Abstract
Calcium is an ubiquitous cellular signaling molecule that controls a variety of cellular processes and is strictly maintained in the cellular compartments by the coordination of various Ca2+ pumps and channels. Two such fundamental calcium pumps are plasma membrane calcium ATPase (PMCA) and Sarco/endoplasmic reticulum calcium ATPase (SERCA) which play a pivotal role in maintaining intracellular calcium homeostasis. This intracellular Ca2+ homeostasis is often disturbed by the protozoan parasite Leishmania donovani, the causative organism of visceral leishmaniasis. In the present study we have dileneated the involvement of PMCA4 and SERCA3 during leishmaniasis. We have observed that during leishmaniasis, intracellular Ca2+ concentration was up-regulated and was further controlled by both PMCA4 and SERCA3. Inhibition of these two Ca2+-ATPases resulted in decreased parasite burden within the host macrophages due to enhanced intracellular Ca2+. Contrastingly, on the other hand, activation of PMCA4 was found to enhance the parasite burden. Our findings also highlighted the importance of Ca2+ in the modulation of cytokine balance during leishmaniasis. These results thus cumulatively suggests that these two Ca2+-ATPases play prominent roles during visceral leishmaniasis.
Highlights
Leishmania donovani, an obligatory intracellular protozoan parasite which resides and multiplies within the host macrophages [1], is the causative agent of visceral leishmaniasis or Kala-azar, a fatal disease which is endemic in many parts of the tropical world [2,3]
Leishmania donovani infection is associated with abrogated calcium dependent protein kinase C (PKC) activation in macrophages [8]
Since intracellular organelles are limited by their storage capacity, longterm calcium homeostasis is regulated solely by the plasma membrane Ca2+-ATPases (PMCA) [21]
Summary
Leishmania donovani, an obligatory intracellular protozoan parasite which resides and multiplies within the host macrophages [1], is the causative agent of visceral leishmaniasis or Kala-azar, a fatal disease which is endemic in many parts of the tropical world [2,3]. For effective parasite clearance, activated macrophages induce various host-protective immune responses [4]. To counteract these anti-Leishmania responses, the parasites induce various immune-silencing mechanisms for its intracellular survival inside the hostile environment of macrophages. On the basis of structural and regulatory properties, PKC has been grouped into three subfamilies [5,6]; conventional or classical (cPKCs), novel (n-PKCs), and atypical (a-PKCs). Out of these three families, only conventional PKCs (a, bI, bII, and c) require Ca2+ along with DAG and phosphatidylserine for their activation
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