immunology of infectious and parasitic diseases - XXXVII Congress ...

“ADENOSINE AND ADENOSINE MONOPHOSPHATE FROM
PHLEBOTOMUS PAPATASI SALIVARY GLAND EXACERBATE
LEISHMANIASIS BY INDUCING TREGS DEPENDENT OF TOLEROGENIC
DENDRITIC CELLS”
1 1 1
VANESSA CARREGARO, DJALMA LIMA-JÚNIOR, DIEGO L. COSTA,
3 1 4,5
Carlo J. F. Oliveira, CRISTIANE M. MILANEZI, JESUS G. VALENZUELA,
4,5 1,2 1
JOSÉ M. C. RIBEIRO, FERNANDO Q. CUNHA AND JOÃO S. SILVA
1 2
Department of Biochemistry and Immunology, and Department of
Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo,
Brazil; Institute of Biological and 3 Natural Sciences, Federal University of
Triângulo Mineiro, Minas Gerais, Brazil, 4 Section of Vector Biology, and 5 Vector
Molecular Biology Unit, Laboratory of Malaria and Vector Research, NIAID/NIH,
USA
INTRODUCTION: Phlebotomines saliva plays a crucial role in the
establishment of Leishmania infection. Among several potent pharmacologic
substances, we recently purified and identified adenosine-(ADO) and
adenosine-monophosphate-(AMP) as saliva‟s active pharmacologic compounds
presents on P. papatasii that inhibits dendritic cells-(DC) functions through
PGE2/IL-10-dependent mechanism. AIM: We evaluate whether ADO and 5'AMP
are compounds present into Phlebotomus papatasii saliva responsible for
leishmania establishment into vertebrate host and such immunomodulatory
mechanism. METHODS. C57BL/6WT or C57BL/6IL-10 -/- mice were
coinoculated with L. amazonensis promastigotes forms (1x10 5 parasites/eari.d.route)
in the presence of ADO+AMP or vehicle (PBS). The ear lesion size,
parasites burden, cytokines production and inflammatory infiltrated were
analyzed at 12 nd week post infection. RESULTS: ADO+AMP mimicked the
exacerbative effect of saliva in leishmaniasis, increasing parasites numbers and
ear lesion. Enzymatic catabolism of salivary nucleosides reversed the SGEinduced
immunosuppressive effect. Such effect was associated with proinflammatory
cytokines reduction (IFN-γ,TNF-α) and IL-10 enhancement.
Moreover, ADO+AMP failed to enhance ear lesion and parasite burden in IL-10 -
/- infected mice. Enzymatic catabolism of salivary nucleosides reversed the
SGE-induced immunosuppressive effect. Interestingly, nucleosides increased
Tregs makers (GITR; CTLA-4; CD39; CD73 expression) on CD4 + CD25 -
population, suggesting the induction of Tregs on T effector cells. Treg induction
was associated with nucleosides-induced tolerogenic dendritic cells (tDC)
expressing higher levels of COX2 and IL-10. Furthermore, nucleosides-induced
tDC displayed a semi-mature phenotype and produced lower levels of
proinflammatory cytokines in vitro and in vivo. CONCLUSION: We
demonstrated that ADO and 5‟AMP are constituents present in P.papatasi