Dietary Cholesterol Modulates Pathogen Blocking by Wolbachia

Caragata, Eric P.; Rancès, Edwige; Hedges, Lauren M.; Gofton, Alexander W.; Johnson, Karyn N.; O'Neill, Scott Leslie; McGraw, Elizabeth A.

doi:10.1371/journal.ppat.1003459

Cited by 258 publications

(247 citation statements)

References 44 publications

Supporting

Mentioning

239

Contrasting

Unclassified

Order By: Relevance

“…There is evidence that multiple host mechanisms may be involved in inhibiting viral replication including synthesis of reactive oxygen and cholesterol and induction of host autophagy (Le Clec'h et al 2012;Pan et al 2012;Caragata et al 2013;Wong et al 2015). Our finding that Wolbachia dramatically alters host ER morphology and relies on the ERAD pathway to maintain titer suggests the involvement of a previously unsuspected mechanism in preventing the replication of positive-strand RNA viruses.…”

Section: Discussionmentioning

confidence: 77%

Reliance of Wolbachia on High Rates of Host Proteolysis Revealed by a Genome-Wide RNAi Screen of Drosophila Cells

et al. 2017

View full text Add to dashboard Cite

Wolbachia are gram-negative, obligate, intracellular bacteria carried by a majority of insect species worldwide. Here we use a Wolbachia-infected Drosophila cell line and genome-wide RNA interference (RNAi) screening to identify host factors that influence Wolbachia titer. By screening an RNAi library targeting 15,699 transcribed host genes, we identified 36 candidate genes that dramatically reduced Wolbachia titer and 41 that increased Wolbachia titer. Host gene knockdowns that reduced Wolbachia titer spanned a broad array of biological pathways including genes that influenced mitochondrial function and lipid metabolism. In addition, knockdown of seven genes in the host ubiquitin and proteolysis pathways significantly reduced Wolbachia titer. To test the in vivo relevance of these results, we found that drug and mutant inhibition of proteolysis reduced levels of Wolbachia in the Drosophila oocyte. The presence of Wolbachia in either cell lines or oocytes dramatically alters the distribution and abundance of ubiquitinated proteins. Functional studies revealed that maintenance of Wolbachia titer relies on an intact host Endoplasmic Reticulum (ER)-associated protein degradation pathway (ERAD). Accordingly, electron microscopy studies demonstrated that Wolbachia is intimately associated with the host ER and dramatically alters the morphology of this organelle. Given Wolbachia lack essential amino acid biosynthetic pathways, the reliance of Wolbachia on high rates of host proteolysis via ubiquitination and the ERAD pathways may be a key mechanism for provisioning Wolbachia with amino acids. In addition, the reliance of Wolbachia on the ERAD pathway and disruption of ER morphology suggests a previously unsuspected mechanism for Wolbachia's potent ability to prevent RNA virus replication.

show abstract

Section: Discussionmentioning

confidence: 77%

Reliance of Wolbachia on High Rates of Host Proteolysis Revealed by a Genome-Wide RNAi Screen of Drosophila Cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Two recent studies support this notion: Wolbachia and Drosophila C virus compete for cholesterol, resulting in a delay in virus-induced mortality for Wolbachia-infected flies (40), and upregulation of an A. aegypti methyltransferase gene by Wolbachia contributes to dengue virus inhibition (41). These results are important in an applied context of utilizing Wolbachia infections for dengue virus control.…”

mentioning

confidence: 77%

The Toll and Imd Pathways Are Not Required for Wolbachia-Mediated Dengue Virus Interference

Rancès

Johnson

Popovici

et al. 2013

J Virol

Self Cite

View full text Add to dashboard Cite

c Wolbachia blocks dengue virus replication in Drosophila melanogaster as well as in Aedes aegypti. Using the Drosophila model and mutations in the Toll and Imd pathways, we showed that neither pathway is required for expression of the dengue virusblocking phenotype in the Drosophila host. This provides additional evidence that the mechanistic basis of Wolbachia-mediated dengue virus blocking in insects is more complex than simple priming of the host insect innate immune system. T he common intracellular bacterium Wolbachia pipientis (1) is maternally inherited through the eggs of its insect hosts. It is able to successfully invade host populations through a range of reproductive manipulations that either directly or indirectly favor its transmission between insect generations (2-8). In its natural host, it has recently been shown that the presence of Wolbachia can block the replication of RNA viruses (9-13). This effect is the basis for the recent development of Wolbachia as a biocontrol approach to block dengue virus (DENV) transmission by the mosquito Aedes aegypti (14,15).The main vector of DENV, the mosquito Aedes aegypti, is not naturally infected with Wolbachia. However, different strains of Wolbachia have recently been artificially introduced from Drosophila melanogaster (Wolbachia strains wMel and wMelPop) or Aedes albopictus (Wolbachia strain wAlbB) into A. aegypti and are stably maintained in laboratory and wild mosquito populations (8,(16)(17)(18). The expectation is that the negative impact that Wolbachia has on DENV replication in the insect will reduce virus transmission to humans and subsequent disease (18)(19)(20).The mechanism(s) that underlies the ability of Wolbachia to affect the replication of DENV appears complex. Using the heterologous association of Wolbachia-infected A. aegypti, transcriptomic and biochemical studies have demonstrated that Wolbachia induces the production of reactive oxygen species (ROS); primes the innate immune system of the mosquito, especially the Toll signaling pathway; and induces the production of various antimicrobial effectors (19)(20)(21)(22)(23). In addition, the use of RNA interference (RNAi) depletion to partially knock down defensin and cecropin genes in Wolbachia-infected A. aegypti lowered resistance to DENV and suggested a role for the innate immune system in mediating virus resistance (22). In contrast, in their natural host D. melanogaster, the same Wolbachia strains do not induce overexpression of immune genes, including the Toll pathway and cecropin-and defensin-encoding genes, yet RNA virus interference, including DENV interference, occurs (23,24). These results demonstrated that induction of the Toll pathway by Wolbachia is not the exclusive mechanism mediating resistance. However, gene expression studies are not sufficient to make a link between a phenotype and a genetic pathway. Since previous studies confirmed the ability of DENV to replicate, and of Wolbachia to block its replication in Drosophila (23), we took advantage of preexisting and wel...

show abstract

“…(2016) and Caragata et al. (2013) who demonstrated that larval nutrition and adult carbohydrate intake did not affect DENV infection rates in w Mel mosquitoes. Temperature, in contrast, has been shown to determine whether the w AlbB Wolbachia strain inhibits, enhances, or has a neutral effect on oocyte infection rate and intensity of Plasmodium yoelii in An.…”

Section: Discussionmentioning

confidence: 99%

Wolbachia enhances insect‐specific flavivirus infection in Aedes aegypti mosquitoes

Amuzu

Tsyganov

Koh

et al. 2018

Ecology and Evolution

Self Cite

View full text Add to dashboard Cite

Mosquitoes transmit a diverse group of human flaviviruses including West Nile, dengue, yellow fever, and Zika viruses. Mosquitoes are also naturally infected with insect‐specific flaviviruses (ISFs), a subgroup of the family not capable of infecting vertebrates. Although ISFs are not medically important, they are capable of altering the mosquito's susceptibility to flaviviruses and may alter host fitness. Wolbachia is an endosymbiotic bacterium of insects that when present in mosquitoes limits the replication of co‐infecting pathogens, including flaviviruses. Artificially created Wolbachia‐infected Aedes aegypti mosquitoes are being released into the wild in a series of trials around the globe with the hope of interrupting dengue and Zika virus transmission from mosquitoes to humans. Our work investigated the effect of Wolbachia on ISF infection in wild‐caught Ae. aegypti mosquitoes from field release zones. All field mosquitoes were screened for the presence of ISFs using general degenerate flavivirus primers and their PCR amplicons sequenced. ISFs were found to be common and widely distributed in Ae. aegypti populations. Field mosquitoes consistently had higher ISF infection rates and viral loads compared to laboratory colony material indicating that environmental conditions may modulate ISF infection in Ae. aegypti. Surprisingly, higher ISF infection rates and loads were found in Wolbachia‐infected mosquitoes compared to the Wolbachia‐free mosquitoes. Our findings demonstrate that the symbiont is capable of manipulating the mosquito virome and that Wolbachia‐mediated viral inhibition is not universal for flaviviruses. This may have implications for the Wolbachia‐based DENV control strategy if ISFs confer fitness effects or alter mosquito susceptibility to other flaviviruses.

show abstract

Dietary Cholesterol Modulates Pathogen Blocking by Wolbachia

Cited by 258 publications

References 44 publications

Reliance of Wolbachia on High Rates of Host Proteolysis Revealed by a Genome-Wide RNAi Screen of Drosophila Cells

Reliance of Wolbachia on High Rates of Host Proteolysis Revealed by a Genome-Wide RNAi Screen of Drosophila Cells

The Toll and Imd Pathways Are Not Required for Wolbachia-Mediated Dengue Virus Interference

Wolbachia enhances insect‐specific flavivirus infection in Aedes aegypti mosquitoes

Contact Info

Product

Resources

About