Akt and foxo Dysregulation Contribute to Infection-Induced Wasting in Drosophila

Animal models have long been used in tuberculosis research to understand disease pathogenesis and to evaluate novel vaccine candidates and anti-mycobacterial drugs. However, all have limitations and there is no single animal model which mimics all the aspects of mycobacterial pathogenesis seen in humans. Importantly mice, the most commonly used model, do not normally form granulomas, the hallmark of tuberculosis infection. Thus there is an urgent need for the development of new alternative in vivo models. The insect larvae, Galleria mellonella has been increasingly used as a successful, simple, widely available and cost-effective model to study microbial infections. Here we report for the first time that G. mellonella can be used as an infection model for members of the Mycobacterium tuberculosis complex. We demonstrate a dose-response for G. mellonella survival infected with different inocula of bioluminescent Mycobacterium bovis BCG lux, and demonstrate suppression of mycobacterial luminesence over 14 days. Histopathology staining and transmission electron microscopy of infected G. mellonella phagocytic haemocytes show internalization and aggregation of M. bovis BCG lux in granuloma-like structures, and increasing accumulation of lipid bodies within M. bovis BCG lux over time, characteristic of latent tuberculosis infection. Our results demonstrate that G. mellonella can act as a surrogate host to study the pathogenesis of mycobacterial infection and shed light on host-mycobacteria interactions, including latent tuberculosis infection.

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“…This has also been described by Dionne and Schnieder in the D. melanogaster model of M. marinum infection [39]. …”

Section: Discussionsupporting

confidence: 58%

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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“…A potential bias of this approach is that changes in pathogen behavior, such as reflected by variations in tissue tropism and accumulation are not account for. An alternative approach is to quantify pathogen load in "whole body", as performed routinely in flies 5,9,10,127 . This is more challenging in other species, including rodents, but can be achieved, for example, using transgenic pathogens expressing reporter probes quantified throughout the course of an infection by whole body imaging 29 .…”

Section: Box 2: Identifying Mechanisms Controlling Disease Tolerance mentioning

confidence: 99%

Disease tolerance and immunity in host protection against infection

2017

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The immune system has most likely evolved to limit the negative impact exerted by pathogens on host homeostasis. This defense strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defense strategy that limits the extent of dysfunction imposed to host parenchyma tissues during infection, without exerting a direct negative impact on pathogens.This defense strategy, called disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens, while uncoupling immunedriven resistance mechanisms from immunopathology and disease. Here we provide a unifying view of resistance and disease tolerance within the framework of immunity to infection.

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“…Mycobacterium marinum has been used as a Drosophila model for tuberculosis and exhibits the slow killing and wasting characteristics of the disease in humans [25,26].…”

Section: Gram-positive Bacteriamentioning

confidence: 99%

“…A third method is PCR-based quantification of bacterial genes on fly extracts (see [89] for Spiroplasma and [26] for M. marinum).…”

Section: References Commentsmentioning

confidence: 99%

Methods to study Drosophila immunity

Neyen

Bretscher

Binggeli

et al. 2014

Methods

127

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a b s t r a c tInnate immune mechanisms are well conserved throughout evolution, and many theoretical concepts, molecular pathways and gene networks are applicable to invertebrate model organisms as much as vertebrate ones. Drosophila immunity research benefits from an easily manipulated genome, a fantastic international resource of transgenic tools and over a quarter century of accumulated techniques and approaches to study innate immunity. Here we present a short collection of ways to challenge the fruit fly immune system with various pathogens and parasites, as well as read-outs to assess its functions, including cellular and humoral immune responses. Our review covers techniques for assessing the kinetics and efficiency of immune responses quantitatively and qualitatively, such as survival analysis, bacterial persistence, antimicrobial peptide gene expression, phagocytosis and melanisation assays. Finally, we offer a toolkit of Drosophila strains available to the research community for current and future research.

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Akt and foxo Dysregulation Contribute to Infection-Induced Wasting in Drosophila

Cited by 289 publications

References 56 publications

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Disease tolerance and immunity in host protection against infection

Methods to study Drosophila immunity

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