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Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.

Niu G, Wang B, Zhang G, King JB, Cichewicz RH, Li J - Sci Rep (2015)

Bottom Line: The inhibition specificity was confirmed by immunofluorescence assays.Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes.Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.

ABSTRACT
Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

No MeSH data available.


Related in: MedlinePlus

Isolate Chapel SA-3 colonies and spores.The fungus was grown on potato dextrose agar in a petri dish (a) and observed under the light microscope at 4X, and 40X magnification ((b,c), respectively). The spores were separated and examined at 100X magnification (d).
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f5: Isolate Chapel SA-3 colonies and spores.The fungus was grown on potato dextrose agar in a petri dish (a) and observed under the light microscope at 4X, and 40X magnification ((b,c), respectively). The spores were separated and examined at 100X magnification (d).

Mentions: We examined the morphology of the fungus using microscopy and identified the fungal species by molecular analyses. The fungus has very dark green, almost black spores. Based on the morphological observation shown in Fig. 5, we classified the fungus to the genus of Aspergillus Section Nigri (i.e., the black aspergilli). Thus, we sought to identify the fungus species by molecular analyses using PCR sequencing with standard internal transcribed spacer region (ITS) primers. We extracted the fungal genomic DNA, PCR-amplified the ITS DNA fragment using the fungal genomic DNA as templates, and sequenced the PCR product. The sequence was found to be 99% identical to A. niger, as well as its cryptic phylogenetic species A. foetidus, and A. awamori31 in the NCBI database. Considering the fungus morphology and its ITS PCR sequence, the fungus belongs to A. niger aggregate strains.


Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.

Niu G, Wang B, Zhang G, King JB, Cichewicz RH, Li J - Sci Rep (2015)

Isolate Chapel SA-3 colonies and spores.The fungus was grown on potato dextrose agar in a petri dish (a) and observed under the light microscope at 4X, and 40X magnification ((b,c), respectively). The spores were separated and examined at 100X magnification (d).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4593950&req=5

f5: Isolate Chapel SA-3 colonies and spores.The fungus was grown on potato dextrose agar in a petri dish (a) and observed under the light microscope at 4X, and 40X magnification ((b,c), respectively). The spores were separated and examined at 100X magnification (d).
Mentions: We examined the morphology of the fungus using microscopy and identified the fungal species by molecular analyses. The fungus has very dark green, almost black spores. Based on the morphological observation shown in Fig. 5, we classified the fungus to the genus of Aspergillus Section Nigri (i.e., the black aspergilli). Thus, we sought to identify the fungus species by molecular analyses using PCR sequencing with standard internal transcribed spacer region (ITS) primers. We extracted the fungal genomic DNA, PCR-amplified the ITS DNA fragment using the fungal genomic DNA as templates, and sequenced the PCR product. The sequence was found to be 99% identical to A. niger, as well as its cryptic phylogenetic species A. foetidus, and A. awamori31 in the NCBI database. Considering the fungus morphology and its ITS PCR sequence, the fungus belongs to A. niger aggregate strains.

Bottom Line: The inhibition specificity was confirmed by immunofluorescence assays.Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes.Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.

ABSTRACT
Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.

No MeSH data available.


Related in: MedlinePlus