Dataset Information

Transcriptional and proteomic dynamics of severe fever with thrombocytopenia syndrome virus infection in Rhipicephalus microplus cells identify antiviral host factors.

ABSTRACT: Ticks are vectors of arboviruses in many parts of the world. The rising incidence and emergence of tick-borne arboviral infections across human populations indicates that further transmission control strategies including those based on vectors, will be required to reduce the burden of disease. However, arbovirus-tick interactions at the cellular level remain poorly understood in general, and particularly neglected for negative strand RNA arboviruses. In this study we developed a proteomics informed by transcriptomics approach to characterize the cellular response of Rhipicephalus microplus-derived cell cultures to infection with the tick-borne pathogen severe fever with thrombocytopenia syndrome virus (SFTSV, Phenuiviridae). For this, we generated the first de novo transcriptomes and confirmed proteomes of SFTSV- or mock-infected tick cell cultures derived from a vector species that transmits the virus in nature. Through comprehensive annotation of genes, proteins and pathway analysis, we identified core host responses and regulatory processes mediated in response to SFTSV infection. Moreover, examining the interactome of the virally encoded nucleoprotein (N) allowed us to integrate host responses with the analysis of cellular factors required for viral replication. The influence of specific host genes on SFTSV replication was systematically assessed through dsRNA-mediated gene silencing. This functional genomics approach pinpointed two tick-derived RNA helicases as critical antiviral factors capable of restricting SFTSV infection: the DexD/box helicase (DHX9) and the Up-Frameshift Protein 1 (UPF1). Collectively, our findings enrich the repository of resources available for understanding the antiviral response to SFTSV infection in Rh. microplus vector cells and support the identification of SFTSV-antiviral restrictions factors.

INSTRUMENT(S):

ORGANISM(S): Severe Fever With Thrombocytopenia Syndrome Virus Rhipicephalus Microplus Bunyavirales

TISSUE(S): Cell Culture

DISEASE(S): Thrombocytopenia,Fever

SUBMITTER: Pietro Scaturro

LAB HEAD: Pietro Scaturro

PROVIDER: PXD052311 | Pride | 2025-05-26

REPOSITORIES: Pride

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			Action	DRS
	221012_CF_3IP1N_MJP_Slot1-17_1_3130.d.zip	Other
	221012_CF_3IP1T_MJP_Slot1-21_1_3136.d.zip	Other
	221012_CF_3IP2N_MJP_Slot1-18_1_3131.d.zip	Other
	221012_CF_3IP2T_MJP_Slot1-22_1_3137.d.zip	Other
	221012_CF_3IP3N_MJP_Slot1-19_1_3132.d.zip	Other

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Publications

Multi-omics analysis of SFTS virus infection in Rhipicephalus microplus cells reveals antiviral tick factors.

Petit Marine J MJ Flory Charlotte C Gu Quan Q Fares Mazigh M Lamont Douglas D Score Alan A Davies Kelsey K Bell-Sakyi Lesley L Scaturro Pietro P Brennan Benjamin B Kohl Alain A

Nature communications 20250521 1

The increasing prevalence of tick-borne arboviral infections worldwide necessitates advanced control strategies, particularly those targeting vectors, to mitigate the disease burden. However, the cellular interactions between arboviruses and ticks, especially for negative-strand RNA viruses, remain largely unexplored. Here, we employ a proteomics informed by transcriptomics approach to elucidate the cellular response of the Rhipicephalus microplus-derived BME/CTVM6 cell line to severe fever with ...[more]

PMID: 40399277

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Project description:Ticks are blood feeding arthropod ectoparasites that transmit pathogens, which cause diseases in humans and animals worldwide. In the past ten decades, the continuous human exploitation of environmental resources and the increase in human outdoor activities has promoted contact with arthropod vectors normally present in the wild, resulting in increased transmission of vector-borne pathogens. In addition, vector populations are expanding in response to climate change and human interventions that impact reservoir host movement and human exposure to infected vectors. Among these emerging vector-borne pathogens, Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae) has become an important tick-borne pathogen in the United States, Europe and Asia, with increasing numbers of infected people and animals every year. Diseases caused by A. phagocytophilum include human granulocytic anaplasmosis (HGA), equine and canine granulocytic anaplasmosis and tick-borne fever (TBF) in ruminants. The natural infection cycle of A. phagocytophilum is dependent upon the presence of infected vertebrate reservoir hosts and Ixodid tick vectors. In the United States and Europe the main vector species are Ixodes scapularis, Ixodes pacificus, and Ixodes ricinus, while a wide range of mammals, lizards, and birds serve as reservoir hosts for various A. phagocytophilum genotypes. A. phagocytophilum initially infects tick midgut cells and then subsequently develops in salivary glands for transmission to susceptible hosts during tick feeding where the pathogen infects granulocytic cells, primarily neutrophils. Anaplasma phagocytophilum develops within membrane-bound inclusions in the host cell cytoplasm. This pathogen has evolved with its tick and vertebrate hosts through dynamic processes involving genetic traits of the pathogen and hosts that collectively mediate pathogen infection, development, persistence, and survival. However, the mechanisms used by A. phagocytophilum for molecular mechanisms involved in tick-pathogen interactions have not been fully characterized. The objective of this study is to characterize the dynamics of the microRNA response in the tick vector Ixodes scapularis in response to A. phagocytophilum infection. To address this objective, the composition of tick microRNAs was characterize using RNA sequencing in I. scapularis tick cells in response to A. phagocytophilum infection. The discovery of these mechanisms provides evidence that a control strategy could be developed targeted at both vertebrate and tick hosts for more complete control of A. phagocytophilum and its associated diseases.

Project description:Ticks are among the most economically important arthropod parasites due to the heavy infestations they provoke, affecting human and animal health and food production. Ticks are also important vectors of pathogens, mediating the dispersion of livestock and zoonotic diseases. Some examples of livestock diseases vectored by ticks include bovine babesiosis, anaplasmosis, theileriosis, and/or heartwater disease, all of which are enlisted by the World Organization for Animals as possible threats to animals and public health. The family Ixodidae (hard ticks) is of veterinary relevance, and many ixodid tick species within the genera Ixodes, Dermacentor, Amblyomma, Haemophysalis, Hyalomma, and Rhipicephalus, among others, impact farming production worldwide. However, there is no doubt that most pernicious tick species is Rhipicephalus microplus, commonly known as the southern cattle fever tick. This specie is not only the major economically important tick parasite for livestock production, but it is also the vector of Babesia bovis and B. bigemina, the causal agents of babesiosis, a severe disease that affects cattle from tropical and subtropical regions. Currently, global economic losses of the cattle industry attributable to R. microplus are estimated at around $18.7 US billion dollars per year. The economic impact is the leading reason to develop different strategies to constrains R. microplus and its vector-borne pathogens, including chemical, mechanical or environmental treatments, biological control, and/or genetic methods. Chemical, among other methods, are the most frequently applied, but the intense use worldwide, has led to the selection of acaricidal-resistant ticks populations. The molecular adaptations of ticks to overcome the effects of acaricides (e.g., deltamethrin, cypermethrin, amitraz, ivermectin) includes metabolic detoxiﬁcation mechanisms and/or the selection of mutated molecular targets. Recently, a couple of systematic reviews pointed out a significant increment in the number of studies intended to understand the acaricidal resistance in ticks. These reports highlighted the acaricide resistance observed in R. microplus and the wide geographical dispersion of this problem. Whereas many acaricide-resistant R. microplus populations have been reported in Brazil, India, and Mexico, the lack of strict regulatory policies on tick control, leaving the application of acaricides at discretion of farmers. Therefore, the correct implementation of existing strategies together with novel sustainable control methods may be crucial to safeguard livestock production in the context of growing population and global warming. However, until the implementation of such sanitary measures becomes the rule, the main control strategy will still rely on the use of chemical acaricides, such as ivermectin (IVM). Ivermectin is an antiparasitic macrocyclic lactone used to control the populations of R. microplus and other ticks in livestock farming. As occurs in other countries, in Mexico ivermectin is the primary synthetic antiparasitic drug, and its abuse during the last three decades represents an important selection pressure that boosted the development of ivermectin-resistant populations of R. microplus. Therefore, the understanding of the molecular basis of the R. microplus resistance to ivermectin, especially in those cases occurring in tropical and subtropical areas of developing countries, can help to underpin the development of novel strategies to tackle this problem. In this context, omics tools can provide helpful information for the discovery of the molecular mechanisms behind the ivermectin resistance in R. microplus and other related tick species. Previous studies identified the main proteomic components of ovaries of R. microplus, including proteins involved in protein synthesis, post-translational modification, nuclear regulation, cytoskeleton, proteasome, transcriptional regulation, energetic metabolism, detoxification metabolism, or energy storage. Recently, the vitellogenin receptor (VgR) was suggested as a target for tick control because of its essential role in egg formation and maturation. However, molecular information on tick ovaries currently available limits explores the feasibility of VgR or other reproduction-related molecules as promissory targets for tick control.

Project description:In addressing R. microplus - A. marginale interactions, we propose and test three linked hypotheses. The first is that the tick gene response is organ specific: the midgut gene regulation is unique during feeding and during acquisition of A. marginale as compared to the salivary gland. This distinction is relevant as the two organs serve very different roles in the transmission biology of A. marginale with early survival and replication within the midgut epithelium, composed of highly phagocytic cells, required for initial colonization while a second round of replication in the salivary gland acini, composed of highly secretory cells, is required for transmission of an infectious dose in the saliva. Importantly, both the midgut epithelium and salivary glands have been identified as separate and distinct barriers for transmission of A. marginale and thus represent two potential sites where transmission could be blocked. The second hypothesis to be tested is that the salivary gland transcriptome is temporally dynamic. Initiation of tick attachment and feeding involves secretion of a virtual pharmacopeia including lytic enzymes, anticoagulants, and inhibitors of the mammalian innate immune and nocioceptive systems. Concomitantly, the acini provide an environment where A. marginale replicates >100 fold and are secreted into the saliva. Prior studies show that duration of feeding is a critical component of transmission efficiency, with increased efficiency positively correlated with time of tick feeding. The third hypothesis to be tested is that A. marginale colonization does not significantly modulate the tick midgut and salivary gland transcriptome. This hypothesis is based on observations by ourselves and others that tick infection does not impart a significant fitness cost on the vector. This is in contrast to other bacterial and protozoal pathogens that have dramatic effects on success of tick attachment, engorgement, and survival. A. marginale, similar to other tick-borne pathogens in the Family Anaplasmataceeae, is believed to have evolved from an arthropod-specific bacterium with relatively late adaptation to specific niches in mammalian hosts. Consequently, we predict that A. marginale is well adapted to its tick vector and utilizes the normal signaling pathways of the feeding tick with few, if any, effects on the midgut and salivary gland transcriptome. In this manuscript, we report the testing of these three hypotheses and present the results in context of the vector-pathogen-mammalian host interaction at the time of transmission. A Roche NimbleGen high-density gene expression microarray was custom designed based on the expressed sequence tag (EST) database, B. microplus Gene Index Version 2 (BmiGI V2) for R. microplus. The expression level of 14,447 R. microplus genes was analyzed from total RNA extracted from 10 different tick tissue samples; 30 arrays were included since triplicates of each different sample were analyzed as follow: unfed (midgut and salivary glands), blood feeding (2 days midgut and 2, 6 and 9 days salivary glands), A. marginale-infected blood feeding (2 days midgut and 2, 6 and 9 days salivary glands).