Mammalian Transforming Growth Factor β1 Activated after Ingestion byAnopheles stephensiModulates Mosquito Immunity

Abstract

During the process of bloodfeeding by Anopheles stephensi, mammalian latent transforming growth factor ␤1 (TGF-␤1) is ingested and activated rapidly in the mosquito midgut. Activation may involve heme and nitric oxide (NO), agents released in the midgut during blood digestion and catalysis of L-arginine oxidation by A. stephensi NO synthase (AsNOS). Active TGF-␤1 persists in the mosquito midgut to extended times postingestion and is recognized by mosquito cells as a cytokine. In a manner analogous to the regulation of vertebrate inducible NO synthase and malaria parasite (Plasmodium) infection in mammals by TGF-␤1, TGF-␤1 regulates AsNOS expression and Plasmodium development in A. stephensi. Together, these observations indicate that, through conserved immunological cross talk, mammalian and mosquito immune systems interface with each other to influence the cycle of Plasmodium development.

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

“…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]).…”

“…Previously, we reported that AsNOS was induced by parasite infection in the midgut greater than twofold at 6 and at 36 and 48 h pBM relative to uninfected blood-fed insects [17]. This biphasic induction leads to the synthesis of nitrogen oxides in the midgut lumen range from 75 to >160 μM at 12-24 h pBM [17]. Values in excess of 75 μM are consistent with inflammatory levels of nitrite/nitrate reported in human serum under conditions of sepsis [66,67] and therefore indicate that the NO-mediated response of A. stephensi to Plasmodium infection is an inflammatory response.…”

“…5). Whereas we suspect that this RNOS is toxic to developing parasites, midgut nitroxyl may also be associated with rapid activation of ingested human latent transforming growth factor-β1, which regulates parasite development in A. stephensi [17]. As such, AsPrx-4783 seems to protect mosquito cells against an RNOS that likely participates directly in parasite killing and indirectly in the regulation of parasite killing.…”

“…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]. Like AsNOS, A. gambiae NOS is induced in response to parasite infection [39].…”

“…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].…”