The mosquito<i>Anopheles stephensi</i>limits malaria parasite development with inducible synthesis of nitric oxide

Luckhart, Shirley; Vodovotz, Yoram; Rosenberg, Ronald

doi:10.1073/pnas.95.10.5700

Cited by 379 publications

(410 citation statements)

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“…The induction of AsPrx-4783 at 7 days pBM suggests a role at extended times postdigestion. Consistent with such a role, we observed that AsNOS is induced in the midguts of blood-fed insects relative to nonfed insects at 6 and 9 days pBM and that nitrate/nitrite levels in circulating hemolymph are elevated at 7 days pBM and then gradually decrease in uninfected insects through 14 days pBM [15]. Thus, elevated AsPrx-4783 would be available to protect against ROS and RNOS generated during and after blood digestion.…”

Section: Discussionsupporting

confidence: 74%

“…We also demonstrated that AsNOS catalytic activity leads to an increase in midgut nitrosative stress [15][16][17]. Our data indicate that inflammatory levels of midgut RNOS limit or inhibit parasite growth [15,17]. These RNOS, however, also impose stress on the mosquito host (reviewed in [18]).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 60%

“…These stresses are relevant to midgut conditions in A. stephensi and in the closely related A. gambiae after feeding and during parasite infection. In previous studies, we reported that AsNOS was upregulated in a step-wise pattern after feeding and parasite infection from a few hours after blood feeding to the completion of blood digestion [15,17]. This induction leads to the synthesis of inflammatory levels of nitrogen oxides, which are likely produced from reactions involving NO and ROS [17].…”

Section: Discussionmentioning

confidence: 94%

“…We previously observed a similar pattern of induction of AsNOS expression in A. stephensi. Specifically, AsNOS is expressed at low levels before blood feeding, at higher levels in response to blood ingestion, and at the highest levels in response to parasite infection [15]. Hence, the step-wise increases in AsPrx-4783 expression mirror the step-wise increases in AsNOS induction in the A. stephensi midgut.…”

Section: Discussionmentioning

confidence: 95%

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

Peterson

Luckhart

2006

Free Radical Biology and Medicine

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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...

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Section: Discussionsupporting

confidence: 74%

Section: Nih-pa Author Manuscriptmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 95%

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

Peterson

Luckhart

2006

Free Radical Biology and Medicine

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“…infection [1,2]. Parasite development in the mosquito begins with the ingestion of blood containing sexual-stage gametocytes.…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection

Peterson

Gow

Luckhart

2007

Free Radical Biology and Medicine

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100

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Malaria parasite infection in anopheline mosquitoes is limited by inflammatory levels of nitric oxide metabolites. To assess the mechanisms of parasite stasis or toxicity, we investigated the biochemistry of these metabolites within the blood-filled mosquito midgut. Our data indicate that nitrates, but not nitrites, are elevated in the Plasmodium-infected midgut. Although levels of S-nitrosothiols do not change with infection, blood proteins are S-nitrosylated after ingestion by the mosquito. In addition, photolyzable nitric oxide, which can be attributed to metal nitrosyls, is elevated following infection and, based on the abundance of hemoglobin, likely includes heme iron nitrosyl. The persistance of oxyhemoglobin throughout blood digestion and changes in hemoglobin conformation in response to infection suggest that hemoglobin catalyzes the synthesis of nitric oxide metabolites in a reducing environment. Provision of urate, a potent reductant and scavenger of oxidants and nitrating agents, as a dietary supplement to mosquitoes increased parasite infection levels relative to allantoin-fed controls, suggesting that nitrosative and/or oxidative stresses negatively impact developing parasites. Collectively, our results reveal a unique role for nitric oxide in an oxyhemoglobin-rich environment. In contrast to facilitating oxygen delivery by hemoglobin in the mammalian vasculature, nitric oxide synthesis in the blood-filled mosquito midgut drives the formation of toxic metabolites that limit parasite development.

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Cytotoxicity and cytotoxic molecules in invertebrates

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The mosquitoAnopheles stephensilimits malaria parasite development with inducible synthesis of nitric oxide

Cited by 379 publications

References 39 publications

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

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

Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection

Cytotoxicity and cytotoxic molecules in invertebrates

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