Table 1.

Examples of evasion strategies and underlying molecular mechanisms by which Leishmania parasites promote their survival in macrophages.

Step of defense	Process elicited by Leishmania infection	Molecular mechanism(s)	Leishmania species studied	References
Macrophage polarization towards activated (M1) macrophages	Transcriptional reprogramming towards permissive macrophages	1. Metabolic reprogramming of the host cell
		(a)Maintenance and upregulation of retinoid X receptor α-associated genes	L. donovani	[260]
		(b)Upregulation of genes for the synthesis of sterols, fatty acids, sterols and putrescine	L. amazonensis	[261]
		(c)Upregulation of glycolysis, downregulation of lipid metabolism	L. major, L. mexicana	[262], [263]
		(d)Switch from glycolysis to mitochondrial oxidative phosphorylation	L. infantum, L. donovani	[240], [264]
		2. Suppression of the production of proinflammatory cytokines
		(a)AHR- and Egr2-dependent upregulation of SOCS1 → suppression of IFN-γ- and STAT1-mediated IL-12 production	L. donovani	[177]
		(b)Amastigote-mediated hypoacetylation of H3K49/14 and hypo-trimethylation of H3K4 → reduced activation of NFκB and NLRP3 → reduced production of IL-1β and IL-18	L. amazonensis	[181]
		(c)Smyd-mediated demethylation of H3K36 at TNF promoter → reduced expression of TNF	L. donovani	[265]
		(d)Exosome-mediated suppression of TNF and induction of IL-10	L. major, L. donovani etc.	[236], [266]
		3. Skewing of CD40-signaling to ERK-1/2 and IL-10 induction	L. major	[267]
		4. LRV1-/TLR3-dependent induction of microRNA155 and PI3Kinase/Akt promoting macrophage survival and parasite persistence	L. guyanensis	[227]
	Translational reprogramming	1. Cleavage of the mammalian/ mechanistic target of rapamycin (mTOR) by the metalloprotease gp63 (leishmanolysin; expressed on the surface of pro- and amastigotes) → activation of the translational repressor 4E-BP1 → reduced type I IFN-production, increased parasite proliferation	L. major	[248]
		2. Enhancement of mTOR- and eIF4A-sensitive mRNA-translation (inhibition of eIF4A promoted parasite elimination, whereas inhibition of mTOR supported parasite persistence)	L. donovani	[247]
Macrophage uptake of parasites	Inhibition of alternative complement activation	Conversion of C3b into iC3b by gp63 → parasite uptake by macrophages via CR1 and CR3; resistance to complement-mediated lysis	L. major, L. mexicana, L. amazonensis and others	[235], [268], [269]
Macrophage antimicrobial activity	Inhibition of phagolysosomal fusion by LPG	Alteration of physical properties of phagosomal membrane by LPG (expressed on the surface of promastigotes)? Inhibition of recruitment of the small GTPase rab7?	L. donovani, L. major	[270], [271], [272]
	Inhibition of phagocyte NADPH oxidase (NOX2) activity	1.Degradation of the heme component of gp91phox via induction of heme oxygenase 1 (HO-1)	L. mexicana pifanoi, L. donovani	[273], [274]
		2.IFN-β-mediated induction of superoxide dismutase (SOD) 1	L. amazonensis, L. braziliensis	[228]
	Inhibition of NOS2 expression	1.Activation of SHP-1 protein tyrosine phosphatase by gp63-mediated cleavage; SHP-1 inactivates IFN-γ-induced JAK2/STAT1α-pathway	L. major	Reviewed in [235]
		2.Parasite arginase-dependent upregulation of microRNA294 and microRNA721, leading to partial macrophage NOS2 suppression	L. amazonensis	[275]
		3.EZH2-mediated trimethylation of H3K27 at NOS2 promoter → reduced NOS2-expression	L. donovani	[265]
	Inhibition of iron export, thereby increased iron availability for the parasite	Translational suppression of the iron exporter ferroportin-1 via upregulation of iron-regulatory-protein-2 (IRP-2)	L. amazonensis, L. donovani	[276], [277]
Macrophage antigen presentation	Inhibition of antigen presentation and T cell activation	1.Impaired reorientation of the T cell microtubule organizing center towards the macrophage-T-cell contact site	L. donovani	[278] and ref. therein
		2.Impaired expression of costimulatory molecules and disruption of lipid rafts	L. donovani	[279]
Macrophage-/ dendritic cell-mediated generation and expansion of antigen-specific effector T cells (Th1)	Upregulation of indoleamine-2,3-dioxygenase (IDO) by Leishmania parasites	IDO-mediated depletion of L-tryptophan and generation of immunosuppressive kynurenines → suppression of T cell proliferation; generation of regulatory, FoxP3+ T cells	L. major; L. donovani; L. infantum; L. guyanensis	[159], [160], [161], [162]