# Resource reallocation under persistent immune activation drives trade-offs between life history and immunity in pirk-deficient Musca domestica

## TL;DR

This study shows that house flies with a defective immune gene use more energy for immunity, which harms their growth and reproduction.

## Contribution

The study reveals metabolic reprogramming in pirk-deficient house flies due to persistent immune activation.

## Key findings

- Pirk deficiency leads to sustained immune activation and increased resistance to bacterial infections.
- Metabolic shifts in pirk-KO flies prioritize ATP production over biomass synthesis, affecting growth and reproduction.
- Pirk-KO flies show elevated food intake and altered sugar levels but reduced glycogen and triglycerides.

## Abstract

The activation of the immune system by pathogens imposes significant energetic costs on hosts, which may result in the diversion of resources away from other non-essential biological processes, such as growth and reproduction. The underlying mechanisms of trade-offs between immune responses and host fitness remain poorly understood.

We used a Musca domestica mutant (pirk-KO) to evaluate the influence of non-infection-induced immune system activation on female reproduction and larval growth. Pirk, a negative feedback inhibitor of the immune deficiency (Imd) pathway expressed in intestine and fat body, was induced by bacteria. pirk loss enhanced the immune response of house flies, reflected in sustained upregulated antimicrobial peptide gene expression and improved resistance to bacterial infections. The phenotypic traits of pirk-KO house flies, including delayed larval growth, reduced the body weight, and impaired female fertility, were indicative of the adaptive costs associated with aberrant immune activation. The transcriptional heterogeneities between pirk-KO and wild-type (WT) male flies indicated the overactivation of the Imd signaling pathway, accompanied by significant metabolic adaptations to the loss of pirk. The upregulation of pivotal genes involved in glycolysis and the TCA cycle indicated an enhanced central carbon metabolism in pirk-KO. The downregulation of multiple key enzymes involved in the pentose phosphate pathway in pirk-KO flies suggests a reduction in metabolic flux through the pentose phosphate pathway, which in turn results in impaired anabolism. The collective findings indicate that the pirk-KO flies undergo metabolic reprogramming to increase ATP production as a response to excessive immune activation, rather than incorporating nutrients into cellular biomass for cell proliferation. The pirk-KO flies exhibited a significantly elevated food intake and elevated levels of free glucose, trehalose, and fructose in comparison to the WT flies. Nevertheless, the glycogen and triglyceride contents in the pirk-KO flies were observed to be slightly diminished in comparison to the WT group.

When the immune defense is activated, the flies extract more free energy to fuel the immunological deployment by increasing nutrient intake, as well as reducing resource allocation to non-essential life-history traits, primarily reproduction and growth.

The online version contains supplementary material available at 10.1186/s12915-025-02324-6.