Biology subjects

McDowell, M. A.

Publications and source records attributed to McDowell, M. A..

6 recordsLinked to original sources

bioRxiv2025

SND3 is the membrane insertase within a fungal multipass translocon

During the biogenesis of most eukaryotic integral membrane proteins (IMPs), transmembrane domains are inserted into the endoplasmic reticulum membrane by a dedicated insertase or the SEC61 translocon. The SRP-independent (SND) pathway is the least understood route into the membrane, despite catering for a broad range of IMP types. Here, we show that Chaetomium thermophilum SND3 is a membrane insertase of novel fold. We further present a cryo-electron microscopy structure of a ribosome-associated SND3 translocon complex involved in co-translational IMP insertion. The structure reveals that the SND3 translocon additionally comprises the complete SEC61 translocon, CCDC47 and TRAP[a]. Here, the SEC61{beta} N-terminus works together with CCDC47 to prevent substrate access to the translocon. Instead, molecular dynamics simulations show that SND3 disrupts the lipid bilayer to promote IMP insertion via its membrane-embedded hydrophilic groove. Structural and sequence comparisons indicate that the SND3 translocon is a distinct multipass translocon for the insertion of multipass IMPs in fungi, euglenozoan parasites and other eukaryotic taxa.

biophysics↗

bioRxiv2025

Structures of Chaetomium thermophilum TOM complexes with bound preproteins

Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits, and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complex from the thermophilic fungus Chaetomium thermophilum, obtained by single-particle electron cryomicroscopy. Our structures reveal the symmetric arrangement of two copies of the Tom20 receptor subunit in the TOM holo complex. Several different conformations of Tom20 within the TOM holo complex highlight the dynamic nature of the receptor. The structure of preprotein-bound Tom20 provides insight into the early stages of protein translocation.

biophysics↗

bioRxiv2025

Prediction of mosquito vector abundance for threespecies in the Anopheles gambiae complex

BackgroundThe dynamics of vector borne disease transmission depend on the abundances of vectors. The dominant malaria vector species complex of Anopheles gambiae sensu lato is a target of vector control strategies designed to reduce and eliminate malaria transmission. The three most widely distributed dominant malaria vectors within the species complex are An. arabiensis, An. coluzzii and An. gambiae sensu stricto. MethodsPrevious studies across the extent of the species complex range have been restricted to annual predictions of species occurrence or relative abundance. This study incorporated relative abundance data at the species level and abundance data at the species complex level to estimate and predict daily equilibrium vector abundances of each species. Statistical models with interpretable parameters were used to gain insight into how factors such as meteorological conditions, insecticide treated net use, and human density affect the spatial and temporal predictions. The statistical models were used to predict daily equilibrium vector abundance that is an important factor in indices of malaria transmission such as the basic reproduction number and vectorial capacity. ResultsMeteorological factors, such as precipitation and relative humidity, and human factors, such as population density and insecticide treated nets, were important predictors of these three malaria vector species in Africa. Insecticide treated net use was negatively associated with per capita vector abundance of the An. gambiae species complex and interacted with year to suggest an a negative effect on the ratio of An. gambiae s.s. to An. arabiensis at the end of the prediction period that extended from 2002 to 2020. A predicted increasing interannual trend for An. coluzzii was potentially caused by changing species identification methods. ConclusionThe predicted equilibrium abundances of the three species showed potentially high levels of geographical overlap, niche overlap, and evidence for stable coexistence despite substantial interspecific competition. Improving collection of longitudinal species abundance data across the spatial range of the An. gambiae species complex will facilitate future explorations of causal hypotheses that relate vector abundance to control measures, malaria interventions and meteorological conditions.

ecology↗

bioRxiv2022

Genomic Analysis of Two Phlebotomine Sand Fly Vectors of Leishmania from the New and Old World

Phlebotomine sand flies are of global significance as important vectors of human disease, transmitting bacterial, viral, and protozoan pathogens, including the devastating kinetoplastid parasites of the genus Leishmania, the causative agents of diseases collectively termed leishmaniasis. More than 40 pathogenic Leishmania species are transmitted to humans by approximately 35 sand fly species in 98 countries with hundreds of millions of people at risk around the world. As no approved efficacious vaccine exists, available drugs are expensive and/or toxic, and resistance is emerging, management of sand fly populations to break transmission is currently the most effective disease control strategy. To better understand the biology of sand flies, including the mechanisms involved in their vectorial capacity, insecticide resistance, and population structures we sequenced the genomes of two of the most important sand fly species: Phlebotomus papatasi, a cutaneous leishmaniasis vector, (distributed in the Middle East and North Africa) and Lutzomyia longipalpis, a visceral leishmaniasis vector (distributed across Central and South America). We categorized and curated genes involved in processes important to their roles as disease vectors, including chemosensation, blood feeding, circadian rhythm, immunity, and detoxification, as well as mobile genetic elements. We also defined gene orthology and observed micro-synteny among the genomes. Finally, we present the genetic diversity and population structure of these species in their respective geographical areas. These genomes will be a foundation on which to base future efforts to prevent vector-borne transmission of Leishmania parasites. Author SummaryThe leishmaniases are a group of neglected tropical diseases caused by protist parasites from the Genus Leishmania. Different Leishmania species present a wide clinical profile, ranging from mild, often self-resolving cutaneous lesions that can lead to protective immunity, to severe metastatic mucosal disease, to visceral disease that is ultimately fatal. Leishmania parasites are transmitted by the bites of sand flies, and as no approved vaccine exists, available drugs are toxic and/or expensive and resistance is emerging, new dual control strategies to combat these diseases must be developed, combining interventions on human infections and integrated sand fly population management. Effective vector control requires a good understanding of the biology of sand flies. To this end, we sequenced and annotated the genomes of two sand fly species that are important leishmaniasis vectors from the Old and New Worlds. These genomes allow us to better understand, at the genetic level, processes important in the vector biology of these species, such as finding hosts, blood-feeding, immunity, and detoxification. These genomic resources highlight the driving forces of evolution of two major Leishmania vectors and provide foundations for future research on how to better prevent leishmaniasis by control of the sand fly vectors.

genomics↗

bioRxiv2020

Molecular signatures of sexual communication in the phlebotomine sand flies

Phlebotomine sand flies employ an elaborate system of pheromone communication wherein males produce pheromones that attracts other males to leks (thus acting as aggregation pheromone) and females to the lekking males (sex pheromone). In addition, the type of pheromone produced varies among populations. Despite the numerous studies on sand fly chemical communication, little is known of their chemosensory genome. Chemoreceptors interact with chemicals in an organisms environment to elicit essential behaviors such as the identification of suitable mates and food sources, thus, they play important roles during adaptation and speciation. Major chemoreceptor gene families, odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) together detect and discriminate the chemical landscape. Here, we annotated the chemoreceptor repertoire in the genomes of Lutzomyia longipalpis and Phlebotomus papatasi, major phlebotomine vectors in the New World and Old World, respectively. Comparison with other sequenced Diptera revealed a large and unique expansion where over 80% of the ~140 ORs belong to a single, taxonomically restricted clade. We next conducted comprehensive analysis of the chemoreceptors in 63 Lu. longipalpis individuals from four different locations in Brazil representing allopatric and sympatric populations and three aggregation-sex pheromone types (chemotypes). Population structure based on single nucleotide polymorphisms (SNPs) and gene copy number in the chemoreceptors corresponded with their putative chemotypes, and corroborate previous studies that identified multiple populations. Our work provides genomic insights into the underlying behavioral evolution of sexual communication in the L. longipalpis species complex in Brazil, and highlights the importance of accounting for the ongoing speciation in central and South American Lutzomyia that could have important implications for vectorial capacity.

evolutionary biology↗

bioRxiv2019

Phlebotomus papatasi sand fly salivary protein diversity and immune response potential in Egypt and Jordan populations

Phlebotomus papatasi sand flies inject their hosts with a myriad of pharmacologically active salivary proteins to assist with blood feeding and to modulate host defenses. These salivary proteins have been studied for their role in cutaneous leishmaniasis disease outcome with different salivary proteins attenuating or exacerbating lesion size. Studies have shown that while co-administered sand fly saliva exacerbates Leishmania major infections in naive mice, animals pre-exposed to saliva are protected, with the infection attenuated via a delayed-type hypersensitivity immune reaction. These studies highlight the potential of the salivary components to be used as a vaccine. One protein in particular, P. papatasi salivary protein 15 (PpSP15) has been intensively studied because of its ability to protect mice against Le. major challenge. The number of antigenic molecules included in vaccines is restricted thus emphasizing the role of population genetics to identify molecules, like PpSP15, that are functionally significant, conserved across populations and do not experience selection. Three distinct ecotope study sites, one in Egypt (Aswan) and two in Jordan (Swaimeh and Malka), were chosen based on their elevation, rainfall, vegetation, differing reservoir species, and the presence or absence of Le. major. The objective of this work was to analyze the genetic variability of nine of the most abundantly expressed salivary proteins including PpSP12, PpSP14, PpSP28, PpSP29, PpSP30, PpSP32, PpSP36, PpSP42, and PpSP44 and to predict their ability to elicit an immune response. Two proteins, PpSP12 and PpSP14, demonstrated low genetic variability across the three sand fly populations represented in this study, with multiple predicted MHCII epitope binding sites, identified by alleles present in the human populations from the study sites. The other seven salivary proteins revealed greater allelic variation across the same sand fly populations indicating that their use as vaccine targets may prove to be challenging.

genetics↗