Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing
ABSTRACT Plasmodium parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite’s life cycle in the vertebrate host and transmission to a mosquito vector is contingent upon the ability of the parasite to evade...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.04493-22 |
| _version_ | 1827150035518750720 |
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| author | Medard Ernest Thiago F. A. Rosa Zarna Rajeshkumar Pala Heather M. Kudyba Brendan Sweeney Timo Reiss Gabriele Pradel Joel Vega-Rodríguez |
| author_facet | Medard Ernest Thiago F. A. Rosa Zarna Rajeshkumar Pala Heather M. Kudyba Brendan Sweeney Timo Reiss Gabriele Pradel Joel Vega-Rodríguez |
| author_sort | Medard Ernest |
| collection | DOAJ |
| description | ABSTRACT Plasmodium parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite’s life cycle in the vertebrate host and transmission to a mosquito vector is contingent upon the ability of the parasite to evade the host’s defenses. The extracellular stages of the parasite, including gametes and sporozoites, must evade complement attack in both the mammalian host and in the blood ingested by the mosquito vector. Here, we show that Plasmodium falciparum gametes and sporozoites acquire mammalian plasminogen and activate it into the serine protease plasmin to evade complement attack by degrading C3b. Complement-mediated permeabilization of gametes and sporozoites was higher in plasminogen-depleted plasma, suggesting that plasminogen is important for complement evasion. Plasmin also facilitates gamete exflagellation through complement evasion. Furthermore, supplementing serum with plasmin significantly increased parasite infectivity to mosquitoes and lowered the transmission-blocking activity of antibodies to Pfs230, a potent vaccine candidate currently in clinical trials. Finally, we show that human factor H, previously shown to facilitate complement evasion by gametes, also facilitates complement evasion by sporozoites. Plasmin and factor H simultaneously cooperate to enhance complement evasion by gametes and sporozoites. Taken together, our data show that Plasmodium falciparum gametes and sporozoites hijack the mammalian serine protease plasmin to evade complement attack by degrading C3b. Understanding of the mechanisms of complement evasion by the parasite is key to the development of novel effective therapeutics. IMPORTANCE Current approaches to control malaria are complicated by the development of antimalarial-resistant parasites and insecticide-resistant vectors. Vaccines that block transmission to mosquitoes and humans are a plausible alternative to overcome these setbacks. To inform the development of efficacious vaccines, it is imperative to understand how the parasite interacts with the host immune response. In this report, we show that the parasite can co-opt host plasmin, a mammalian fibrinolytic protein to evade host complement attack. Our results highlight a potential mechanism that may reduce efficacy of potent vaccine candidates. Taken together, our results will inform future studies in developing novel antimalarial therapeutics. |
| first_indexed | 2024-03-13T05:20:03Z |
| format | Article |
| id | doaj.art-4b070be639a24e2da5a5fc7d4135b9c4 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2025-03-20T21:27:41Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-4b070be639a24e2da5a5fc7d4135b9c42024-08-11T19:21:26ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.04493-22Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement KillingMedard Ernest0Thiago F. A. Rosa1Zarna Rajeshkumar Pala2Heather M. Kudyba3Brendan Sweeney4Timo Reiss5Gabriele Pradel6Joel Vega-Rodríguez7Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USADivision of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Aachen, GermanyLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USALaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USALaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USADivision of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Aachen, GermanyDivision of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Aachen, GermanyLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USAABSTRACT Plasmodium parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite’s life cycle in the vertebrate host and transmission to a mosquito vector is contingent upon the ability of the parasite to evade the host’s defenses. The extracellular stages of the parasite, including gametes and sporozoites, must evade complement attack in both the mammalian host and in the blood ingested by the mosquito vector. Here, we show that Plasmodium falciparum gametes and sporozoites acquire mammalian plasminogen and activate it into the serine protease plasmin to evade complement attack by degrading C3b. Complement-mediated permeabilization of gametes and sporozoites was higher in plasminogen-depleted plasma, suggesting that plasminogen is important for complement evasion. Plasmin also facilitates gamete exflagellation through complement evasion. Furthermore, supplementing serum with plasmin significantly increased parasite infectivity to mosquitoes and lowered the transmission-blocking activity of antibodies to Pfs230, a potent vaccine candidate currently in clinical trials. Finally, we show that human factor H, previously shown to facilitate complement evasion by gametes, also facilitates complement evasion by sporozoites. Plasmin and factor H simultaneously cooperate to enhance complement evasion by gametes and sporozoites. Taken together, our data show that Plasmodium falciparum gametes and sporozoites hijack the mammalian serine protease plasmin to evade complement attack by degrading C3b. Understanding of the mechanisms of complement evasion by the parasite is key to the development of novel effective therapeutics. IMPORTANCE Current approaches to control malaria are complicated by the development of antimalarial-resistant parasites and insecticide-resistant vectors. Vaccines that block transmission to mosquitoes and humans are a plausible alternative to overcome these setbacks. To inform the development of efficacious vaccines, it is imperative to understand how the parasite interacts with the host immune response. In this report, we show that the parasite can co-opt host plasmin, a mammalian fibrinolytic protein to evade host complement attack. Our results highlight a potential mechanism that may reduce efficacy of potent vaccine candidates. Taken together, our results will inform future studies in developing novel antimalarial therapeutics.https://journals.asm.org/doi/10.1128/spectrum.04493-22complementcomplement evasiongametemalariaplasminsporozoite |
| spellingShingle | Medard Ernest Thiago F. A. Rosa Zarna Rajeshkumar Pala Heather M. Kudyba Brendan Sweeney Timo Reiss Gabriele Pradel Joel Vega-Rodríguez Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing Microbiology Spectrum complement complement evasion gamete malaria plasmin sporozoite |
| title | Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing |
| title_full | Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing |
| title_fullStr | Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing |
| title_full_unstemmed | Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing |
| title_short | Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing |
| title_sort | plasmodium falciparum gametes and sporozoites hijack plasmin and factor h to evade host complement killing |
| topic | complement complement evasion gamete malaria plasmin sporozoite |
| url | https://journals.asm.org/doi/10.1128/spectrum.04493-22 |
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