Immunization with P10 Peptide Increases Specific Immunity and Protects Immunosuppressed BALB/c Mice Infected with Virulent Yeasts of Paracoccidioides brasiliensis

Abstract

Paracoccidioidomycosis is a systemic granulomatous disease caused by Paracoccidioides spp. A peptide from the major diagnostic antigen gp43, named P10, induces a T-CD4(+) helper-1 immune response in mice and protects against intratracheal challenge with virulent P. brasiliensis. Previously, we evaluated the efficacy of the P10 peptide alone or combined with antifungal drugs in mice immunosuppressed and infected with virulent isolate of P. brasiliensis. In the present work, our data suggest that P10 immunization leads to an effective cellular immune response associated with an enhanced T cell proliferative response. P10-stimulated splenocytes increased nitric oxide (NO) production and induced high levels of IFN-γ, IL-1β and IL-12. Furthermore, significantly increased concentrations of pro-inflammatory cytokines were also observed in lung homogenates of immunized mice. P10 immunization was followed by minimal fibrosis in response to infection. Combined with antifungal drugs, P10 immunization most significantly improved survival of anergic infected mice. Administration of either itraconazole or sulfamethoxazole/trimethoprim together with P10 immunization resulted in 100 % survival up to 200 days post-infection, whereas untreated mice died within 80 days. Hence, our data show that P10 immunization promotes a strong specific immune response even in immunocompromised hosts and thus P10 treatment represents a powerful adjuvant therapy to chemotherapy.

Dendritic Cells Primed with Paracoccidioides brasiliensis Peptide P10 Are Therapeutic in Immunosuppressed Mice with Paracoccidioidomycosis

“…The animals were immunosuppressed as previously described (Muñoz et al, 2014). Dexamethasone phosphate (Sigma, St Louis, MO, United States) was administrated daily in drinking water and the dose was calculated as 0.15 mg/kg considering an average water intake of 5 ml per day.…”

“…Using dexamethasone-treated mice, immunization with P10 has been shown to efficiently modulate the immune response in immunosuppressed hosts. Protection against pulmonary challenge with P. brasiliensis has been demonstrated by increased animal survival, reduced lung fungal burden and reduced pulmonary fibrosis in P10 immunized mice as compared to control animals (Muñoz et al, 2014). …”

“…In the present work, we simulated the acute/subacute form of PCM in immunocompromised mice by administering dexamethasone, which suppresses host immune responses through multiple mechanisms, including modulating inflammatory cytokines (Chung et al, 2011; Muñoz et al, 2014) prior to infection. Our findings show that the administration of P10-primed DCs to dexamethasone suppressed mice infected with P. brasiliensis are therapeutic in the setting of compromised immunity.…”

Linear Epitopes of Paracoccidioides brasiliensis and Other Fungal Agents of Human Systemic Mycoses As Vaccine Candidates

“…IFN-γ and TNF-α, in contrast to IL-4 and IL-10, were secreted in the lungs of mice immunized with P10 in combination with these adjuvants. When combined with antifungal drugs, P10 was protective even in animals submitted to severe immune suppression (47). P10 immunization together with itraconazole or sulfamethoxazole and trimethoprim chemotherapy resulted in 100% survival of infected immunocompromised mice, up to 200 days postinfection, whereas untreated anergic mice died within 80 days.…”

Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment

“…The best-studied antigen for this purpose is gp43 (8), but therapy with a recombinant hsp65 DNA has also decreased fungal burdens and reduced fibrosis formation in a PCM experimental murine model (9). The gp43 main T-cell epitope is a 15-amino-acid-long peptide named P10 that potentiates the effectiveness of fungicidal drugs like itraconazole and sulfamethoxazole-trimethoprim by boosting a Th1-driven immune response (10).…”