The interplay between dose and immune system activation determines fungal infection outcome in the African malaria mosquito, Anopheles gambiae

Rhodes, Victoria L.M.; Thomas, Matthew B.; Michel, Kristin

doi:10.1016/j.dci.2018.04.008

Cited by 19 publications

(23 citation statements)

References 77 publications

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“…To investigate whether CTL4 plays a role in mosquito immunity against fungi, we used the entomopathogenic fungus Beauvaria bassiana , which is virulent and has been shown to trigger the melanization response in A . gambiae [ 9 , 14 , 30 ]. After challenging mosquitoes with an intrathoracic injection of a B .…”

Section: Resultsmentioning

confidence: 99%

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C-type lectin 4 regulates broad-spectrum melanization-based refractoriness to malaria parasites

et al. 2022

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Anopheles gambiae melanization-based refractoriness to the human malaria parasite Plasmodium falciparum has rarely been observed in either laboratory or natural conditions, in contrast to the rodent model malaria parasite Plasmodium berghei that can become completely melanized by a TEP1 complement-like system-dependent mechanism. Multiple studies have shown that the rodent parasite evades this defense by recruiting the C-type lectins CTL4 and CTLMA2, while permissiveness to the human malaria parasite was not affected by partial depletion of these factors by RNAi silencing. Using CRISPR/Cas9-based CTL4 knockout, we show that A. gambiae can mount melanization-based refractoriness to the human malaria parasite, which is independent of the TEP1 complement-like system and the major anti-Plasmodium immune pathway Imd. Our study indicates a hierarchical specificity in the control of Plasmodium melanization and proves CTL4 as an essential host factor for P. falciparum transmission and one of the most potent mosquito-encoded malaria transmission-blocking targets.

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Section: Resultsmentioning

confidence: 99%

“…B . bassiana is also an entomopathogenic fungus that has been developed into an ecologically friendly biopesticide for mosquito control [ 14 , 46 – 50 ]. The increased resistance of CTL4-deficient mosquitoes to both Plasmodium and B .…”

Section: Discussionmentioning

confidence: 99%

C-type lectin 4 regulates broad-spectrum melanization-based refractoriness to malaria parasites

et al. 2022

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“…Nevertheless, we cannot exclude that the susceptibility to fungal infections in CLIPA28 kd mosquitoes may also be due to regulation of cSP cascades acting upstream of the mosquito Toll/Rel1 pathway, especially that the role of Rel1 in anti-fungal immunity has been established in A . gambiae [44] and Ae . aegypti [45].…”

Section: Resultsmentioning

confidence: 99%

The mosquito melanization response requires hierarchical activation of non-catalytic clip domain serine protease homologs

et al. 2019

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Serine protease cascades regulate important insect immune responses namely melanization and Toll pathway activation. An important component of these cascades are clip-domain serine protease homologs (cSPHs), which are non-catalytic, but essential for activating the enzyme prophenoloxidase (PPO) in the melanization response during septic infections. The activation of cSPHs requires their proteolytic cleavage, yet factors that control their activation and the complexity of their interactions within these cascades remain unclear. Here, we report the identification of CLIPA28 as a novel immune-related cSPH in the malaria vector Anopheles gambiae. Functional genetic analysis using RNA interference (RNAi) revealed that CLIPA28 is essential for the melanization of Plasmodium berghei parasites in refractory mosquitoes, and for mosquito resistance to fungal infections. We further show, using combined biochemical and genetic approaches, that CLIPA28 is member of a network of at least four cSPHs, whereby members are activated in a hierarchical manner following septic infections. Depletion of the complement-like protein TEP1 abolished the activation of this network after septic infections, whereas, depletion of the serine protease inhibitor 2 (SRPN2) triggered enhanced network activation, even in naïve mosquitoes, culminating in a dramatic reduction in cSPHs hemolymph levels, which paralleled that of PPO. Our data suggest that cSPHs are engaged in complex and multilayered interactions within serine protease cascades that regulate melanization, and identify TEP1 and SRPN2 as two master regulators of the cSPH network.

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“…coli . In support of this hypothesis, strong activation of the Toll immune pathway using RNAi has been shown to dramatically increase mosquito mortality in different mosquito species independent of an infection [41–43]. Though the mechanism is not understood, strong immune activation at the expense of other pathways is thought to impose resource constraints on the mosquito.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of a protease targeting the LRIM1/APL1C complex reveals specificity in complement-like pathway activation in Anopheles gambiae

et al. 2019

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The complement-like pathway of the African malaria mosquito Anopheles gambiae provides protection against infection by diverse pathogens. A functional requirement for a core set of proteins during infections by rodent and human malaria parasites, bacteria, and fungi suggests a similar mechanism operates against different pathogens. However, the extent to which the molecular mechanisms are conserved is unknown. In this study we probed the biochemical responses of complement-like pathway to challenge by the Gram-positive bacterium Staphyloccocus aureus . Western blot analysis of the hemolymph revealed that S . aureus challenge activates a TEP1 convertase-like activity and promotes the depletion of the protein SPCLIP1. S . aureus challenge did not lead to an apparent change in the abundance of the LRIM1/APL1C complex compared to challenge by the Gram-negative bacterium, Escherichia coli . Following up on this observation using a panel of LRIM1 and APL1C antibodies, we found that E . coli challenge, but not S . aureus , specifically activates a protease that cleaves the C-terminus of APL1C. Inhibitor studies in vivo and in vitro protease assays suggest that a serine protease is responsible for APL1C cleavage. This study reveals that despite different challenges converging on activation of a TEP1 convertase-like activity, the mosquito complement-like pathway also includes pathogen-specific reactions.

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The interplay between dose and immune system activation determines fungal infection outcome in the African malaria mosquito, Anopheles gambiae

Cited by 19 publications

References 77 publications

C-type lectin 4 regulates broad-spectrum melanization-based refractoriness to malaria parasites

C-type lectin 4 regulates broad-spectrum melanization-based refractoriness to malaria parasites

The mosquito melanization response requires hierarchical activation of non-catalytic clip domain serine protease homologs

Stimulation of a protease targeting the LRIM1/APL1C complex reveals specificity in complement-like pathway activation in Anopheles gambiae

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