The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

Abstract

The Toll pathway regulates the cellular response to infection via the transcriptional upregulation of antimicrobial peptides. Apart from its role in innate immunity, this pathway has also been reported to be important for the elimination of loser cells in a process referred to as cell competition, which can be locally triggered by secreted factors released from winner cells. In this work we provide evidence that the inhibition of Toll signaling not only increases the fitness of loser cells, but also bestows a clonal growth advantage on wild-type cells. We further demonstrate that this growth advantage depends on basal infection levels since it is no longer present under axenic conditions but exacerbated upon intense pathogen exposure. Thus, the Toll pathway functions as a fine-tuned pro-apoptotic and anti-proliferative regulator, underlining the existence of a trade-off between innate immunity and growth during development.

A Serpin27A-dependent Toll Signaling Underlies Host Genetics of Cancer Resistance inDrosophila

“…While results presented here may appear reminiscent of Toll-mediated cell competition, we do notice an important distinction: namely, that local interactions of cell neighbors—as in localized Toll-mediated tissue surveillance (Alpar et al, 2018; Meyer et al, 2014)—may not suffice for tumor elimination, particularly when the latter displays sufficient growth. Instead, the paradigm of host Toll signaling-dependent tumor remission shown here appears comparable with Toll-mediated tissue surveillance by microbial infection in Drosophila (Germani et al, 2018), or tumor remission induced by Coley’s toxins (Coley) or by TLR agonists (Michaelis et al, 2019).…”

“…Fly stocks were grown on standard axenic corn meal-agar medium supplemented with streptomycin (400μg/ml) along with anti-fungal Antimycotic Nipagin (0.15 g per 100 ml), at 25 °C including those involving Gal4 driver lines and instances of shift to 18± 1°C at 4.5 dAEL (days A fter E gg L aying) are mentioned wherever done. Care has taken to raise larvae and flies under aseptic and uncrowded conditions, especially when assaying for systemic immune responses (also, see Germani et al, 2018).…”

“…Previously, metabolically perturbed cells in Drosophila were shown to be eliminated by a localized Toll-mediated cell competition (Alpar et al, 2018; Meyer et al, 2014) or via systemic production of the Spz Act due to microbial infection (Germani et al, 2018). Tissue surveillance mechanisms like cell competition maintain cell fitness within an organ (for recent review, see Baker, 2020) and are also effective for tumor elimination (Agrawal et al, 1995; Katsukawa et al, 2018; Khan et al, 2013).…”

Cell Competition Triggers Suicide by Autophagy

“…Double knockdown of Atg1 and fwe or azot was not additive, suggesting that they act in a linear pathway, but this was not further explored. Similarly, innate immune signaling has been implicated in elimination of both Myc low and Rpl14E/+ loser cells (Meyer et al, 2014;Germani et al, 2018). Inhibition of innate immune signaling, specifically in Hel25E À/À loser cells, also counteracted cell elimination.…”

P53 and PUMA in Pluripotent Cell Competition

“…They found that during Myc-induced and Minute-induced CC, Toll-related receptors (TRR) are more expressed in loser cells and they are activated by the ligand Spätzle, leading to NF-κβ activation and apoptosis in Drosophila wing disc (Alpar et al, 2018;Meyer et al, 2014). In a later study (Germani et al, 2018), this type of TRR-mediated competition was found to depend on the septic status of flies, indicating that a systemic response to infection is required for TRR-mediated cell competition.…”