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Molecular Biology of Disease Vectors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 30166

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Special Issue Editor

Dr. Michail Kotsyfakis

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Guest Editor

Institute of Parasitology, Biology Center of the Czech Academy of Sciences, 37005 Budweis (Ceske Budejovice), Czech Republic
Interests: biology of disease vectors; ectoparasite/host interaction; protease inhibitors; cystatin; arthropod; transcriptomics; proteomics; arthropod saliva; immunomodulation; hemostasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Arthropod disease vectors transmit not only serious diseases like malaria, but many other diseases as well, many of which are neglected to various extents. In most cases, a tripartite interaction is involved between the arthropod disease vector, the vertebrate host, and the vector-borne pathogens. The aim of this Special issue is to collect the latest data (and up to date information in the case of reviews) about the molecular and biochemical events that mediate this tripartite interaction. The contribution of data (coming for example from systems biology and molecular biology/biochemical approaches or reviews) is anticipated to improve our knowledge of the biology of any of the three key partners involved in vector-borne disease transmission, and/or of their intimate interactions. Specific subtopics to be included in this Special issue, but our interest is not limited to these subtopics, are the following: disease vector–vertebrate host interactions, vector-borne pathogen interactions with the disease vector and the vertebrate host, molecular biology/microbiology of arthropod-borne pathogens, vertebrate host response to arthropod-borne pathogens, and molecular biology of disease vectors (e.g. arthropod immunity, blood meal digestion, oogenesis/reproduction, olfaction and other sensory cues, and insecticide resistance).

Dr. Michail Kotsyfakis
Guest Editor

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Keywords

disease vector biology
arthropod
vector-borne disease
hematophagy
immune response to vector-borne pathogens
arthropod immunity
disease vector–pathogen interaction
disease vector–vertebrate host interactions
disease transmission
disease vector development
insecticide resistance

Published Papers (12 papers)

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Editorial

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3 pages, 193 KiB

Open AccessEditorial

Editorial: Special Issue on the “Molecular Biology of Disease Vectors”

by Michail Kotsyfakis

Int. J. Mol. Sci. 2023, 24(3), 2881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032881 - 02 Feb 2023

Viewed by 1087

Abstract

Arthropod disease vectors not only transmit malaria but many other serious diseases, many of which are, to a greater or lesser degree, neglected [...] Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

Research

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21 pages, 678 KiB

Open AccessArticle

A Deeper Insight into the Tick Salivary Protein Families under the Light of Alphafold2 and Dali: Introducing the TickSialoFam 2.0 Database

by Ben J. Mans, John F. Andersen and José M. C. Ribeiro

Int. J. Mol. Sci. 2022, 23(24), 15613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415613 - 09 Dec 2022

Cited by 6 | Viewed by 1267

Abstract

Hard ticks feed for several days or weeks on their hosts and their saliva contains thousands of polypeptides belonging to dozens of families, as identified by salivary transcriptomes. Comparison of the coding sequences to protein databases helps to identify putative secreted proteins and their potential functions, directing and focusing future studies, usually done with recombinant proteins that are tested in different bioassays. However, many families of putative secreted peptides have a unique character, not providing significant matches to known sequences. The availability of the Alphafold2 program, which provides in silico predictions of the 3D polypeptide structure, coupled with the Dali program which uses the atomic coordinates of a structural model to search the Protein Data Bank (PDB) allows another layer of investigation to annotate and ascribe a functional role to proteins having so far being characterized as “unique”. In this study, we analyzed the classification of tick salivary proteins under the light of the Alphafold2/Dali programs, detecting novel protein families and gaining new insights relating the structure and function of tick salivary proteins. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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15 pages, 2106 KiB

Open AccessArticle

The First Molecular Detection of Aedes albopictus in Sudan Associates with Increased Outbreaks of Chikungunya and Dengue

by Ayman Ahmed, Mustafa Abubakr, Hamza Sami, Isam Mahdi, Nouh S. Mohamed and Jakob Zinsstag

Int. J. Mol. Sci. 2022, 23(19), 11802; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911802 - 05 Oct 2022

Cited by 10 | Viewed by 2319

Abstract

As part of our surveys of the invasive malaria vector Anopheles stephensi in four Sudanese states, including North and South Kordofan, Sennar, and White Nile, we collected 166 larvae. Our morphological identification confirmed that 30% of the collected mosquito samples were Anopheles species, namely An. gambiae s.l. and An. stephensi, while the 117 Aedes specimens were Ae. luteocephalus (39%), Ae. aegypti (32%), Ae. vexans (9%), Ae. vittatus (9%), Ae. africanus (6%), Ae. metalicus (3%), and Ae. albopictus (3%). Considering the serious threat of Ae. albopictus emergence for the public health in the area and our limited resources, we prioritized Ae. albopictus samples for further genomic analysis. We extracted the DNA from the three specimens and subsequently sequenced the cytochrome oxidase 1 (CO1) gene and confirmed their identity as Aedes albopictus and their potential origin by phylogenetic and haplotype analyses. Aedes albopictus, originating from Southeast Asia, is an invasive key vector of chikungunya and dengue. This is the first report and molecular characterization of Ae. albopictus from Sudan. Our sequences cluster with populations from the Central African Republic and La Réunion. Worryingly, this finding associates with a major increase in chikungunya and dengue outbreaks in rural areas of the study region and might be linked to the mosquito’s spread across the region. The emergence of Ae. albopictus in Sudan is of serious public health concern and urges for the improvement of the vector surveillance and control system through the implementation of an integrated molecular xenosurveillance. The threat of major arboviral diseases in the region underlines the need for the institutionalization of the One Health strategy for the prevention and control of future pandemics. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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14 pages, 1728 KiB

Open AccessArticle

Bioinformatic Analysis of Ixodes ricinus Long Non-Coding RNAs Predicts Their Binding Ability of Host miRNAs

by José María Medina, Muhammad Nadeem Abbas, Chaima Bensaoud, Michael Hackenberg and Michail Kotsyfakis

Int. J. Mol. Sci. 2022, 23(17), 9761; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179761 - 28 Aug 2022

Cited by 8 | Viewed by 1512

Abstract

Ixodes ricinus ticks are distributed across Europe and are a vector of tick-borne diseases. Although I. ricinus transcriptome studies have focused exclusively on protein coding genes, the last decade witnessed a strong increase in long non-coding RNA (lncRNA) research and characterization. Here, we report for the first time an exhaustive analysis of these non-coding molecules in I. ricinus based on 131 RNA-seq datasets from three different BioProjects. Using this data, we obtained a consensus set of lncRNAs and showed that lncRNA expression is stable among different studies. While the length distribution of lncRNAs from the individual data sets is biased toward short length values, implying the existence of technical artefacts, the consensus lncRNAs show a more homogeneous distribution emphasizing the importance to incorporate data from different sources to generate a solid reference set of lncRNAs. KEGG enrichment analysis of host miRNAs putatively targeting lncRNAs upregulated upon feeding showed that these miRNAs are involved in several relevant functions for the tick-host interaction. The possibility that at least some tick lncRNAs act as host miRNA sponges was further explored by identifying lncRNAs with many target regions for a given host miRNA or sets of host miRNAs that consistently target lncRNAs together. Overall, our findings suggest that lncRNAs that may act as sponges have diverse biological roles related to the tick–host interaction in different tissues. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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19 pages, 2452 KiB

Open AccessArticle

Trypsin-like Inhibitor Domain (TIL)-Harboring Protein Is Essential for Aedes aegypti Reproduction

by Chinmay Vijay Tikhe, Victor Cardoso-Jaime, Shengzhang Dong, Natalie Rutkowski and George Dimopoulos

Int. J. Mol. Sci. 2022, 23(14), 7736; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147736 - 13 Jul 2022

Cited by 4 | Viewed by 2136

Abstract

Cysteine-rich trypsin inhibitor-like domain (TIL)-harboring proteins are broadly distributed in nature but remain understudied in vector mosquitoes. Here we have explored the biology of a TIL domain-containing protein of the arbovirus vector Aedes aegypti, cysteine-rich venom protein 379 (CRVP379). CRVP379 was previously shown to be essential for dengue virus infection in Ae. aegypti mosquitoes. Gene expression analysis showed CRVP379 to be highly expressed in pupal stages, male testes, and female ovaries. CRVP379 expression is also increased in the ovaries at 48 h post-blood feeding. We used CRISPR-Cas9 genome editing to generate two mutant lines of CRVP379 with mutations inside or outside the TIL domain. Female mosquitoes from both mutant lines showed severe defects in their reproductive capability; mutant females also showed differences in their follicular cell morphology. However, the CRVP379 line with a mutation outside the TIL domain did not affect male reproductive performance, suggesting that some CRVP379 residues may have sexually dimorphic functions. In contrast to previous reports, we did not observe a noticeable difference in dengue virus infection between the wild-type and any of the mutant lines. The importance of CRVP379 in Ae. aegypti reproductive biology makes it an interesting candidate for the development of Ae. aegypti population control methods. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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22 pages, 3775 KiB

Open AccessArticle

MAEBL Contributes to Plasmodium Sporozoite Adhesiveness

by Mónica Sá, David Mendes Costa, Ana Rafaela Teixeira, Begoña Pérez-Cabezas, Pauline Formaglio, Sylvain Golba, Hélèna Sefiane-Djemaoune, Rogerio Amino and Joana Tavares

Int. J. Mol. Sci. 2022, 23(10), 5711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105711 - 20 May 2022

Cited by 4 | Viewed by 1977

Abstract

The sole currently approved malaria vaccine targets the circumsporozoite protein—the protein that densely coats the surface of sporozoites, the parasite stage deposited in the skin of the mammalian host by infected mosquitoes. However, this vaccine only confers moderate protection against clinical diseases in children, impelling a continuous search for novel candidates. In this work, we studied the importance of the membrane-associated erythrocyte binding-like protein (MAEBL) for infection by Plasmodium sporozoites. Using transgenic parasites and live imaging in mice, we show that the absence of MAEBL reduces Plasmodium berghei hemolymph sporozoite infectivity to mice. Moreover, we found that maebl knockout (maebl-) sporozoites display reduced adhesion, including to cultured hepatocytes, which could contribute to the defects in multiple biological processes, such as in gliding motility, hepatocyte wounding, and invasion. The maebl- defective phenotypes in mosquito salivary gland and liver infection were reverted by genetic complementation. Using a parasite line expressing a C-terminal myc-tagged MAEBL, we found that MAEBL levels peak in midgut and hemolymph parasites but drop after sporozoite entry into the salivary glands, where the labeling was found to be heterogeneous among sporozoites. MAEBL was found associated, not only with micronemes, but also with the surface of mature sporozoites. Overall, our data provide further insight into the role of MAEBL in sporozoite infectivity and may contribute to the design of future immune interventions. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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16 pages, 2332 KiB

Open AccessArticle

Identification of microRNAs in the Lyme Disease Vector Ixodes scapularis

by Deepak Kumar, Latoyia P. Downs, Monica Embers, Alex Sutton Flynt and Shahid Karim

Int. J. Mol. Sci. 2022, 23(10), 5565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105565 - 16 May 2022

Cited by 3 | Viewed by 3157

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in many biological processes, including the immune pathways that control bacterial, parasitic, and viral infections. Pathogens probably modify host miRNAs to facilitate successful infection, so they might be useful targets for vaccination strategies. There are few data on differentially expressed miRNAs in the black-legged tick Ixodes scapularis after infection with Borrelia burgdorferi, the causative agent of Lyme disease in the United States. Small RNA sequencing and qRT-PCR analysis were used to identify and validate differentially expressed I. scapularis salivary miRNAs. Small RNA-seq yielded 133,465,828 (≥18 nucleotides) and 163,852,135 (≥18 nucleotides) small RNA reads from Borrelia-infected and uninfected salivary glands for downstream analysis using the miRDeep2 algorithm. As such, 254 miRNAs were identified across all datasets, 25 of which were high confidence and 51 low confidence known miRNAs. Further, 23 miRNAs were differentially expressed in uninfected and infected salivary glands: 11 were upregulated and 12 were downregulated upon pathogen infection. Gene ontology and network analysis of target genes of differentially expressed miRNAs predicted roles in metabolic, cellular, development, cellular component biogenesis, and biological regulation processes. Several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including sphingolipid metabolism; valine, leucine and isoleucine degradation; lipid transport and metabolism; exosome biogenesis and secretion; and phosphate-containing compound metabolic processes, were predicted as targets of differentially expressed miRNAs. A qRT-PCR assay was utilized to validate the differential expression of miRNAs. This study provides new insights into the miRNAs expressed in I. scapularis salivary glands and paves the way for their functional manipulation to prevent or treat B. burgdorferi infection. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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22 pages, 4750 KiB

Open AccessArticle

Aedes aegypti Piwi4 Structural Features Are Necessary for RNA Binding and Nuclear Localization

by Adeline E. Williams, Gaurav Shrivastava, Apostolos G. Gittis, Sundar Ganesan, Ines Martin-Martin, Paola Carolina Valenzuela Leon, Ken E. Olson and Eric Calvo

Int. J. Mol. Sci. 2021, 22(23), 12733; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312733 - 25 Nov 2021

Cited by 7 | Viewed by 2464

Abstract

The PIWI-interacting RNA (piRNA) pathway provides an RNA interference (RNAi) mechanism known from Drosophila studies to maintain the integrity of the germline genome by silencing transposable elements (TE). Aedes aegypti mosquitoes, which are the key vectors of several arthropod-borne viruses, exhibit an expanded repertoire of Piwi proteins involved in the piRNA pathway, suggesting functional divergence. Here, we investigate RNA-binding dynamics and subcellular localization of A. aegypti Piwi4 (AePiwi4), a Piwi protein involved in antiviral immunity and embryonic development, to better understand its function. We found that AePiwi4 PAZ (Piwi/Argonaute/Zwille), the domain that binds the 3′ ends of piRNAs, bound to mature (3′ 2′ O-methylated) and unmethylated RNAs with similar micromolar affinities (K_D = 1.7 ± 0.8 μM and K_D of 5.0 ± 2.2 μM, respectively; p = 0.05) in a sequence independent manner. Through site-directed mutagenesis studies, we identified highly conserved residues involved in RNA binding and found that subtle changes in the amino acids flanking the binding pocket across PAZ proteins have significant impacts on binding behaviors, likely by impacting the protein secondary structure. We also analyzed AePiwi4 subcellular localization in mosquito tissues. We found that the protein is both cytoplasmic and nuclear, and we identified an AePiwi4 nuclear localization signal (NLS) in the N-terminal region of the protein. Taken together, these studies provide insights on the dynamic role of AePiwi4 in RNAi and pave the way for future studies aimed at understanding Piwi interactions with diverse RNA populations. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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18 pages, 2303 KiB

Open AccessArticle

Ixodes ricinus Salivary Serpin Iripin-8 Inhibits the Intrinsic Pathway of Coagulation and Complement

by Jan Kotál, Stéphanie G. I. Polderdijk, Helena Langhansová, Monika Ederová, Larissa A. Martins, Zuzana Beránková, Adéla Chlastáková, Ondřej Hajdušek, Michail Kotsyfakis, James A. Huntington and Jindřich Chmelař

Int. J. Mol. Sci. 2021, 22(17), 9480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179480 - 31 Aug 2021

Cited by 12 | Viewed by 2787

Abstract

Tick saliva is a rich source of antihemostatic, anti-inflammatory, and immunomodulatory molecules that actively help the tick to finish its blood meal. Moreover, these molecules facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-8, a salivary serpin from the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Iripin-8 displayed blood-meal-induced mRNA expression that peaked in nymphs and the salivary glands of adult females. Iripin-8 inhibited multiple proteases involved in blood coagulation and blocked the intrinsic and common pathways of the coagulation cascade in vitro. Moreover, Iripin-8 inhibited erythrocyte lysis by complement, and Iripin-8 knockdown by RNA interference in tick nymphs delayed the feeding time. Finally, we resolved the crystal structure of Iripin-8 at 1.89 Å resolution to reveal an unusually long and rigid reactive center loop that is conserved in several tick species. The P1 Arg residue is held in place distant from the serpin body by a conserved poly-Pro element on the P′ side. Several PEG molecules bind to Iripin-8, including one in a deep cavity, perhaps indicating the presence of a small-molecule binding site. This is the first crystal structure of a tick serpin in the native state, and Iripin-8 is a tick serpin with a conserved reactive center loop that possesses antihemostatic activity that may mediate interference with host innate immunity. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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18 pages, 18581 KiB

Open AccessArticle

Mialostatin, a Novel Midgut Cystatin from Ixodes ricinus Ticks: Crystal Structure and Regulation of Host Blood Digestion

by Jan Kotál, Michal Buša, Veronika Urbanová, Pavlína Řezáčová, Jindřich Chmelař, Helena Langhansová, Daniel Sojka, Michael Mareš and Michail Kotsyfakis

Int. J. Mol. Sci. 2021, 22(10), 5371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105371 - 20 May 2021

Cited by 8 | Viewed by 2593

Abstract

The hard tick Ixodes ricinus is a vector of Lyme disease and tick-borne encephalitis. Host blood protein digestion, essential for tick development and reproduction, occurs in tick midgut digestive cells driven by cathepsin proteases. Little is known about the regulation of the digestive proteolytic machinery of I. ricinus. Here we characterize a novel cystatin-type protease inhibitor, mialostatin, from the I. ricinus midgut. Blood feeding rapidly induced mialostatin expression in the gut, which continued after tick detachment. Recombinant mialostatin inhibited a number of I. ricinus digestive cysteine cathepsins, with the greatest potency observed against cathepsin L isoforms, with which it co-localized in midgut digestive cells. The crystal structure of mialostatin was determined at 1.55 Å to explain its unique inhibitory specificity. Finally, mialostatin effectively blocked in vitro proteolysis of blood proteins by midgut cysteine cathepsins. Mialostatin is likely to be involved in the regulation of gut-associated proteolytic pathways, making midgut cystatins promising targets for tick control strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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Review

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17 pages, 1165 KiB

Open AccessReview

Arboviruses: How Saliva Impacts the Journey from Vector to Host

by Christine A. Schneider, Eric Calvo and Karin E. Peterson

Int. J. Mol. Sci. 2021, 22(17), 9173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179173 - 25 Aug 2021

Cited by 15 | Viewed by 6510

Abstract

Arthropod-borne viruses, referred to collectively as arboviruses, infect millions of people worldwide each year and have the potential to cause severe disease. They are predominately transmitted to humans through blood-feeding behavior of three main groups of biting arthropods: ticks, mosquitoes, and sandflies. The pathogens harbored by these blood-feeding arthropods (BFA) are transferred to animal hosts through deposition of virus-rich saliva into the skin. Sometimes these infections become systemic and can lead to neuro-invasion and life-threatening viral encephalitis. Factors intrinsic to the arboviral vectors can greatly influence the pathogenicity and virulence of infections, with mounting evidence that BFA saliva and salivary proteins can shift the trajectory of viral infection in the host. This review provides an overview of arbovirus infection and ways in which vectors influence viral pathogenesis. In particular, we focus on how saliva and salivary gland extracts from the three dominant arbovirus vectors impact the trajectory of the cellular immune response to arbovirus infection in the skin. Full article

(This article belongs to the Special Issue Molecular Biology of Disease Vectors)

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