Autophagy regulates Wolbachia populations across diverse symbiotic associations

Abstract

Wolbachia are widespread and abundant intracellular symbionts of arthropods and filarial nematodes. Their symbiotic relationships encompass obligate mutualism, commensalism, parasitism, and pathogenicity. A consequence of these diverse associations is that Wolbachia encounter a wide range of host cells and intracellular immune defense mechanisms of invertebrates, which they must evade to maintain their populations and spread to new hosts. Here we show that autophagy, a conserved intracellular defense mechanism and regulator of cell homeostasis, is a major immune recognition and regulatory process that determines the size of Wolbachia populations. The regulation of Wolbachia populations by autophagy occurs across all distinct symbiotic relationships and can be manipulated either chemically or genetically to modulate the Wolbachia population load. The recognition and activation of host autophagy is particularly apparent in rapidly replicating strains of Wolbachia found in somatic tissues of Drosophila and filarial nematodes. In filarial nematodes, which host a mutualistic association with Wolbachia, the use of antibiotics such as doxycycline to eliminate Wolbachia has emerged as a promising approach to their treatment and control. Here we show that the activation of host nematode autophagy reduces bacterial loads to the same magnitude as antibiotic therapy; thus we identify a bactericidal mode of action targeting Wolbachia that can be exploited for the development of chemotherapeutic agents against onchocerciasis, lymphatic filariasis, and heartworm.Brugia malayi | innate immunity | chemotherapy | helminth | endosymbiont W olbachia is a widespread and abundant endosymbiotic bacterium of arthropods and filarial nematodes that resides in vacuoles of host germline and somatic cells. Wolbachia show a diverse variety of symbiotic associations with their host, ranging from obligate mutualism in filarial nematodes to commensal, parasitic, or pathogenic associations in insects and other arthropod hosts (1-5).In filarial nematodes Wolbachia is obligatory for normal larval growth and development, embryogenesis, and survival of adult worms (1). Although the molecular basis of this mutualistic relationship remains unknown, a comparison of host and bacterial genomes suggests that intact biosynthetic pathways for haem, nucleotides, riboflavin, and FAD may be among the contributions of the bacteria to the biology of the nematode host (6-8). The biological processes most sensitive to Wolbachia loss include larval growth and development and embryogenesis in adult females. These processes have a high metabolic demand because of the rapid growth, development, and organogenesis of the nematode and are associated with the rapid expansion of Wolbachia populations following larval infection of mammalian hosts and in reproductively active adult females (9). Loss of Wolbachia results in extensive apoptosis of germline and somatic cells of embryos, microfilariae, and fourth-stage (L4) larvae, presumably because of the lack of provision of ...

Antimicrobial peptides and cell processes tracking endosymbiont dynamics

“…Autophagy is classically activated in response to organelle damage and nutritional deficiency. This process is also involved in many host -bacterial interactions, notably in the clearance of the intracellular pathogen Listeria monocytogenes in Drosophila [74], and in the regulation of Wolbachia populations in nematodes, crustaceans and insects [75,76]. It also plays a critical role in the elimination of dinoflagellate symbionts in the sea anemone Aiptasia pallida [77,78].…”

Effect of Wolbachia Infection on Aging and Longevity-Associated Genes in Drosophila

“…One of the autophagy-related genes, autophagy-specific gene 8a (Atg8a) encodes protein that is necessary to control the intracellular Wolbachia density in many invertebrates (Voronin et al 2012). It was shown that autophagy gene Atg8a was three times overexpressed in D. melanogaster infected by pathogenic Wolbachia strain wMelPop when compared to uninfected flies (Voronin et al 2012). Increased expression of Atg8a in the nervous system of adult flies can increase life span due oxidative stress resistance and elimination of damaged cell components (Simonsen et al 2008).…”

“…In D. melanogaster, autophagy is regulated by crosstalk between IMD, JNK, TOR and IIS pathways (Gelino and Hansen 2012). One of the autophagy-related genes, autophagy-specific gene 8a (Atg8a) encodes protein that is necessary to control the intracellular Wolbachia density in many invertebrates (Voronin et al 2012). It was shown that autophagy gene Atg8a was three times overexpressed in D. melanogaster infected by pathogenic Wolbachia strain wMelPop when compared to uninfected flies (Voronin et al 2012).…”

Wolbachia endosymbionts and human disease control

“…Finally, it may be that Wolbachia and the host have co-evolved to use pre-existing host biochemistry and cellular function [28]. Some of these mechanisms may be shared among arthropod systems and filarial ones, such as Wolbachia titer regulation by autophagy [31,55,56]. However, it would perhaps not be surprising if several different strategies have evolved [51].…”