Table 3.

Role of ROS in Protozoan Infections of Medical Importance

Pathogen	Observed effects of ROS/antioxidants on pathogen's burden	Model	Associated mechanisms of resistance	Suspected mechanisms underlying results	References
Leishmania major	NAC treatment of BALB/c mice reduced burden, whereas BSO (a drug that depletes gluthatione) increased burden in C57BL/6 footpads	Mice were treated with NAC	Increase in the frequency of IFN-γ-secreting lymphocytes in draining popliteal lymph nodes from NAC-treated mice	It remains unknown whether reduction of burden is dependent on IFN-γ-secreting lymphocytes	(56, 270, 276)
	Treatment of infected macrophages with GSH-depleting BSO before IFN-γ/LPS activation increased burden	Elicited peritoneal macrophages(C57BL/6 mice) treated with BSO for 24 h, activated with IFN-γ/LPS	GSH depletion was associated with a decrease in NO production	It remains unknown whether GSH inhibited L. major growth in macrophages	(276)
	NRF2-activator resveratrol reduced parasite burden of infected macrophages	Elicited peritoneal macrophages or J774 murine cell line treated with resveratrol	Resveratrol acts to reduce parasite burden in macrophages at lower doses than directly	The mechanisms activated by resveratrol remain unknown	(138)
Leishmania amazonensis	NAC treatment reduced parasite burden in footpads from infected BALB/c mice	NAC treatment of BALB/c mice	No clues to how NAC reduced footpad parasite burden	No suspected mechanism	(205)
	DETC, an inhibitor of SOD activity, promoted parasite destruction in infected macrophages or reduced parasite burden in vivo, NAC reversed this effect	Peritoneal macrophages from BALB/c mice	Superoxide production seems to be a killing mechanism. No controls treated only with NAC	IFN β increases parasite burden through induction of SOD and decrease of superoxide	(141)
Trypanosoma cruzi	ROS exposure of epimastigotes increased their growth	Epimastigotes grow more actively in LIT medium containing H2O2	ROS affects cell signaling.	No similar mechanisms are known in amastigotes	(77, 226)
	Increased infection under oxidative conditions and vice versa, in macrophages and in vivo. Burden reduced in infected macrophages incubated with antioxidants, transfected with Nrf2 or HO-1, and vice versa in H2O2 or PMA. Treatment with NRF2-activators reduce parasitemia, also reduced in gp91phox−/−.mice	Elicited peritoneal macrophages, BMMs or THP-1 cells; C57BL/6 and NOX2(gp91phox)−/− mice	Reduction of labile iron pool associated with reduction in parasite growth by antioxidants. NO, type I IFN, and apoptosis of infected cells not involved	Direct effects of ROS on amastigote proliferation were not ruled out, nor were mechanisms indirectly associated with reduction of labile iron pool	(93, 210, 218, 235, 272, 285)

BSO, buthionine sulfoximine; LPS, lipopolysaccharide; NO, nitric oxide; SOD, superoxide dismutase.