Biology subjects

Tepa, A.

Publications and source records attributed to Tepa, A..

3 recordsLinked to original sources

bioRxiv2026

Transcriptomic profile of Anopheles gambiae Kisumu mosquitoes infected by neglected malaria parasite Plasmodium ovale from gametocyte-carriers in Cameroon

Successful transmission of malaria depends on the complex interactions between the Anopheles mosquito vector and the Plasmodium parasites. Plasmodium ovale, a neglected malaria parasite, successfully develops from ookinete to sporozoite within the Anopheles vector. To elucidate the molecular mechanisms underlying this interaction, we compared RNA-seq-based gene expression profiles of Anopheles gambiae infected with P. ovale and uninfected mosquitoes at 24 hours, 9 days, and 17 days post-infection. The results showed that 2,885 P. ovale transcripts were present only 24 hours after infection. During ookinete invasion (24 h post-infection), differential gene expression analyses revealed the up-regulation of genes related to metabolic processes and the down-regulation of genes associated with cytoskeletal activity in the mosquito. Notably, the non-immune genes with unspecific function AGAP003776, (Fold Change, FC 132.0), AGAP003777, (FC 88.3), and AGAP003778, (FC 104.1), Troponin C (Fold Change, FC 85) and Myofilin (FC 33.3) exhibited the most significant overexpression. Among the immune genes that were upregulated CTL3 (FC 55.9), CLIPB12 (FC 49.4), CTLMA5 (FC 14.5), TRYP7 (FC 24.4), CLIP C9 (FC 12.1) TRYP5 (FC 12.2), LRIM10 (FC 11.2), PPO6 (FC 7.7). This initial analysis of the interaction between P. ovale and An. gambiae identified several well-known candidates for transmission-blocking strategies, including LRIM1, APN1, and D7 family proteins. In addition, new potential candidates, including AGAP003776, AGAP003777, and AGAP003778 cluster, CLIPB12, LRIM10, the APN cluster, AGAP004860, ABCC9, CYP9K1 and GSTD3 were identified. These potential new candidate genes could play a significant role in the development of transmission-blocking strategies for An. gambiae infected with Plasmodium, particularly P. ovale. The urgent functional validation of these genes is required.

microbiology↗

bioRxiv2025

A panel of CYP6Z genes drives broad-spectrum cross-resistance to public health insecticides in the major malaria vector An. gambiae s.s.

The spread of multiple and intense insecticide resistance in major African malaria vectors is jeopardising control efforts. Mitigating this threat requires deciphering its underlying molecular mechanisms. Here, by integrating transcriptomic profiling, analysis of genetic diversity and functional genomics approaches, we established the role of the CYP6Z genes in conferring multiple- and cross-resistance to insecticides. Investigation of CYP6Z gene expression and genetic diversity analyses indicate that resistance is primarily associated with transcriptional upregulation rather than fixed coding mutations since no predominant haplotype was selected. Structural characterisation reveals a flexible, promiscuous active site in CYP6Z enzymes, enabling binding of multiple insecticide classes. In vitro functional validation confirms that recombinant CYP6Z3 efficiently metabolizes deltamethrin (percentage depletion of 59%), permethrin (52%), -cypermethrin (37%), pirimiphos-methyl (36%), fenitrothion (25%), propoxur (25%), and possibly bendiocarb (17%). RNAi-mediated knockdown of CYP6Z genes in field-collected An. gambiae s.s. restores susceptibility to several insecticides including clothianidin: dsCYP6Z1 (mortality = 50.29%; p < 0.01), dsCYP6Z2 (47.28%; p < 0.01) and dsCYP6Z3 (39.12%; p < 0.05) compared to the control (mortality = 27.67%). Furthermore, transgenic expression in Drosophila melanogaster flies revealed that expression of CYP6Z genes alone confer cross-resistance to pyrethroids, organophosphates, carbamates and neonicotinoids, but increases susceptibility to the pro-insecticide chlorfenapyr: CYP6Z1 (mortality = 100%; p < 0.01), CYP6Z3 (98.18%; p < 0.01), and CYP6Z4 (98.01%; p < 0.01) vs. control (88.03%). This study establishes An. gambiae CYP6Z genes operate in concert to drive a broad-spectrum metabolic resistance, towards several classes of public health insecticides, while in contrast bioactivating chlorfenapyr to its more insecticidally active metabolite.

molecular biology↗

bioRxiv2024

A single E205D allele of a key P450 CYP6P3 is driving metabolic pyrethroid resistance in the major African malaria vector Anopheles gambiae

Deciphering the molecular drivers of insecticide resistance is paramount to extend the effectiveness of malaria vector control tools. Here, we demonstrated that the E205D amino acid change in a key metabolic resistance P450 CYP6P3 drives pyrethroid resistance in the major malaria vector, Anopheles gambiae. Spatio-temporal whole genome Poolseq analyses in Cameroon detected a major P450-linked locus on chromosome 2R beside the sodium channel locus. In vitro metabolism assays with recombinantly expressed CYP6P3 protein revealed that the catalytic efficiency of 205D was 2.5 times higher than E205 with -cypermethrin. Similar patterns were observed for permethrin. Overexpression of the 205D allele in transgenic flies confers higher more pyrethroids and carbamates resistance, compared to controls. A DNA-based assay further supported that the CYP6P3-205D variant strongly correlates with pyrethroid resistance in field populations (OR=26.4; P<0.0001) and that it reduces the efficacy of pyrethroid-only LLINs with homozygote RR genotype exhibiting significantly higher survival following PermaNet 3.0 exposure compared to the SS genotype (OR: 6.1, p = 0.0113). Furthermore, the CYP6P3-E205D combines with the kdr target-site resistance mechanisms to worsen the loss of bednet efficacy. The 205D mutation is now predominant in West and Central Africa but less abundant or absent in East and South Africa with signs of introgression with An. coluzzii in Ghana. This study highlights the importance of P450-based resistance and designs field-applicable tools to easily track the spread of metabolic resistance and assess its impact on control interventions. One Sentence Summary: The major obstacle to malaria control and elimination is the spread of parasite resistance to anti-malarial drugs, and mosquito resistance to insecticides. In this study, we identified a key point mutation E205D in the metabolic gene CYP6P3 (cytochrome P450) conferring resistance to pyrethroids by enhancing the breakdown of insecticides used for bednets impregnation. DNA-based assays were then designed and used to determine the spread of the resistance across Africa and demonstrate that the CYP6P3-205D allele works together with the knockdown resistance in the voltage-gated Sodium channel to reduce the efficacy of insecticide-treated bednets.

genomics↗