Research Article: Involvement of Tetraspanin C189 in Cell-to-Cell Spreading of the Dengue Virus in C6/36 Cells

Date Published: July 1, 2015

Publisher: Public Library of Science

Author(s): Chao-Fu Yang, Cheng-Hsun Tu, Yin-Ping Lo, Chih-Chieh Cheng, Wei-June Chen, Ken E. Olson.

Abstract: Dengue virus (DENV) is naturally transmitted by mosquitoes to humans, infecting cells of both hosts. Unlike in mammalian cells, DENV usually does not cause extremely deleterious effects on cells of mosquitoes. Despite this, clustered progeny virions were found to form infection foci in a high density cell culture. It is thus interesting to know how the virus spreads among cells in tissues such as the midgut within live mosquitoes. This report demonstrates that cell-to-cell spread is one way for DENV to infect neighboring cells without depending on the “release and entry” mode. In the meantime, a membrane-bound vacuole incorporating tetraspanin C189 was formed in response to DENV infection in the C6/36 cell and was subsequently transported along with the contained virus from one cell to another. Knockdown of C189 in DENV-infected C6/36 cells is shown herein to reduce cell-to-cell transmission of the virus, which may be recovered by co-transfection with a C189-expressing vector in DENV-infected C6/36 cells. Moreover, cell-to-cell transmission usually occurred at the site where the donor cell directly contacts the recipient cell. It suggested that C189 is crucially involved in the intercellular spread of progeny viral particles between mosquito cells. This novel finding presumably accounts for the rapid and efficient infection of DENV after its initial replication within tissues of the mosquito.

Partial Text: Dengue virus (DENV) consists of four serotypes that manifest similar symptoms, ranging from a mild febrile illness to a life-threatening dengue hemorrhagic fever [1]. Taxonomically, DENV is one of some 70 members of the family Flaviviridae and is transmitted between humans by Aedes mosquitoes [2], particularly Aedes aegypti [3]. Dengue fever (DF) and dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) have become increasingly important public health problems in over 100 countries in tropical and subtropical regions [4]. It is estimated that 2.5–3 billion people are risk of dengue infection in the world [5]. As DENV is naturally transmitted to humans by mosquitoes, indicating the virus can also infect and replicate in the mosquito cell during its journey from the midgut to salivary glands [6]. In humans bitten by an infected mosquito, DENV inoculated with mosquito saliva initially infects Langerhan cells and keratocytes residing in the epidermis where it begins to replicate [7]. Subsequently, the virus can infect other organs including circulatory macrophages/monocytes, lymphoid tissues, liver, spleen, kidneys, and lungs [8], as well as the brain in a few cases [9]. DENV has also been detected in megakaryocyte progenitors and circulating platelets [10], suggesting that thrombocytopenia in dengue patients is closely associated with DENV infection [11, 12]. Such host cells are usually infected by DENV through receptor(s)-mediated endocytosis [13] and mostly end up undergoing apoptosis in response to dengue virus infection [14]. A huge number of viral particles from infected cells burst into the blood stream or a culture to become the source of infection for other cells.

Arboviruses naturally infect vertebrate hosts through biting by hematophagous arthropod vectors, requiring the ability to replicate in the cells of both hosts. Like most arboviruses in humans, free DENVs are usually released into the circulatory system and subsequently infect susceptible cells via endocytosis, which are usually receptor(s)-mediated and clathrin-dependent [34, 35]. DENVs can also infect mosquito cells via a mode similar to that which occurs in vertebrate cells [36], although their specific receptors have not yet been clearly identified [13]. DENV dissemination within the mosquito has recently attracted increased attention. It seems that DENV-2 can infect various organs (e.g., neural tissue and salivary glands [20]) disseminating from the midgut, which is the original lodging and replication site of the virus when ingested along with blood meals [37]. The virus travels from the midgut to salivary glands before being transmitted to another host.



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