Enhancement of Experimental Cutaneous Leishmaniasis by Leishmania Molecules Is Dependent on Interleukin-4, Serine Protease/Esterase Activity, and Parasite and Host Genetic Backgrounds

Abstract

Most inbred strains of mice, like the BALB/c strain, are susceptible to Leishmania amazonensis infections and resistant to Leishmania braziliensis infections. This parasite-related difference could result from the activity of an L. amazonensis-specific virulence factor. In agreement with this hypothesis, it is shown here that the intravenous injection of BALB/c mice with L. amazonensis amastigote extract (LaE) but not the L. braziliensis extract confers susceptibility to L. braziliensis infection. This effect was associated with high circulating levels of IgG1 anti-L. amazonensis antibodies and with an increase in interleukin-4 (IL-4) production and a decrease in gamma interferon production by draining lymph node cells. Moreover, the effect was absent in IL-4-knockout mice. The biological activity in the LaE was not mediated by amphiphilic molecules and was inhibited by pretreatment of the extract with irreversible serine protease inhibitors. These findings indicate that the LaE contains a virulence-related factor that (i) enhances the Leishmania infection by promoting Th2-type immune responses, (ii) is not one of the immunomodulatory Leishmania molecules described so far, and (iii) is either a serine protease or has an effect that depends on that protease activity. In addition to being Leishmania species specific, the infection-enhancing activity was also shown to depend on the host genetic makeup, as LaE injections did not affect the susceptibility of C57BL/6 mice to L. braziliensis infection. The identification of Leishmania molecules with infection-enhancing activity could be important for the development of a vaccine, since the up-or downmodulation of the immune response against a virulence factor could well contribute to controlling the infection.

Serine Proteases and Vaccines against Leishmaniasis: A Dual Role

“…A similar effect was observed in the pre-vaccination treatment when using whole L. amazonensis antigen from amastigotes named L. amazonensis amastigote extract (LaE) followed by a challenge with L. braziliensis [34]. The increase of susceptibility of infection in immunized mice was dependent on the maintenance of serine protease activity.…”

“…This suggested that LaSP-Sol induced an immune response with a Th2 profile and/or activation of regulatory T cells. However, a comparison between effects using LaSP-Sol to LaAg in BALB/c mice immunized intramuscularly showed a similar profile in lesions and parasite burden compared to non-vaccinated mice [34].…”

“…Proteases can convert latent TGFbeta in active TGF-beta [35]. It has been shown that cysteine peptidase from L. chagasi also can enzymatically convert TGF-beta to active form [36,37]; yet, the pre-treatment of LaAg with cysteine peptidase inhibitor was not as effective as the pre-treatment with serine protease inhibitor to overcome the counter-protective effect of LaAg [34]. Since TGF-beta can be related to T cell activity [38][39][40], it could explain the failure of this vaccination approach within our model system, which is in contrast the success observed in another model, the Shistosoma manasoni vaccination [31].…”

Leishmania (Viannia) shawi purified antigens confer protection against murine cutaneous leishmaniasis

“…Concerning the humoral immune response, only F1-immunized animals exhibited an increase in the production of IgG2a compared to non-immunized mice, which could have a direct association with high IFN-c levels [34]. F5-immunized mice exhibited an increase in IgG1 isotype, which can be associated directly with high levels of IL-4 and parasitism in lymph nodes [43]. Therefore, immunization with F1 confers protection on skin and popliteal lymph nodes, associated with an increasing Th1 immune response; however, F5-immunized animals could limit parasite infection of the skin and were associated with a mixed immune response.…”

Isolation of Aureobasidium pullulans and the effect of different conditions for pullulanase and pullulan production

“…Recent studies have shown that some secreted factors from L. major possess immunosuppressive properties, could dampen lymphoproliferative capabilities and skew T cell polarization toward a susceptible Th2 phenotype (Tabatabaee, Abolhassani, Mahdavi, Nahrevanian, & Azadmanesh, 2011). Similarly, extracts of L. amazonensis , a causative agent of CL in the New World, promote a Th2 type immune response in the host, thereby enhancing infection (Silva et al, 2011). …”