Nitrophorins

Nitrophorins are special proteins that occur in the salivary glands of certain blood-sucking insects, especially predatory bugs (e.g. of the genus Rhodnius) but also of bedbugs (see below cimicoids, bug bites). They play an important role in the blood meal of these insects. Here is an overview of their properties and functions. Nitrophorins are an example of how parasites develop molecular mechanisms to effectively manipulate their hosts.

Cimex lectularius (bed bug) nitrophorin (cNP) accomplishes this with a cysteine-ligated iron(III) heme. In the acidic environment of the insect's salivary glands, NO binds firmly to cNP. During a blood meal, cNP-NO is released to the feeding site, where dilution and increased pH lead to the release of NO. It has been shown that cNP not only binds heme, but also nitrosates the proximal cysteine, leading to the formation of Cys-NO (SNO). The formation of SNO requires the oxidation of proximal cysteine, which is presumably metal-assisted by the concomitant reduction of ferric heme and the formation of Fe(II)-NO (Badgandi HB et al. 2023)-

Binding and transport of nitric oxide (NO): Nitrophorins bind nitric oxide (NO) in the insect's salivary glands and release it into the host's skin when they bite. NO has a vasodilating effect, which increases the blood flow at the sting site and facilitates bloodsucking. Cimex lectularius (bed bug) nitrophorin (cNP) achieves this by releasing nitrophorin (cNP) through a cysteine-ligated iron(III) heme.

In the acidic environment of the insect's salivary glands, NO binds tightly to cNP. During a blood meal, cNP-NO is released to the feeding site, where dilution and increased pH lead to the release of NO. It has been shown that cNP not only binds heme but also nitrosates the proximal cysteine, leading to the formation of Cys-NO (SNO) (Auerbach H et al. 2023). The formation of SNO requires the oxidation of proximal cysteine, which is presumably metal-assisted by the concomitant reduction of ferric heme and the formation of Fe(II)-NO (Badgandi HB et al. 2023).

Anticoagulation: NO thus inhibits blood coagulation, preventing the puncture site from clogging and allowing the insect to suck blood unhindered.

Immunosuppression: In addition to promoting blood flow, NO can also suppress the host's immune system, reducing the likelihood of an immune response.

Biological research: Nitrophorins are of great interest in medical research as they offer insights into the mode of action of NO and its potential therapeutic applications, for example in the treatment of blood clotting disorders or inflammation.

Allergy: see pathophysiology below

A patient with bullous bite reactions after sequential contact with C. lectularius over a period of one year was described. Immediate reactions to the salivary gland solution of C. lectularius were observed in skin tests, followed by a pronounced, partially blistering late phase. Immunoblot analysis of patient serum with salivary gland extracts and recombinant C. lectularius salivary proteins revealed specific IgE antibodies against the 32 kDa C. lectularius nitrophorin, but not against the 37 kDa C. lectularius apyrase. These data indicate that bullous cimicosis is the late phase of an allergic IgE-mediated hypersensitivity to C. lectularius nitrophorin (Leverkus M et al. 2006).

1. Auerbach H et al. (2023) Heme protonation affects iron-NO binding in the NO transport protein nitrophorin. J Inorg Biochem 246:112281
2. Badgandi HB et al. (2023) Nitric oxide delivery and heme-assisted S-nitrosation by the bedbug nitrophorin. J Inorg Biochem 246:112263.
3. Leverkus M et al. (2006) Bullous allergic hypersensitivity to bed bug bites mediated by IgE against salivary nitrophorin. J Invest Dermatol 126:91-96.