Vector Signals Podcast Por Maddy Chang McDonough arte de portada

Vector Signals

Vector Signals

De: Maddy Chang McDonough
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 A private, AI-curated podcast delivering 15-20 minute deep dives into the latest Nature articles on mosquito-borne viruses and AI-driven therapeutic breakthroughs. Designed for the researchers of the Saleh Lab at Institut Pasteur, each episode distills cutting-edge science into accessible insights—so you can stay current, even during your busiest bench days.© 2025 Maddy Chang McDonough Ciencia Ciencias Biológicas
Episodios
  • Greenland Mosquito Virome: Arctic Aedes Uniqueness (May 2025)

    Greenland Mosquito Virome: Arctic Aedes Uniqueness (May 2025)
    May 30 2025
    Briefing Document: Unique Virome of Arctic Mosquitoes in GreenlandSource: https://doi.org/10.1038/s41598-025-01086-z: "Metagenomic analysis of mosquitoes from Kangerlussuaq, Greenland reveals a unique virome" by Schilling, Jagdev, Thomas, & Johnson (2025). Date: Received - 17 January 2025 | Accepted - 02 May 2025 | Published - 17 May 2025Subject: Metagenomic analysis of mosquito viromes in Kangerlussuaq, Greenland and implications in the context of climate change.Summary: This study provides the first metagenomic analysis of the virome of two prevalent Arctic mosquito species, Aedes impiger and Aedes nigripes, sampled near Kangerlussuaq, Greenland. The research employed next-generation sequencing (NGS) to identify viruses present in pooled mosquito samples collected in July 2022 and July 2023. The findings reveal a diverse and, importantly, a unique virome in these Arctic mosquitoes compared to other Aedes species. The study highlights the critical need to understand these viromes in light of climate change, which is significantly impacting Arctic ecosystems and potentially increasing the risk of vector-borne disease emergence and spread.Key Findings and Themes:Dominance of Aedes impiger: Contrary to previous assumptions that Aedes nigripes was the sole mosquito species in western Greenland, this study found Aedes impiger to be the predominant species collected at the Kangerlussuaq site.Fact: "Where a definitive identification could be made, A. impiger was the most frequently sampled mosquito at the Kangerlussuaq site."Fact: In 2023, "49 mosquitoes were identified as A. impiger (70%) and 16 as A. nigripes (23%)."Novel and Diverse Arctic Mosquito Virome: Metagenomic analysis identified a range of RNA viruses belonging to various families in both Aedes impiger and Aedes nigripes. Many of these viruses are novel and exhibit low sequence identity (sometimes as low as 34% at the amino acid level) when compared to previously published virus sequences from other mosquito species.Quote: "Metagenomic analysis of RNA extracted from species pools detected a number of novel RNA viruses belonging to a range of different virus families, including Flaviviridae, Orthomyxoviridae, Bunyavirales, Totiviridae and Rhabdoviridae."Quote: "However, the sequence identities when compared to previously published, were as low as 34% at the amino acid level."Fact: "Within the family of Flaviviridae, two novel flavi-like virus sequences were identified, with their polyproteins displaying 35% similarity to the nearest published polyprotein..."Fact: "Similarly, two novel orthomyxo-like sequences were identified within the family of Orthomoyxoviridae... Their nucleoprotein comprised only 36% identity to that of Byreska virus..."Fact: "Within the order of Bunyavirales, we discovered two novel phasiviruses as well as two novel phasmaviruses."Uniqueness of the Arctic Mosquito Virome: A significant finding is the distinct virome of Aedes impiger and Aedes nigripes compared to other Aedes species, particularly Aedes aegypti, which has the most well-characterized virome. Only a small percentage of the identified viruses overlapped with those found in other Aedes species.Quote: "To emphasize the uniqueness of the virome of A. impiger and A. nigripes, we compared our findings to a database of viruses published for other Aedes species... The heatmap... reveals that the majority of sequences derived from Greenland mosquitoes were unique to A. impiger and A. nigripes..."Fact: "...only 36 (of a total of 94, 38%) assigned viruses overlapping with viruses published for other Aedes spp."Fact: "Only 22 (23%) overlapped with Aedes aegypti..."Quote: "This makes the virome composition of A. cantans the most similar published virome composition to that of the mosquitoes we sampled near Kangerlussuaq."Influence of Climate Change on Arctic Vector Ecology: The study explicitly links its findings to the dramatic effects of climate change on Arctic ecosystems, including the potential for shifts in vector distribution and an increased likelihood of vector-borne disease emergence in previously unaffected areas.Quote: "Climate change is dramatically affecting vector ecology in extreme environments such as the Arctic."Quote: "Global changes in climate are causing a shift in the distribution of vectors and increasing the likelihood of vector-borne disease outbreaks in regions that have not experienced such disease emergence."Quote: "With rapid environmental change, and warming at twice the global average the ecology of Arctic insects will be dramatically affected."Potential for Zoonotic Transmission Risk: While the detected viruses are likely insect-specific, the study highlights the potential for Aedes impiger and Aedes nigripes to replicate viruses belonging to families with known zoonotic potential. The documented human feeding behavior of Aedes impiger further underscores this risk.Quote: "Our findings further support the capability of A. nigripes and A. ...
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    21 m
  • Novel Quinolones Counteract Insecticide Resistance in Malaria Vectors (May 2025)

    Novel Quinolones Counteract Insecticide Resistance in Malaria Vectors (May 2025)
    May 30 2025
    BRIEFING DOCUMENT: Novel Approach to Malaria Control Targeting Mosquito-Stage Plasmodium ParasitesDate: Received - 29 March 2025 | Accepted - 17 April 2025 | Published - 21 May 2025Source: Excerpts from "In vivo screen of Plasmodium targets for mosquito-based malaria control" by Probst et al. (Published online xx xx xxxx, Nature) https://doi.org/10.1038/s41586-025-09039-2Subject: Development and testing of novel antiparasitic compounds for incorporation into mosquito bed nets to combat insecticide resistance and reduce malaria transmission.Summary:This research presents a promising new strategy for malaria control by targeting the Plasmodium falciparum parasite directly within its mosquito vector (Anopheles species). Recognizing the growing challenge of insecticide resistance in mosquitoes, the study explores the potential of incorporating antiparasitic compounds into long-lasting insecticide-treated nets (LLINs). The authors performed an in vivo screen of 81 compounds, identifying 22 active against mosquito-stage parasites. Notably, endochin-like quinolones (ELQs) targeting the parasite's cytochrome bc1 complex (CytB) showed high potency and were further optimized through medicinal chemistry. Two lead ELQ compounds, ELQ-453 and ELQ-613, demonstrated potent, long-lasting activity when incorporated into bed net-like materials, including in insecticide-resistant mosquitoes. The study also highlights the potential of a dual-target strategy using a combination of Qo-site and Qi-site ELQ inhibitors to reduce the risk of resistance, as CytB mutants show impaired development in mosquitoes. This approach offers a complementary tool to existing malaria control strategies, particularly in areas with high insecticide resistance.Key Themes and Important Ideas/Facts:Malaria Burden and the Challenge of Insecticide Resistance:Malaria deaths have stalled in recent years, with an estimated 263 million cases and 597,000 deaths in 2023.Vector control, particularly LLINs, has been crucial in reducing malaria prevalence, but widespread insecticide resistance in Anopheles vectors is jeopardizing their effectiveness."The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)..."Targeting Mosquito-Stage Parasites as a Mitigation Strategy:Directly killing parasites during their mosquito-stage development by incorporating antiparasitic compounds into LLINs can prevent onward transmission, even if insecticides lose efficacy.This strategy avoids conferring fitness costs or selective pressure on the mosquito, thus preventing vector resistance to the antiparasitic compound."Interventions that directly target parasites in the mosquito represent a promising approach to disrupt parasite transmission and to reduce malaria burden...""Of note, the use of a Plasmodium-specific compound would not confer any fitness cost or selective pressure to the anopheline mosquito, which therefore avoids potential development of resistance by the vector."In Vivo Compound Screening and Identification of Key Targets:An in vivo screen of 81 antiplasmodial compounds with diverse modes of action was performed in Anopheles gambiae mosquitoes.22 compounds spanning seven distinct P. falciparum targets significantly reduced parasite infection (oocyst prevalence) in the mosquito midgut.Key identified targets included the ubiquinol oxidation (Qo) and ubiquinone reduction (Qi) sites of the P. falciparum cytochrome bc1 complex (CytB), the sodium-proton antiporter P-type ATPase 4 (ATP4), and eukaryotic elongation factor 2 (EF2)."This screen ultimately identified 22 compounds that significantly reduced parasite infection, and these compounds spanned seven P. falciparum targets..."Endochin-Like Quinolones (ELQs) as Lead Compounds:Endochin-like quinolones (ELQs) targeting CytB were among the most effective compounds in the topical screen.ELQ-456 (targeting the CytB Qo-site) completely inhibited infection in topical applications.ELQ-331 (targeting the CytB Qi-site) strongly reduced infection prevalence.Medicinal chemistry was used to improve the antiparasitic activity of ELQ hits, particularly for uptake via tarsal contact (mosquito legs).Tarsal Contact Activity and the Importance of Compound Structure:Tarsal contact assays, mimicking mosquito interaction with treated surfaces like bed nets, showed that most compounds active in topical application were inactive.Only ELQ-456 initially showed significant activity in tarsal contact assays.Modifications to the ELQ structure significantly enhanced tarsal-based efficacy. ELQ-453 (Qo-site inhibitor) and ELQ-613 (Qi-site inhibitor), with specific alkyl chain lengths, demonstrated potent activity after tarsal contact."Of the 13 compounds we tested in tarsal-contact assays, only our most potent hit in the topical screen, ELQ-456 (CytB Qo-site inhibitor) reduced infection (69.5% ...
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    25 m
  • Blocking Malaria Transmission with PfPIMMS43 Nanobodies (April 2025)

    Blocking Malaria Transmission with PfPIMMS43 Nanobodies (April 2025)
    May 3 2025
    Briefing Document: Nanobody-Mediated Blocking of Malaria Transmission Targeting PfPIMMS43Source: Excerpts from "s42003-025-08033-8.pdf" (A Nature Portfolio journal; https://doi.org/10.1038/s42003-025-08033-8) Authors: Chiamaka Valerie Ukegbu, et al. Date: Received - 04 December 2024 | Accepted - 02 April 2025 | Published - 30 April 2025Executive Summary:This study explores a novel strategy to block malaria transmission by targeting the Plasmodium falciparum protein PfPIMMS43 using single-domain VHH antibodies, also known as nanobodies. PfPIMMS43 is a critical surface protein for the parasite's development within the mosquito, specifically during the transition from ookinete to oocyst, and aids in evading the mosquito's immune response. Building on previous research demonstrating the potential of polyclonal antibodies against PfPIMMS43, this study successfully developed and characterized high-affinity nanobodies derived from llamas. These nanobodies were shown to significantly reduce both the intensity and prevalence of P. falciparum infection in Anopheles mosquitoes using both laboratory and field strains of the parasite. The study mapped the binding epitopes of the nanobodies to conserved regions in the second half of PfPIMMS43, confirming epitope accessibility. These findings establish PfPIMMS43 as a promising target for malaria transmission-blocking interventions and propose an innovative strategy utilizing genetically modified mosquitoes expressing these nanobodies in conjunction with gene drive technology for enhanced malaria control and elimination efforts.Key Themes and Important Ideas:Malaria Transmission as a Target: The study emphasizes the importance of targeting the parasite's development within the mosquito vector to interrupt the human-to-mosquito and mosquito-to-human transmission cycle. This is presented as a crucial approach to complement existing malaria control measures, especially in the face of challenges like insecticide failure, climate change, and funding limitations. The transition from ookinete to oocyst in the mosquito midgut is identified as a "key developmental bottleneck" for the parasite.PfPIMMS43 as a Critical Transmission Target: The research highlights PfPIMMS43 as an "indispensable" surface protein for P. falciparum ookinetes and sporozoites. It is crucial for the ookinete-to-oocyst transition and plays a role in the parasite's ability to "evade the mosquito immune responses," specifically the complement-like system in the hemolymph. Previous studies, including those by the authors, had already indicated the potential of polyclonal antibodies targeting this protein in reducing transmission.Nanobodies as a Promising Intervention Tool: The study focuses on the development and application of VHH domain nanobodies as an alternative and potentially superior approach to conventional antibodies for transmission blocking. Nanobodies, derived from camelids and sharks, are described as "smaller, more easily produced monoclonal, heavy-chain variable (VHH) domain antibodies." Their advantages include:"small size (~15 kDa)""structural simplicity""strong binding affinity"Easily bioengineered for targeting parasite antigens in mosquito vectors.Development and Characterization of PfPIMMS43 Nanobodies: High-affinity nanobodies targeting PfPIMMS43 were successfully generated by immunizing llamas with recombinant PfPIMMS43. Nine nanobodies were selected based on variations in their antigen-binding regions (CDR1-3). Four nanobodies (G9, E5, C12, and E2) exhibited high nanomolar binding affinities to recombinant PfPIMMS43 (3, 5, 6, and 8 nM, respectively). These four nanobodies were also able to detect endogenous PfPIMMS43 protein expressed by P. falciparum ookinetes in infected mosquito midguts.Significant Transmission Blocking Activity (TRA): The developed nanobodies demonstrated significant transmission-reducing activity in mosquito feeding assays.In standard membrane feeding assays (SMFAs) using laboratory P. falciparum NF54 and An. coluzzii mosquitoes, the four high-affinity nanobodies (G9, E5, C12, and E2) significantly reduced oocyst numbers at a concentration of 100 µg/ml, with reductions ranging from 83% to 99%. Oocyst reduction was concentration-dependent.In direct membrane feeding assays (DMFAs) using natural P. falciparum isolates from gametocytaemic children in Tanzania and local An. gambiae mosquitoes, G9 and E5 (the two nanobodies with the highest affinities to recombinant PfPIMMS43) also showed significant TRA, with reductions of 99% and 79% at 100 µg/ml, respectively. Both nanobodies significantly reduced mosquito infection prevalence in field conditions.Epitope Mapping and Structural Insights: Epitope mapping revealed that the four nanobodies bind to "conserved regions in the second half of PfPIMMS43," specifically beyond amino acid residue 258. This suggests the C-terminal half of the protein is more immunogenic. G9 and E5 appear to recognize similar conformational ...
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    13 m
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