The CLIP-Domain Serine Protease Homolog SPCLIP1 Regulates Complement Recruitment to Microbial Surfaces in the Malaria Mosquito Anopheles gambiae

Povelones, Michael; Bhagavatula, Lavanya; Yassine, Hassan; Tan, Lee Aun; Upton, Leanna M.; Osta, Mike A.; Christophides, George K.

doi:10.1371/journal.ppat.1003623

Cited by 85 publications

(175 citation statements)

References 36 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…These interactions and the activity of chitinase, coupled with the digestive activity of plasmin on the ookinete surface (39), may result in a disruption of the PM structure, ultimately facilitating parasite invasion. After ookinetes cross the PM to invade midgut epithelial cells other proteins in mosquito hemolymph may perhaps interact with parasites and impact infection intensity (40,41). By extension, our model predicts that blocking FREP1 activity or interaction with Plasmodium parasites will significantly reduce the capacity for mosquitoes to transmit malaria.…”

Section: Discussionmentioning

confidence: 82%

Anopheles Midgut FREP1 Mediates Plasmodium Invasion

Zhang

Niu

Franca

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: The molecular mechanisms of Plasmodium invasion in mosquito midguts are not well understood. Results: The mosquito midgut peritrophic matrix protein FREP1 binds Plasmodia. Blocking parasite-FREP1 interactions or ablating FREP1 expression reduced P. falciparum infection in mosquitoes. Conclusion: FREP1 functions as a critical host factor that mediates Plasmodium invasion in mosquito midguts. Significance: Targeting FREP1 may inhibit Plasmodium transmission to mosquitoes and the spread of malaria.

show abstract

Section: Discussionmentioning

confidence: 82%

Anopheles Midgut FREP1 Mediates Plasmodium Invasion

Zhang

Niu

Franca

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…So far TEP1 is known to be regulated by two classes of proteins: the leucine-rich immune proteins LRIM1 and APL1C form a heterodimeric complex that binds to and stabilizes TEP1 cut , the active form of TEP1, in the mosquito hemolymph [9,10], while the two noncatalytic CLIPs, SPCLIP1 [12] and CLIPA2 [13], positively and negatively regulate TEP1 cut accumulation on microbial surfaces, respectively. In order to provide insight into the functional interaction between CLIPA2 and TEP1, and with the aim of identifying novel complement regulators with similar roles to CLIPA2, we set out to determine the identity of proteins that coIP with CLIPA2 from the hemolymph of B. bassiana -infected mosquitoes using MS.…”

Section: Resultsmentioning

confidence: 99%

“…The bioparticle surface extraction assay was performed exactly as previously described [12]. Proteins in the soluble and bound fractions were resolved by nonreducing SDS-PAGE and Western blot was performed as described above.…”

Section: Methodsmentioning

confidence: 99%

“…Following activation, TEP1 accumulation on microbial surfaces is also controlled by two noncatalytic clip domain serine proteases (CLIPs), SPCLIP1 and CLIPA2, which act as positive and negative regulators of that process, respectively, suggesting the presence of a convertase-like activity analogous to that in mammalian complement. Silencing LRIM1 in naive mosquitoes triggered the loss of TEP1 cut [9,10], SPCLIP1 [12] and CLIPA2 [13] from the hemolymph, demonstrating the tight association of these CLIPs with TEP1 activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Functional Interaction between Apolipophorins and Complement Regulate the Mosquito Immune Response to Systemic Infections

Kamareddine

Nakhleh

Osta³

2016

J Innate Immun

Self Cite

View full text Add to dashboard Cite

The complement-like protein thioester-containing protein 1 (TEP1) is the hallmark effector molecule against Plasmodium ookinetes in the malaria vector Anopheles gambiae. We have previously shown that the knockdown of the noncatalytic clip domain serine protease CLIPA2 increased TEP1-mediated killing rendering mosquitoes more resistant to Plasmodium, bacterial and fungal infections. Here, CLIPA2 coimmunoprecipitation from the hemolymph of Beauveria bassiana-infected mosquitoes followed by mass spectrometry and functional genetic analysis led to the identification of the Apolipophorin-II/I gene, encoding the two lipid carrier proteins Apo-I and II, as a novel negative regulator of TEP1-mediated immune response during mosquito systemic infections. Apo-II/I exhibits a similar RNAi phenotype as CLIPA2 in mosquito bioassays characterized by increased resistance to B. bassiana and Escherichia coli infections. We provide evidence that this enhanced resistance to systemic infections is TEP1 dependent. Interestingly, silencing Apo-II/I but not CLIPA2 upregulated the expression of TEP1 following systemic infections with E. coli and B. bassiana in a c-Jun N-terminal kinase pathway-dependent manner. Our results suggest that mosquito Apo-II/I plays an important immune regulatory role during systemic infections and provide novel insight into the functional interplay between lipid metabolism and immune gene regulation.

show abstract

“…During invasion, ookinetes are marked by epithelial nitration in a response regulated by the Jun N-terminal kinase (JNK) pathway, to promote thioester-containing protein 1 (TEP1) binding to the ookinete surface (2,3). Once bound, TEP1 is believed to initiate a complement-like cascade that ultimately leads to parasite lysis or melanization (4)(5)(6)(7).…”

mentioning

confidence: 99%

Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae

Smith

Barillas‐Mury

Jacobs-Lorena

2015

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

143

View full text Add to dashboard Cite

Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNFα transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete-to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of a wound-healing response. LL3 silencing abrogates the ability of mosquito hemocytes to differentiate and respond to parasite infection, implicating hemocytes as critical modulators of the late-phase immune response.osquitoes of the genus Anopheles are the obligate vectors for the transmission of the malaria parasite. Despite much effort invested to understand the interactions between the mosquito immune system and the parasite, our knowledge of these processes remains incomplete. The mosquito innate immune response effectively reduces parasite numbers, resulting in a severe bottleneck at the oocyst stage (1). There is evidence to suggest that multiple pathways contribute to parasite killing during two separate stages, or phases, of parasite development (1). An "early phase" occurs ∼18-24 h after blood feeding, as Plasmodium ookinetes invade the midgut epithelium and emerge on the basal side facing the hemocoel. During invasion, ookinetes are marked by epithelial nitration in a response regulated by the Jun N-terminal kinase (JNK) pathway, to promote thioester-containing protein 1 (TEP1) binding to the ookinete surface (2, 3). Once bound, TEP1 is believed to initiate a complement-like cascade that ultimately leads to parasite lysis or melanization (4-7).Parasites that evade this early-phase complement-like recognition and elimination are thought to be subjected to a second, "latephase" immune response that further decreases parasite numbers. This model is supported by the observation that the number of mature oocysts is significantly less than the number of early oocysts (8). Silencing the transcription factors STAT-A and STAT-B significantly increases oocyst survival, thus implicating the STAT pathway in this response (8). Conversely, constitutive activation of the STAT pathway via silencing the repressor SOCS (suppressor of cytokine signaling) resulted in increased levels of nitric oxide synthase (NOS) production and enhanced oocyst killing (8). These observations are in agreement with other studies that implicate NOS and subsequent NO production as important determinants of malaria parasite survival (9-11).Previously, we have characterized a LITAF-like transcription factor, LPS-induced TNFα transcription factor (LITAF)-like 3 (LL3), in Anopheles gambiae that mediates a potent antiPlasmod...

show abstract

The CLIP-Domain Serine Protease Homolog SPCLIP1 Regulates Complement Recruitment to Microbial Surfaces in the Malaria Mosquito Anopheles gambiae

Cited by 85 publications

References 36 publications

Anopheles Midgut FREP1 Mediates Plasmodium Invasion

Anopheles Midgut FREP1 Mediates Plasmodium Invasion

Functional Interaction between Apolipophorins and Complement Regulate the Mosquito Immune Response to Systemic Infections

Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae

Contact Info

Product

Resources

About