Macrophage Kinases in Leishmaniasis

Abstract

Leishmania is an obligatorily intracellular parasite residing and replicating in mammalian macrophages as amastigotes. Once activated, macrophages destroy Leishmania amastigotes. The macrophages can be activated by stimulating CD40, a costimulatory receptor, with an agonistic antibody or a recombinant CD40-ligand. CD40-induced macrophage activation involves different kinases. CD40 signals reciprocally trigger counteractive effector functions through two mitogen-activated protein kinases: p38MAPK and ERK-1/2. The reciprocity stems from two basic mechanisms. First, CD40 signalosomes in detergent-resistant, cholesterol-rich membrane domains or in detergent-soluble, cholesterol-poor membrane domains trigger p38MAPK or ERK-1/2 activation, respectively. Second, the signaling intermediates that carry the CD40 signals from these two membrane domains are organized in two modules. These intermediates can crosscheck the strength of CD40 signals in each of the bimodular pathways to reroute the signal accordingly. Quantitative analysis reveals that the bimodular architecture of the kinase network is endowed with several properties such as reciprocity, plasticity, and the ability to adjust signal strength in each of the modules. As an evasion strategy, Leishmania inhibits the kinases Lyn, PI3 K, PKCb and p38 MAPK that are used by the host cell to eliminate the parasite, whereas it promotes the activity of Syk, Raf-1, PKC-f and ERK-1/2 that are required for parasite survival. Targeting these kinases -syk, PKCz and ERK-1/2 -resulted in host-protection in a susceptible mouse strain. In this chapter, a novel CD40 signaling system is described that organizes kinases bimodularly to trigger reciprocal and adaptable signals working at the interface of the host and the parasite.

SHP-1 Plays a Crucial Role in CD40 Signaling Reciprocity

“…The quality of the response pertains to its counteractively functioning elements. Using CD40 as a model receptor with crucial roles in diverse immune functions, we previously showed that such counteractive functions or the quality of the response-proinflammatory or antiinflammatory-are regulated by a signaling system with signal strength calibrating feedback loops (7,10). The CD40 signaling system consists of cascades of kinases in two modules: one module transmits CD40 signal through lyn and p38MAPK while the other module transmits CD40 signal through syk and ERK-1/2.…”

“…Although these reports argued that the levels of activation are dependent on the extent of phosphorylation of p38MAPK and ERK-1/2, we argue that the observed reciprocity of MAPK phosphorylation is a function of a phosphatase that dephosphorylates these MAPKs differentially, as the cycle of phosphorylation and dephosphorylation of a kinase maintains the homeostasis of cellular signaling. Indeed, CD40-induced activation of MKP-1 and MKP-3, the dual-specific phosphatases, reciprocally regulates CD40 signaling through p38MAPK and ERK-1/2 and controls the host-protective antileishmanial immune response (9,10).…”

Towards discovery of new leishmanicidal scaffolds able to inhibitLeishmaniaGSK-3

“…The characterisation of the divergences between the kinome of several parasites from those of their mammalian host has become a source of new targets for novel anti-infective drugs 8 , 9 . Moreover, the pharmacological role of PKis has been extended beyond the selective inhibition of PKs from the pathogen to revert changes in the protein phosphorylation pattern of the host, driven by the pathogen in order to ensure its survival inside the host 10 , 11 . Concerning the former mode of action, two different approaches have been used: first, the design of PKis for atypical kinases of the pathogen 12 which are absent in the host, and second, to exploit the often subtle differences between homologue kinases of the parasite and of the host 13 .…”