A mosquito 2-Cys peroxiredoxin protects against nitrosative and oxidative stresses associated with malaria parasite infection

Abstract

Malaria parasite infection in anopheline mosquitoes induces nitrosative and oxidative stresses that limit parasite development, but also damage mosquito tissues in proximity to the response. Based on these observations, we proposed that cellular defenses in the mosquito may be induced to minimize self-damage. Specifically, we hypothesized that peroxiredoxins (Prxs), enzymes known to detoxify reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), protect mosquito cells. We identified an Anopheles stephensi 2-Cys Prx ortholog of Drosophila melanogaster Prx-4783, which protects fly cells against oxidative stresses. To assess function, AsPrx-4783 was overexpressed in D. melanogaster (S2) and in A. stephensi (MSQ43) cells and silenced in MSQ43 cells with RNA interference before treatment with various ROS and RNOS. Our data revealed that AsPrx-4783 and DmPrx-4783 differ in host cell protection and that AsPrx-4783 protects A. stephensi cells against stresses that are relevant to malaria parasite infection in vivo, namely nitric oxide (NO), hydrogen peroxide, nitroxyl, and peroxynitrite. Further, AsPrx-4783 expression is induced in the mosquito midgut by parasite infection at times associated with peak nitrosative and oxidative stresses. Hence, whereas the NO-mediated defense response is toxic to both host and parasite, AsPrx-4783 may shift the balance in favor of the mosquito. KeywordsMalaria; Mosquito; Peroxiredoxin; Plasmodium; Anopheles; Nitric oxide; Nitrosative stress; Free radicals It has long been recognized that reactive oxygen species (ROS) and, more recently, reactive nitrogen oxide species (RNOS) function to defend hosts against pathogens [1]. Although ROS and RNOS are cytotoxic to pathogens and parasites, they also induce oxidative and nitrosative stresses in the host and can damage host tissues [1]. Host protection against oxidative and nitrosative stress, therefore, is vital for homeostasis and hence survival. Gene products that confer protection against ROS are well known. In contrast, gene products that confer protection against RNOS have been identified, but are less well studied. The peroxiredoxins (Prxs) are a recently discovered family of antioxidant peroxidases that can reduce hydrogen peroxide and alkyl hydroperoxides to water and the corresponding alcohols, respectively, and can protect cells from widely divergent organisms against a variety of nitrosative stress challenges [2][3][4][5][6].Prxs do not show sequence homology to other known antioxidant enzymes. Crystal structures of PrxI, II, V, and VI have revealed that Prxs are novel members of the thioredoxin fold * Corresponding author. Fax: +1 530 752 8692. E-mail address: sluckhart@ucdavis.edu (S. Luckhart). NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript superfamily [7,8]. Unlike most peroxidases-which contain a heme ring at their active site (e.g., cytochrome c peroxidase) or a redox-sensitive moiety like selenocysteine (glutathione peroxidase; GPx), vanadium (algal bro...

Proteomic analysis of methyl parathion-responsive proteins in Sparus latus liver

“…In our research, MP elicited an increased Prx 2 level in houttuyn liver. This is consistent with a report of Prx 2 overexpression against the oxidative stress associated with malarial parasite infection [47]. Other studies show that Prx 2 overexpression provides resistance to cytotoxic agents [48,49].…”

Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection

“…At the same time, however, induction of mosquito 2-Cys peroxiredoxin, which protects against ROS-and NO x -mediated cell death [49], would tip the balance in favor of the mosquito. As such, a complex immunological system within A. stephensi produces reactive species to limit infection and cytoprotective enzymes to preserve host cell function.…”

Apoptosis-like death as a feature of malaria infection in mosquitoes

“…Our understanding of the regulation of the mosquito inducible NOS and the damage that nitrosative stress may cause to vector tissues is still rudimentary. Interestingly, the recently identified mosquito peroxiredoxin enzyme, A. stephensi 2-Cys peroxiredoxin (AsPrx-47830) has been shown to protect against stresses induced by NO, nitroxyl, peroxynitrite and hydrogen peroxide (Peterson and Luckhart, 2006). Peroxinitrite, for instance, is involved in reactions that cause DNA damage and nitration of proteins (see discussion in Peterson and Luckhart, 2006).…”

“…Interestingly, the recently identified mosquito peroxiredoxin enzyme, A. stephensi 2-Cys peroxiredoxin (AsPrx-47830) has been shown to protect against stresses induced by NO, nitroxyl, peroxynitrite and hydrogen peroxide (Peterson and Luckhart, 2006). Peroxinitrite, for instance, is involved in reactions that cause DNA damage and nitration of proteins (see discussion in Peterson and Luckhart, 2006). Feeding on an uninfected blood meal was shown to induce an increase in AsPrx-47830 midgut expression from 2-20 h post blood meal with a higher level of induction being observed in P. berghei infected-mosquito midguts from 12 .…”