Serine proteases of Leishmania amazonensis as immunomodulatory and disease-aggravating components of the crude LaAg vaccine.
We previously demonstrated that intradermal and intramuscular vaccination with Leishmania amazonensis promastigote antigens (LaAg) increases the susceptibility of BALB/c mice to cutaneous leishmaniasis. In this study, we investigated the role played by serine and cysteine proteases as disease-promoting components of LaAg. Mice were immunized by the intramuscular route with LaAg that was pre-treated with a pool of serine or cysteine protease inhibitors (SPi and CPi, respectively) prior to infection with L. amazonensis. Neutralization of either enzyme type reversed the disease-promoting effect of LaAg, as seen by the slower lesion development. However, the parasite burden was only effectively controlled in mice receiving SPi-treated LaAg. Protection was associated with diminished production of TGF-beta and particularly IL-10 in response to parasite antigens by the lesion-draining lymph node cells of vaccinated mice relative to control. In vitro, soluble proteases isolated from LaAg (LaSP-Sol) directly activated IL-4, IL-10 and TGF-beta production by immune cells. Like native LaAg, vaccination with LaSP-Sol primed mice to respond to parasite challenge with a strong Jones-Mote cutaneous hypersensitivity reaction, and increased susceptibility to infection. Furthermore, neutralization of serine but not cysteine proteases blocked the capacity of LaAg to sensitize mice for Jones-Mote reaction. Together, these results indicate that soluble serine proteases are key components of LaAg responsible for its disease-promoting immunity.
de Matos Guedes
Herbert Leonel
HL
Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil.
Pinheiro
Roberta Olmo
RO
Chaves
Suzana Passos
SP
De-Simone
Salvatore Giovanni
SG
Rossi-Bergmann
Bartira
B
D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D007891:Leishmania / Q000201:enzymology / Q000276:immunology*; D007896:Leishmaniasis / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control*; D054332:Leishmaniasis Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D057057:Serine Proteases / Q000276:immunology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D054332:Leishmaniasis Vaccines; D015800:Protozoan Proteins; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases