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Review
. 2018 Mar 21;10(4):141.
doi: 10.3390/v10040141.

Conflict in the Intracellular Lives of Endosymbionts and Viruses: A Mechanistic Look at Wolbachia-Mediated Pathogen-blocking

Affiliations
Review

Conflict in the Intracellular Lives of Endosymbionts and Viruses: A Mechanistic Look at Wolbachia-Mediated Pathogen-blocking

Amelia R I Lindsey et al. Viruses. .

Abstract

At the forefront of vector control efforts are strategies that leverage host-microbe associations to reduce vectorial capacity. The most promising of these efforts employs Wolbachia, a maternally transmitted endosymbiotic bacterium naturally found in 40% of insects. Wolbachia can spread through a population of insects while simultaneously inhibiting the replication of viruses within its host. Despite successes in using Wolbachia-transfected mosquitoes to limit dengue, Zika, and chikungunya transmission, the mechanisms behind pathogen-blocking have not been fully characterized. Firstly, we discuss how Wolbachia and viruses both require specific host-derived structures, compounds, and processes to initiate and maintain infection. There is significant overlap in these requirements, and infection with either microbe often manifests as cellular stress, which may be a key component of Wolbachia's anti-viral effect. Secondly, we discuss the current understanding of pathogen-blocking through this lens of cellular stress and develop a comprehensive view of how the lives of Wolbachia and viruses are fundamentally in conflict with each other. A thorough understanding of the genetic and cellular determinants of pathogen-blocking will significantly enhance the ability of vector control programs to deploy and maintain effective Wolbachia-mediated control measures.

Keywords: Aedes; Drosophila; antiviral; arbovirus; endosymbiont; symbiosis; vector control.

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Wolbachia modifies the intracellular environment of the host. 1. Wolbachia typically exhibits a perinuclear localization, and closely associates with host derived-membranes (Wolbachia are marked with a “W”). Wolbachia associates with the ER in particular, which results in atypical ER morphologies, including expansion and swelling; 2. Wolbachia are enclosed by three distinct membranes: a host derived vesicle (likely of Golgi-origin), and two Wolbachia derived membranes (inset); 3. During Wolbachia replication, daughter cells temporarily share the host-derived membrane, which later abscises; 4. Wolbachia have been observed fused to the ER, and having a direct connection to the ER lumen (inset), likely facilitating the exchange of proteins or other metabolites; 5. The Type Four Secretion System (T4SS) allows Wolbachia to export effector proteins directly to the host (inset); 6. The Wolbachia genome also encodes a number of transporters that likely facilitate uptake of nutrients from the host; 7. In addition to associating with intracellular membranes, Wolbachia is known to alter the host cytoskeleton (depicted as green dashed lines); 8. The presence of Wolbachia results in the production of reactive oxygen species (ROS), contributing to cellular stress; 9. Lastly, Wolbachia is often associated with upregulation of immune-related genes and pathways including antimicrobial peptides (AMPs), Gram-negative binding proteins (GNBPs), peptidoglycan recognition proteins (PGRPs), and miRNAs (10).
Figure 2
Figure 2
Overview of RNA virus replication in an arthropod cell. 1. Incoming virus particle enters the cell following receptor-mediated endocytosis; 2. Viral genome is delivered into the cytoplasm after the internalized virion escapes the endosome, either by pore-formation or after undergoing fusion with the endosomal membrane; 3. Genome replication occurs inside cytoplasmic virus cores (dsRNA viruses) or within modified membrane-associated structures (see inset) containing virus-encoded replication complexes (RCs). Double-stranded viral RNA (dsRNA) is synthesized as a replication intermediate; 4. After synthesis of viral structural proteins, some are trafficked to the plasma membrane while core proteins encapsulate newly synthesized viral RNA to form cytoplasmic cores; 5. Some viruses obtain their envelope at the plasma membrane before exiting from the cell while others exit following lysis. Presence of virus in the cell also elicits different antiviral responses; 6. Recognition of viral proteins by pattern recognition receptors (PRRs) triggers innate immune pathways, activating transcription factors that induce expression of effectors and antiviral factors; 7. Viral dsRNA triggers RNAi pathways that also aid in viral inhibition; 8. Although poorly understood in arthropods, extracellular interferon-like signaling and the presence of intracellular dsRNA might cause activation of PKR orthologues PERK or GCN2, leading to eIF2α phosphorylation and subsequent stress granule (SG) assembly. Such an event might lead to repression of viral translation and genome replication (inset). Changes in membrane composition and structure is common during RNA virus replication in the cell. Many RNA viruses require the presence of cholesterol (shown in red) or other lipids in the membrane to allow proper localization and functioning of their replication complexes.
Figure 3
Figure 3
Wolbachia-mediated virus inhibition in arthropods. Wolbachia-mediated virus inhibition is likely a cumulative effect arising from multiple roadblocks at different stages of virus life cycle. 1. Reactive oxygen species (ROS) are produced in a Wolbachia-infected cell that might lead to stress granule (SG) assembly (inset (A)); 2. Moreover, competition for intracellular cholesterol and amino acids (inset (B)) between virus and Wolbachia may lead to metabolite depletion, giving rise to ER stress in the cell and vice versa; 3. Presence of Wolbachia can also trigger expression of host miRNAs, antimicrobial peptides (AMPs) and genes associated with antiviral immunity (e.g., Dnmt2, Toll pathway genes); 4. Modulation of the cellular cytoskeletal network (depicted as green dashed lines) by Wolbachia might disrupt vesicular trafficking, thus affecting virus entry and/or exit steps; 5. Cholesterol depletion in membranes might affect viral genome uncoating and delivery into the cytoplasm (inset (A)); 6. Additionally, lack of cholesterol in membranes (shown in red) might disrupt assembly and functionality of viral replication complexes (RCs), abrogating viral genome replication; 7. Post-transcriptional modification (PTM) of viral RNA (vRNA) by the host RNA methyltransferase Dnmt2 might allow viral RNA trafficking to SGs, leading to inhibition of viral genome replication; 8. PTM of vRNA on its own can also compromise its ability to be replicated, leading to reduced viral protein synthesis; 9. PTM modified and/or Dnmt2-bound vRNA might also lead to RNAi-mediated virus inhibition; 10. Modified vRNA may also cause improper packaging into virions; 11. Defects in virion structure and/or modified nature of the encapsidated vRNA might result in the production of virus particles that are incapable of initiating a fresh round of replication in other cells, limiting virus spread from cell-to-cell.

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