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

DEVELOPMENT OF MURINE PLACENTAL MALARIA IS DEPENDENT ON
TLR4/MYD88 PATHWAY.
RENATO BARBOZA 1 ; ARAMYS SILVA DOS REIS 1 ; WESLEY L. FOTORAN 1 ;
LEANDRO GUSTAVO DA SILVA 1 ;GERHARD WUNDERLICH 1 ; NIELS OLSEN
SARAIVA CÂMARA 3 ; SILVIA BEATRIZ BOSCARDIN 1 ; SABRINA EPIPHANIO 2
& CLAUDIO ROMERO FARIAS MARINHO 1
1 Departamento de Parasitologia, ICB, Universidade de São Paulo, São Paulo,
Brasil; 2 Departamento de Imunologia, ICB, Universidade de São Paulo, São
Paulo, Brasil; 3 Departamento de Ciências Biológicas, Universidade Federal de
São Paulo, Diadema, Brasil.
Introduction: Toll like receptors (TLR) are components of innate immune
system that recognize pathogens through distinct molecular patterns.
Recruitment of MyD88 is a common pathway of TLR signaling, which leads to
induction of NF-kB-dependent inflammatory cytokine production. It has been
described that TLR4 recognize components of Plasmodium sp. and affect the
host immune response. Despite the fact that the activation of innate immune
system by Plasmodium sp. during pregnancy can result in a range of
complications affecting both mother and fetus, the aim of this work was to
evaluate the effects of TLR4/MyD88 pathway on the development of placental
malaria (PM). Methods & Results: Initially, to ascertain if TLR4 could
recognize P. berghei NK65 infected red blood cells (iRBC), COS-7 cells were
co-transfected with mouse CD14 and TLR4. For luciferase reporter assay, cells
were also co-transfected with ELAM-1-firefly luciferase and beta-actin-Renilla
luciferase plasmids. Our results showed that iRBC were able to activate TLR4.
To verify the effects of TLR activation, we infected pregnant TLR4 -/- , MyD88 -/-
and C57BL/6 (WT) mice with P. berghei NK65 on the 13th gestational day.
Histopathological analysis of the placentas showed a decrease of vascular
spaces in WT infected mice when compared with placentas from non-infected
mice (39.444.75 vs. 48.134.57 % of vascular space, respectively). On the
other hand, placentas from infected and non-infected of both strains TLR4 and
MyD88 did not present differences when compared with the control. As the
reduction of vascular space can be a consequence of inflammatory processes,
our next step was to analyze the placental expression of IL-6, TNF-alpha and
IP-10 mRNA. Our results show that only WT infected mice presented an
increase in the expression of these cytokines as compared with TLR4 -/- and
MyD88 -/- mice. Conclusion: In summary, this study illustrates the importance of
a severe inflammatory response in the development of PM pathogenesis via
TLR4/MyD88 signaling and, additionally, indicates the TLR4 and adaptor
protein MyD88 as potential targets for therapeutics intervention.