Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors

Abstract

BackgroundKinins liberated from plasma–borne kininogens, are potent innate stimulatory signals. We evaluated whether resistance to infection by Leishmania (L.) chagasi depends on activation of G-protein coupled bradykinin B2 receptors (B2R).FindingsB2R −/− C57BL/6 knock-out (KOB2) and B2R+/+ C57BL/6-wild type control mice (C57) were infected with amastigotes of Leishmania (L.) chagasi. Thirty days after infection, the KOB2 mice showed 14% and 32% relative increases of liver (p< 0.017) and spleen weights (p<0.050), respectively, whereas liver parasite load increased 65% (p< 0.011) in relation to wild type mice. The relative weight increases of liver and spleen and the parasite load were positively correlated (R = 0.6911; p< 0.007 to R = 0.7629; p< 0.001, respectively). Conversely, we found a negative correlation between the increased liver relative weight and the weakened DTH response (a strong correlate to protection or natural resistance to VL) or the decreased levels of IgG2b antibodies to leishmanial antigen. Finally, we also found that IFN-γ secretion by splenocytes, an adaptive response that was significantly decreased in KOB2 mice (p< 0.002), was (i) negatively correlated to the increase in liver LDU (R = −0.6684; p = 0.035) and liver/body relative weight (R = −0.6946; p = 0.026) and (ii) positively correlated to serum IgG2b levels (R = 0.8817; p = 0.001).ConclusionsWe found that mice lacking B2R display increased susceptibility to the infection by Leishmania (L.) chagasi. Our findings suggest that activation of the bradykinin/B2R pathway contributes to development of host resistance to visceral leishmaniasis.

In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis

“…This may be the case, given that this weight increase was still significant in experimental mice in relation to naïve mice even after subtracting weight changes caused by normal body mass increase. This finding is supported by a recent study which recorded 14% and 32% weight increase in L. chagazi infected B2R-/- C57BL/6 knock-out (KOB2) mouse livers and spleens, respectively [20] . The weight increase in mice used in the present study may be an early event in visceral leishmaniasis infected subjects before substantial damage to the viscera which subsequently results in weight loss.…”

Ecotin-Like ISP ofL. majorPromastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B2and B1Receptors

“…The temporal course and dynamics of the plasma leakage response evoked by WT promastigotes were quite different from the classical responses elicited by BK, histamine, or leukotrienes, all of which cause a maximal increase within 10 min and reversed to steady-state conditions within 30 min [ 39 , 40 ]. Intriguingly, we found that the leakage responses evoked by L. major (WT) promastigotes were generally more robust than those induced by the same inoculum of L. donovani promastigotes ( Figure 1(c) ) [ 16 ] or T. cruzi (tissue culture trypomastigotes, Dm28c strain) [ 35 ]. Akin to the findings made in the above-mentioned studies, we found that topically applied HOE-140 (B 2 R antagonist) markedly reduced L. major (WT-) induced plasma leakage ( Figure 1(a) ).…”

A novel locus on mouse chromosome 7 that influences survival after infection with tick-borne encephalitis virus

“…Their role in defense against flaviviruses has not been described. Kallikrein-bradykinin system have been described to contribute to protection against Leishmania [ 34 ] and Trypanosoma cruzi [ 35 ] parasites in mice. Interestingly, on the mouse chromosome 7 were in the strain CcS-11 mapped loci Lmr21 and Tbbr3 that control susceptibility to L. major [ 36 ] and T. b. brucei [ 17 ], respectively.…”