Why do insects evolve immune priming? A search for crossroads

Abstract

Until recently, it was assumed that insects lack immune memory since they do not have vertebrate-like specialized memory cells. Therefore, their most well studied evolutionary response against pathogens was increased basal immunity. However, growing evidence suggests that many insects also exhibit a form of immune memory (immune priming), where prior exposure to a low dose of infection confers protection against subsequent infection by the same pathogen that acts both within and across generations. Most strikingly, they can rapidly evolve as a highly parallel and mutually exclusive strategy from basal immunity, under different selective conditions and with divergent evolutionary trade-offs. However, the relative importance of priming as an optimal immune strategy also has contradictions, primarily because supporting mechanisms are still unclear. In this review, we adopt a comparative approach to highlight several emerging evolutionary, ecological and mechanistic features of priming vs basal immune responses that warrant immediate attention for future research.

Keywords: Coinfections; Cost of immunity; Immune priming; Resistance; Specificity; Tolerance.

Figure 1. A brief summary of known (1-3) vs proposed (4-7) priming mechanisms from recent studies

(1) Humoral response: (a) Activation of IMD- (immune deficiency), Toll- (TLR-like receptor), and JAK/STAT (Janus kinase signal transducer and activator of transcription) signalling pathways leading to synthesis & production of inducible AMPs (Sheehan et al., 2020) such as Attacins, Defensins & Coleoptericins in flour beetles (Greenwood et al., 2017; Ferro et al., 2019); Cecropins in fruit flies (Chakrabarti and Visweswariah, 2020); Cecropin, Attacin, Gloverin, Moricin & Lysozyme in silkworms (Yi et al., 2019); Gallerimycin & Galiomicin in wax-moths (Bergin et al., 2006); Cecropin in tobacco moths (Roesel et al., 2020) (b) Upregulated PGRP-SC (peptidoglycan recognition proteins - receptor for IMD pathway) and GNBPs (gram-negative binding proteins - receptor for Toll-pathway) in flour beetles (Ferro et al., 2019); Downregulated PGRP-LB (negative regulator of IMD-pathway) in fruit flies (Bozler et al., 2019) (c) Phenoloxidase (PO) response: Increased PO activity in flour beetles and mealworm beetles (Tetreau et al., 2019); Increased DDC (dopa-decarboxylase – a gene involved in PO cascade) in flour beetles (Ferro et al., 2019). (d) RNAi-pathway mediated specific priming against viral pathogens in fruit flies (Mondotte et al., 2018). (2) Cellular immunity: Increased phagocytosis activity (Pham et al., 2007; Weavers et al., 2016) and production of lamellocytes (Bozler et al., 2019) in fruit flies; Haemocyte differentiation induced by lipoxin (a lipid carrier) in mosquitoes (Rodrigues et al., 2010; Ramirez et al., 2015). (3) Down syndrome cell adhesion molecule (Dscam): Suspected role in specific immunity of flour beetles, fruit flies and other insects (Armitage et al., 2015); Acts as receptor during phagocytosis in crabs (Li et al., 2018); Upregulated in primed silkworms (Yi et al., 2019). (4) Epithelial response: Activation of haemocytes via intracellular accumulation of H₂O₂ (hydrogen peroxide) produced by DUOX (Reactive oxygen species producing dual-oxidase) through Toll & JAK/STAT pathway activation & Draper (damage associated signal molecules) in fruit flies (Chakrabarti and Visweswariah, 2020) (5) Metabolism and energetics: Downregulated metabolism-associated genes - hexokinase type 2 and sedoheptulokinase in flour beetles (Ferro et al., 2019); Upregulated trehalose transporter, GDP-D-glucose phosphorylase in mosquito Anopheles. albimanus (Maya-Maldonado et al., 2021) (6) Host-associated microbiota: Loss of priming in flour beetles (Futo et al., 2017) and Anopheles. gambiae mosquitoes (Rodrigues et al., 2010) after depleting microbiota. (7) Epigenetic mechanisms and reprogramming: Upregulated histone H3 gene, RNA polymerase II (transcription subunit 15) & exosome complex exonuclease (RRP6-like) (Ferro et al., 2019); Upregulated lncRNAs (long non-coding RNAs – necessary for regulating- metabolic, immune signalling and epigenetic processes (Ali et al., 2019) in flour beetles.

Figure 2

A diagrammatic representation linking (I) hosts ability to either resist pathogen growth, by immune activation, or (II) tolerate pathogen burden, by reducing the fitness costs of infection or immune activation without directly reducing the pathogen numbers to (III) the outcome of immune priming (i.e., post-infection survival benefits after priming relative to unprimed controls) or basal infection response (i.e., survival response to infection without prior priming relative to uninfected control). At the mechanistic level, a complex interplay between immune pathways & molecules, host metabolism, epigenetic reprogramming and host-associated microbiota might be collectively responsible for evolving priming vs basal immunity and infection responses. Figures on tolerance and resistance are adapted from Råberg et al., 2007.