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- Title
Anopheles Midgut Epithelium Evades Human Complement Activity by Capturing Factor H from the Blood Meal.
- Authors
Khattab, Ayman; Barroso, Marta; Miettinen, Tiera; Meri, Seppo
- Abstract
Hematophagous vectors strictly require ingesting blood from their hosts to complete their life cycles. Exposure of the alimentary canal of these vectors to the host immune effectors necessitates efficient counteractive measures by hematophagous vectors. The Anopheles mosquito transmitting the malaria parasite is an example of hematophagous vectors that within seconds can ingest human blood double its weight. The innate immune defense mechanisms, like the complement system, in the human blood should thereby immediately react against foreign cells in the mosquito midgut. A prerequisite for complement activation is that the target cells lack complement regulators on their surfaces. In this work, we analyzed whether human complement is active in the mosquito midgut, and how the mosquito midgut cells protect themselves against complement attack. We found that complement remained active for a considerable time and was able to kill microbes within the mosquito midgut. However, the Anopheles mosquito midgut cells were not injured. These cells were found to protect themselves by capturing factor H, the main soluble inhibitor of the alternative complement pathway. Factor H inhibited complement on the midgut cells by promoting inactivation of C3b to iC3b and preventing the activity of the alternative pathway amplification C3 convertase enzyme. An interference of the FH regulatory activity by monoclonal antibodies, carried to the midgut via blood, resulted in increased mosquito mortality and reduced fecundity. By using a ligand blotting assay, a putative mosquito midgut FH receptor could be detected. Thereby, we have identified a novel mechanism whereby mosquitoes can tolerate human blood. Author Summary: Mosquitoes are important vectors in the transmission of many human diseases. Their life cycle requires a blood meal to be completed. Ingested blood contains bioactive molecules belonging to the innate immune defense mechanisms against microbes, like the complement system, that can damage foreign cells. We have identified in this study a mechanism whereby mosquitoes can escape the damaging activity of the complement system in the ingested human blood. The mosquito midgut epithelial cell surface captured factor H, a natural regulator of the alternative pathway of complement activation, from the ingested blood. Consequently, the deposition of C3b, a key complement component, on the epithelial cell surface was impaired and cell death was avoided. Interfering with the complement regulatory activity of factor H by monoclonal antibodies, carried to the midgut via blood feeding, increased mosquito mortality and reduced fecundity. The putative Anopheles mosquito factor H binding proteins could be transmission blocking vaccine candidates targeting the malaria parasite carrying vectors.
- Subjects
ECULIZUMAB; ANOPHELES; COMPLEMENT factor H; LIFE cycles (Biology); ALIMENTARY canal; COMPLEMENT inhibition
- Publication
PLoS Neglected Tropical Diseases, 2015, Vol 9, Issue 2, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0003513