Editorial: Leishmania survival mechanisms: the role of host phosphatases

The phagocytic and antimicrobial properties of macrophages are critical to innate immune recognition and clearance of pathogens. During infection, macrophages release a myriad of antimicrobial molecules. ROS and NO, along with the byproduct peroxinitrite, are known to be the most effective types of macrophage microbicidal molecules [1]. However, some pathogens, such as the sandfly-transmitted Leishmania parasite, have evolved elegant mechanisms to subvert these primordial defense systems and survive the harsh antimicrobial environment of the macrophage. Such an intriguing survival capacity leaves one to wonder how the Leishmania parasite manages to elude the host’s innate immune defense machinery. Numerous escape mechanisms have been described. On the one hand, Leishmania parasites can synthesize antioxidants, such as superoxide dismutase and other ROS scavengers, which undermine the production of ROS [1]. Surprisingly, the parasite seems to produce arginase that up-regulates host arginase activity, thereby favoring the progression of the Leishmania parasite within the murine host [2]. On the other hand, Leishmania parasites also inhibit several host innate inflammatory functions, such as phagosome-lysosome maturation and expression of costimulatory molecules required for antigen presentation. Leishmania causes deviation from the normal immune response by inducing the activity of suppressive cytokines, such as IL-10, PGE2, and TGF. More importantly, Leishmania suppresses macrophage microbicidal functions by down-regulating NADPH oxidase and iNOS expression, thereby inhibiting ROS and NO production, respectively [1]. Although the molecules required for protection and susceptibility of Leishmania infection are well studied, the molecular mechanisms and the operative signaling programs required for host response require further investigation. Notably, a balance between kinases and phosphatases is required for optimal macrophage response and control of parasitic infection. Phosphatases can be classified based on their effector functions as PTPs, DSPs, and STPs. The PTP superfamily is divided further into transmembrane receptor and nonreceptor tyrosine phosphatases [3]. PTP expression in macrophages is in perfect harmony with their kinase counterparts; this balance ensures the regulation of several functions during resting and activated states of the macrophages. However, the role of some phosphatases as a negative regulator of signaling pathways can be exploited by various pathogens such as Mycobacteria, Trypanosoma cruzi, HIV-1, and adenovirus [4, 5], and Leishmania parasites are particularly effective at hijacking macrophage signaling and antimicrobial functions [1]. The powerful ability of Leishmania to shut down the macrophage antimicrobial machinery allows the parasite to avoid the initial innate immune response and create a safe environment for proliferation. In particular, Leishmania activates host PTPs and inhibits the host’s effector mechanisms (Fig. 1). The first observation of the latter mechanism was reported a decade ago, when Olivier et al. [6], using the PTP inhibitor bpV(phen), demonstrated that in vivo inhibition of host PTPs resulted in the control of cutaneous and visceral leishmaniasis progression by enhancing NO production. This was followed by the demonstration that the SHP-1 was activated rapidly upon Leishmania donovani infection, which involved the dephosphorylation of JAKs and MAPK. Thereafter, it was reported that SHP-1deficient mice did not develop footpad swelling in response to Leishmania major infection, and this result occurred concomitantly with elevated NO production [1]. These data indicated clearly that the capacity of the parasite to exploit macrophage phosphatases is somehow necessary for its survival and disease progression. Recently, Gomez et al. [7] revealed that in addition to SHP-1, two other nonreceptor PTPs (PTP1B and T cell PTP) are activated upon Leishmania infection, leading to inactivation of JAK kinase family members. Furthermore, in