by producing lytic antibodies and antigen-specific CD4+ and CD8+ IFNɣ secreting lymphocytes. More than 90% of vaccinated animals survived after lethal challenges with T. cruzi, whereas all control mice died before 30 days post-infection. Vaccination also induced a strong decrease in chronic tissue parasitism and generated immunological memory that allowed vaccinated and infected animals to control both the reactivation of the infection after immunosuppression and a second challenge with T. cruzi. Interestingly, inoculation with wild-type baculovirus partially protected the mice against T. cruzi. In brief, we demonstrated for the first time that the combination of the baculovirus platform and the TcTASV family provides effective protection against Trypanosoma cruzi, which is a promising vaccine for Chagas disease.

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Nasal immunization with a L. lactis-derived trans-sialidase antigen plus c-di-AMP protects against acute oral T. cruzi infection

Cited by 10 publications

References 73 publications

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

Immunization With Lipopolysaccharide-Activated Dendritic Cells Generates a Specific CD8+ T Cell Response That Confers Partial Protection Against Infection With Trypanosoma cruzi

The high identity of the Trypanosoma cruziGroup‐I of trans‐sialidases points them as promising vaccine immunogens

Vaccination with parasite-specific TcTASV proteins combined with recombinant baculovirus as a delivery platform protects against acute and chronic Trypanosoma cruzi infection

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