The Role of Environmental, Virological and Vector Interactions in Dictating Biological Transmission of Arthropod-Borne Viruses by Mosquitoes

Joan L. Kenney; Aaron C. Brault1    Arbovirus Research Branch, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, U.S. Centers for Disease Control and Prevention, Fort Collins, Colorado, USA
1 Corresponding author: abrault@cdc.gov

1 Background

Arthropod-borne viruses (arboviruses) are grouped by their common means of transmission to vertebrate hosts by the bite of infected arthropod vectors. Although arboviruses have been documented to be transmitted between vertebrate hosts by flies, sandflies, midges (Depaquit, Grandadam, Fouque, Andry, & Peyrefitte, 2010; Kramer, Jones, Holbrook, Walton, & Calisher, 1990; Mellor, Boorman, & Baylis, 2000), cliff swallow bugs (Brown, Moore, Young, Padhi, & Komar, 2009), and ticks (Nuttall, Jones, Labuda, & Kaufman, 1994), the majority are transmitted by mosquitoes and therefore mosquito-borne viruses will be the focus of this chapter. Typically, these viruses exist in a dual-host cycle between the mosquito and some vertebrate host such as a bird, rodent, amphibian, or primate. Infection of mosquitoes with arboviruses occurs in a dose-dependent manner (Weaver, 1994) following ingestion of an infectious blood meal and thus only vertebrate hosts that manifest sufficient titers can contribute to the transmission cycle. Mosquito-borne arboviruses belong to a number of families including Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, and Rhabdoviridae. With few exceptions, such as dengue viruses (DENV) 1–4, yellow fever virus (YFV), and chikungunya virus (CHIKV), humans serve as “dead-end” hosts by not manifesting sufficient viremias for the oral infection of additional vectors to propagate the viral cycle. In addition to dual-host (vertebrate and vector-infecting viruses) mosquito-borne viruses, a number of mosquito-specific viruses have been identified for which the capacity for replication in vertebrate cells has not been observed. These viruses have been described extensively in the family Flaviviridae (Cook et al., 2012) and recently in the families Togaviridae (Nasar et al., 2012) and Bunyaviridae (Marklewitz et al., 2013). The discovery of these viruses should allow for in-depth study of mechanisms of vertical transmission of different viral families in mosquitoes as well as novel mechanisms of RNAi antagonism of vector species in addition to the fundamental elements that restrict host range of these viruses.

Arboviruses can be transmitted to a vertebrate host via a mosquito vector by two distinct mechanisms: mechanical or biological transmission (Hardy, Houk, Kramer, & Reeves, 1983). Mechanical transmission occurs by direct contact of contaminated mouthparts of the arthropod vector with the vertebrate host, thus not requiring amplification of the virus within the vector (Gray & Banerjee, 1999; Kaufman & Nuttall, 1996; Mayr, 1983). Biological transmission, in contrast, necessitates the direct amplification of the virus in mosquito tissue prior to transmission. As such, amplification of the virus in mosquito cells has resulted in a number of evolutionary processes that will be addressed throughout this chapter for the virus to directly antagonize the innate immune response of the mosquito as well as offset indirect fitness effects on viral replicative homeostasis. Nevertheless, viruses such as West Nile virus (WNV) for which biological transmission is the predominant mechanism for transmission by mosquitoes have been documented to be mechanically transmitted by stable flies through contaminated mouthparts (Doyle et al., 2011; Johnson, Panella, Hale, & Komar, 2010). A series of intrinsic and extrinsic factors such as the ability to productively infect the midgut epithelium of the vector combine to determine the efficacy of a virus–vector relationship (Chamberlain & Sudia, 1961). Several examples will be provided for various arboviruses to demonstrate these barriers throughout this chapter.

Biological transmission of an arbovirus in a mosquito vector entails passing through a number of physical and physiological barriers in order for the virus to be imbibed by a mosquito in an infectious blood meal and transmitted upon expectoration during probing and feeding of the mosquito at the initiation of the subsequent gonotrophic cycle (Fig. 2.2). Infection of midgut epithelial cells (Fig. 2.2, panel 1a and b), productive viral propagation, dissemination of virus from midgut epithelial cells to cell populations present in the hemocoel, infection of salivary glandular acinar cells (Fig. 2.2, panel 2a), and deposition of virus in the apical cavities and salivary ducts of the salivary gland for transmission (Fig. 2.2, panel 2b) during feeding are required to complete the cycle. The time period between the ingestion of an infectious blood meal and the transmission of an arbovirus is known as the extrinsic incubation period (EIP) as this is the period observed in which the arbovirus was not replicating in the vertebrate (or intrinsic) host. Given the multiple sets of intricate physical and evolutionarily selective barriers that have arisen for the establishment of persistent infections of arboviruses in mosquito vectors and the potential that infection of mosquitoes with an arbovirus has been documented to occur in the absence of actual amplification in the vertebrate host (Higgs, Schneider, Vanlandingham, Klingler, & Gould, 2005; Reisen, Fang, & Martinez, 2007), it is becoming clear that such a simple designation as “extrinsic incubation” in the invertebrate host might be an improper descriptive term for these complex interactions. As previously alluded to, viral, vector, and environmental factors of both an intrinsic and extrinsic nature can alter each stage of biological transmission. A number of barriers to infection have been described for arthropod-borne viruses. These include (1) barrier to midgut infection (midgut infection barrier) that results in the failure of a virus to bind, enter, and/or replicate within the midgut epithelial cells (typically associated with the presence of receptors on the surface of the midgut epithelial cells); (2) a barrier to dissemination (midgut escape barrier) from productively infected midgut epithelial cells; (3) a barrier to the productive infection of acinar cells of the salivary glands; and finally (4) a barrier to the replication within and escape from the salivary gland cells (Hardy et al., 1983). The original description of these barriers focused on the environmental (temperature) that restricted or promoted viral replication in the mosquito and physical barriers that were found between these replication sites present on the midgut epithelial cells such as receptors, the thickness and pore size limitations of the basal lamina (BL) that could prevent viral dissemination from infected midgut epithelial cells, and similar barriers for infection and release from the acinar cells of the salivary glands. The recent advances in understanding of the complex innate immune responses that mosquitoes can mount to arboviruses has indicated that the barriers are also significantly affected by either direct innate immune responses targeting viral replication intermediates or indirect effects from microbiome priming of the mosquito innate immune system (Ramirez et al., 2012; Xi, Ramirez, & Dimopoulos, 2008).

2 Vectorial Capacity

Vectorial capacity is described as the “combined effect of all of the physiological, ecological, and environmental factors relating vector, host, and pathogen that determine the ability of a given mosquito species to serve as a competent vector...