Two Mosquito LRR Proteins Function as Complement Control Factors in the TEP1-Mediated Killing of Plasmodium

Fraiture, Malou; Baxter, Richard H. G.; Steinert, Stefanie; Chelliah, Yogarany; Frolet, Cécile; Quispe-Tintaya, Wilber; Hoffmann, Jules A.; Blandin, Stéphanie; Levashina, Elena A.

doi:10.1016/j.chom.2009.01.005

Cited by 204 publications

(272 citation statements)

References 31 publications

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“…In fact, the mature TEP1 protein must physically interact with two leucine-rich repeat proteins (APL1 and LRIM1) encoded by genes on an independent chromosome, 2L (32,33). Thus, efficiency of parasite binding and killing may be a function of polymorphisms in TEP1 itself, and/or in APL1, LRIM1, or other proteins that control its function.…”

Section: Resultsmentioning

confidence: 99%

Adaptive divergence between incipient species of Anopheles gambiae increases resistance to Plasmodium

White

Lawniczak

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

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The African malaria mosquito Anopheles gambiae is diversifying into ecotypes known as M and S forms. This process is thought to be promoted by adaptation to different larval habitats, but its genetic underpinnings remain elusive. To identify candidate targets of divergent natural selection in M and S, we performed genomewide scanning in paired population samples from Mali, followed by resequencing and genotyping from five locations in West, Central, and East Africa. Genome scans revealed a significant peak of M-S divergence on chromosome 3L, overlapping five known or suspected immune response genes. Resequencing implicated a selective target at or near the TEP1 gene, whose complement C3-like product has antiparasitic and antibacterial activity. Sequencing and allele-specific genotyping showed that an allelic variant of TEP1 has been swept to fixation in M samples from Mali and Burkina Faso and is spreading into neighboring Ghana, but is absent from M sampled in Cameroon, and from all sampled S populations. Sequence comparison demonstrates that this allele is related to, but distinct from, TEP1 alleles of known resistance phenotype. Experimental parasite infections of advanced mosquito intercrosses demonstrated a strong association between this TEP1 variant and resistance to both rodent malaria and the native human malaria parasite Plasmodium falciparum. Although malaria parasites may not be direct agents of pathogen-mediated selection at TEP1 in nature-where larvae may be the more vulnerable life stage-the process of adaptive divergence between M and S has potential consequences for malaria transmission.ecological speciation | malaria vector | population genomics | thioester immune gene

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Section: Resultsmentioning

confidence: 99%

Adaptive divergence between incipient species of Anopheles gambiae increases resistance to Plasmodium

White

Lawniczak

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

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“…Several studies showed that the malaria vector Anopheles gambiae defends itself against invading Plasmodium parasites by activating a complement‐like pathway with the complement C3‐like protein TEP1, which is responsible for the killing and clearance through lysis and melanization of Plasmodium ookinetes that traverse the midgut epithelium (Blandin et al ., 2004; Fraiture et al ., 2009; Povelones et al ., 2011). TEP1 is secreted into the hemolymph by the phagocytic hemocytes and knockdown of TEP1 leads to a fivefold increase of developing oocysts.…”

Section: The Effect Of Midgut Factors On Parasite Developmentmentioning

confidence: 99%

“…TEP1 is secreted into the hemolymph by the phagocytic hemocytes and knockdown of TEP1 leads to a fivefold increase of developing oocysts. For the binding of TEP1 to the parasite surface, two members of the LRR protein family, LRIM1 and APL1C, are required, which form a disulfide‐bonded complex (Fraiture et al ., 2009; Povelones et al ., 2011). This complex helps to stabilize and promote the binding of a proteolytically cleaved mature TEP1 (Povelones et al ., 2011).…”

Section: The Effect Of Midgut Factors On Parasite Developmentmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

167

155

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SummaryThe mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.

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“…Constitutive cleavage is observed in the hemolymph within a protease-sensitive region similar to that of C3. Proteolysis of TEP1 in the protease-sensitive region in vitro does not appear to cause a conformational change, and the thioester remains present in the resulting cleaved form of TEP1 (13), referred to here as TEP1 cut , implying that additional factors regulate activation of TEP1 in vivo..Two leucine-rich repeat (LRR) proteins were recently shown to control the function of TEP1 in A. gambiae (13,14). LeucineRich Immune Molecule 1 (LRIM1) was initially identified as having an antimalarial phenotype within the P. berghei model system and also as a factor required for efficient phagocytosis of Gram-negative but not Gram-positive bacteria (15-17).…”

mentioning

confidence: 99%

“…Two leucine-rich repeat (LRR) proteins were recently shown to control the function of TEP1 in A. gambiae (13,14). LeucineRich Immune Molecule 1 (LRIM1) was initially identified as having an antimalarial phenotype within the P. berghei model system and also as a factor required for efficient phagocytosis of Gram-negative but not Gram-positive bacteria (15-17).…”

mentioning

confidence: 99%

A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae

Baxter

Steinert

Chelliah

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

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The leucine-rich repeat (LRR) proteins LRIM1 and APL1C control the function of the complement-like protein TEP1 in Anopheles mosquitoes. The molecular structure of LRIM1 and APL1C and the basis of their interaction with TEP1 represent a new type of innate immune complex. The LRIM1/APL1C complex specifically binds and solubilizes a cleaved form of TEP1 without an intact thioester bond. The LRIM1 and APL1C LRR domains have a large radius of curvature, glycosylated concave face, and a novel C-terminal capping motif. The LRIM1/APL1C complex is a heterodimer with a single intermolecular disulfide bond. The structure of the LRIM1/APL1C heterodimer reveals an interface between the two LRR domains and an extensive C-terminal coiled-coil domain. We propose that a cleaved form of TEP1 may act as a convertase for activation of other TEP1 molecules and that the LRIM1/APL1C heterodimer regulates formation of this TEP1 convertase.host-pathogen interactions | innate immunity | malaria | thioester C omplement is an innate immune system in vertebrates comprising a number of serum proteins that function to detect and destroy microorganisms. Insects possess a complement-like immune response to bacteria, fungi, and protozoan parasites (1-4). Anopheles gambiae thioester-containing protein 1 (TEP1) is structurally and functionally homologous to complement factor C3 (3, 5-7), including an intramolecular thioester bond that mediates covalent labeling of pathogens. Covalent attachment of TEP1 to bacteria promotes their phagocytosis (3), whereas binding of TEP1 to Plasmodium berghei ookinetes targets them for lysis (1).Complement activation centers upon a conformational change in C3 that is regulated by proteolysis. C3 is cleaved twice; first during intracellular processing, then a second activating cleavage that dissociates a small protein domain known as anaphylatoxin, or C3a. This dissociation triggers a large conformational change in the remaining molecule, known as C3b, exposing the thioester bond (8, 9). The proteolytic activation of C3 is regulated by the formation of a transient complex between a protease and a complement factor, known as a convertase.The alternative pathway involves self-activation of C3. Hydrolysis of the C3 thioester bond induces a conformational change, producing C3ðH 2 OÞ which has a similar conformation to C3b. C3ðH 2 OÞ can recruit the protease Factor B. Cleavage of Factor B by Factor D produces the transient complex C3ðH 2 OÞBb that is a C3 convertase (10). The alternative pathway is inhibited in the fluid phase and the presence of self surfaces by the binding of Factor H, which competes with Factor B for binding to the C345C domain of C3 (11, 12).TEP1 lacks both the anaphylatoxin and C345C domains, and is secreted as a full-length molecule. Constitutive cleavage is observed in the hemolymph within a protease-sensitive region similar to that of C3. Proteolysis of TEP1 in the protease-sensitive region in vitro does not appear to cause a conformational change, and the thioester remains present in the result...

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Two Mosquito LRR Proteins Function as Complement Control Factors in the TEP1-Mediated Killing of Plasmodium

Cited by 204 publications

References 31 publications

Adaptive divergence between incipient species of Anopheles gambiae increases resistance to Plasmodium

Adaptive divergence between incipient species of Anopheles gambiae increases resistance to Plasmodium

The development of malaria parasites in the mosquito midgut

A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae

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