Wolbachia-Mediated Resistance to Dengue Virus Infection and Death at the Cellular Level

Abstract

BackgroundDengue is currently the most important arthropod-borne viral disease of humans. Recent work has shown dengue virus displays limited replication in its primary vector, the mosquito Aedes aegypti, when the insect harbors the endosymbiotic bacterium Wolbachia pipientis. Wolbachia-mediated inhibition of virus replication may lead to novel methods of arboviral control, yet the functional and cellular mechanisms that underpin it are unknown.Methodology/Principal FindingsUsing paired Wolbachia-infected and uninfected Aedes-derived cell lines and dengue virus, we confirm the phenomenon of viral inhibition at the cellular level. Although Wolbachia imposes a fitness cost to cells via reduced proliferation, it also provides a significant degree of protection from virus-induced mortality. The extent of viral inhibition is related to the density of Wolbachia per cell, with highly infected cell lines showing almost complete protection from dengue infection and dramatically reduced virus titers compared to lines not infected with the bacteria.Conclusions/SignificanceWe have shown that cells infected with Wolbachia display inhibition of dengue virus replication, that the extent of inhibition is related to bacterial density and that Wolbachia infection, although costly, will provide a fitness benefit in some circumstances. Our results parallel findings in mosquitoes and flies, indicating that cell line models will provide useful and experimentally tractable models to study the mechanisms underlying Wolbachia-mediated protection from viruses.

Autophagy regulates Wolbachia populations across diverse symbiotic associations

“…Autophagy is not the only host-defense mechanism that can be activated by Wolbachia. Natural and experimental infections of Drosophila and mosquitoes with the overreplicating and lifeshortening wMelPop strain can induce up-regulation of host immune responses and inhibit microbial infection with viruses, protozoa, and helminth parasites (27)(28)(29)(30). Nevertheless, not all Wolbachia-host associations lead to activation of host immunity, and among the strains that do not activate host immunity are natural strains infecting Drosophila and Aedes aegypti (31,32).…”

“…Nevertheless, not all Wolbachia-host associations lead to activation of host immunity, and among the strains that do not activate host immunity are natural strains infecting Drosophila and Aedes aegypti (31,32). The induction of host defense and protection from microbial infection therefore is strain dependent and appears to be restricted to strains that have a high replication rate and widespread tissue tropisms (29,31,33). Alternately, it has been suggested that the metabolic demands of such overreplicating bacteria may prevent microbial infection and transmission through competition for host cell resources (27).…”

Male killing Spiroplasma protects Drosophila melanogaster against two parasitoid wasps

“…Spiroplasma bacteria confer protection against fungi in the pea aphid (Lukasik et al, 2012), against a nematode in Drosophila neotestacea (Jaenike et al, 2010b) and against a parasitoid wasp in Drosophila hydei . Wolbachia has been shown to increase resistance or tolerance of Drosophila and mosquitoes against RNA viruses and against the protozoan parasite Plasmodium (Hedges et al, 2008;Teixeira et al, 2008;Moreira et al, 2009;Osborne et al, 2009;Bian et al, 2010;Frentiu et al, 2010;Zele et al, 2012).…”

Wolbachia small noncoding RNAs and their role in cross-kingdom communications

“…Insects were reared at 26°C with 60% relative humidity and a 12-h light regime and fed on a 10% (wt/vol) sucrose solution ad libitum. A. aegypti Aag2 cells were infected with the wMelPop-CLA strain of Wolbachia (Pop) as described for the C6/36.wMelPop-CLA cell line (24). Cells were maintained in growth media in a 1:1 mixture of Mitsuhashi-Maramorosch and Schneider's insect media (Invitrogen), supplemented with 10% FBS.…”