Antimicrobial peptides in the Nervous System: History
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Subjects: Immunology
Contributor:
Sylwia Stączek
,
Małgorzata Cytryńska
,
Agnieszka Zdybicka-Barabas

Antimicrobial peptides (AMPs) are short, mainly positively charged, amphipathic molecules. AMPs are important effectors of the immune response in insects with a broad spectrum of antibacterial, antifungal, and antiparasitic activity. In addition to these well-known roles, AMPs exhibit many other, often unobvious, functions in the host.

  • antimicrobial peptides
  • insect immunity
  • aging
  • neurodegeneration

1. Introduction

Antimicrobial peptides (AMPs) are indispensable components of insect innate immunity. They exhibit antibacterial, antifungal, antiviral, and antiparasitic activity. Since the discovery of the first insect AMP, cecropin in Hyalophora cecropia hemolymph [1], many AMPs with different biochemical and antimicrobial properties have been described in species representing different insect orders. Several families of AMPs have been identified in Drosophila melanogaster (Diptera), e.g., cecropins, defensin, drosocin, drosomycin, diptericins, metchnikowin, and attacins [2]. In lepidopteran species, e.g., the greater wax moth Galleria mellonella or the mulberry silkworm Bombyx mori, cecropins, defensins, gloverins, moricins, proline-rich peptides, attacins, and anionic antimicrobial peptides have been characterized [3][4][5][6]. The Antimicrobial Peptide Database [7] (https://aps.unmc.edu/; accessed on 11 February 2023) collecting AMPs of natural origin contains 3569 peptides, including 367 insect-derived molecules.

2. AMPs in the Nervous System

Research conducted so far shows that there is a connection between alterations in immune signaling and neuronal health, communication, and activity in insects. Changes in neuroimmune communication and glial cell signaling may contribute to behavioral changes in the insect. In addition, the insect nervous system can mount a local immune response to infection, and activation of signaling pathways may lead to neurodegeneration, malfunctioning neurons, and altered behavior [8]. Moreover, the AMP expression pattern is affected by aging independently of infection, and it has been postulated that an increased level of some AMPs produced in non-neuronal tissues during aging can mediate a signal initiating neuronal aging [9].
AMPs are important for regulation of normal functions of the insect brain, e.g., sleep and non-associative learning in Drosophila [10][11]. Results reported by Dissel et al. showed that the transcript levels of metchnikowin (Mtk), drosocin (Dro), and attacin (Att) were differentially increased in glia, neurons, and the head fat body, respectively, in sleep-deprived flies. They further demonstrated that the expression of Mtk in glia but not in neurons and the expression of Dro in neurons but not in glia had a negative effect on memory but modulated sleep in an opposite way. These AMPs were considered as candidates for conferring resilience/vulnerability to sleep deprivation [12]. A further link between sleep regulation and immune response in Drosophila was found by Toda et al. in their research on sleep mutants and the role of nemuri–a gene involved in sleep induction. Nemuri overexpression increased the sleep length and depth in Drosophila. Interestingly, nemuri encodes an AMP that can be secreted ectopically to drive prolonged sleep and to promote survival after infection. This peptide acts non-cell-autonomously to promote sleep. The nemuri peptide contains 64 amino acids, has sequence similarity to a Greenland cod (Gadus ogac) cathelicidin, and kills bacteria in vitro (Serratia marcescens, Escherichia coli) and in vivo. Drosophila adults overexpressing nemuri in neurons and infected with S. marcescens or Streptococcus pneumoniae survived longer, had a longer amount of sleep, and contained a lower bacterial load than control insects [13]. In another study, a Drosophila non-associative long-term memory (LTM) paradigm involving a natural predator of Drosophila, i.e., the endoparasitoid wasp Leptopilina heterotoma, was used for identification of novel memory genes during and after memory formation. The examination of transcriptional changes in the fly brain revealed that cecropin A1 (CecA1), CecA2, Dro, AttA, diptericin (Dpt), and DptB were differentially regulated at various time points. Specifically, CecA1, Dpt, and Dro were downregulated and upregulated in 7-h and 4-day exposed individuals, respectively [14]. Evidence that AMPs can directly affect brain function was also presented by Barajas-Azpeleta et al., who found 10-12-fold upregulation of DptB expression in the adult fly head following behavioral training. Moreover, using DptB null flies, they demonstrated that DptB was required for modulation of long-term memory in Drosophila. Interestingly, only silencing the DptB expression in the head fat body affected long-lasting memory, clearly indicating the head fat body as the only relevant source of DptB for behavioral modification [15].
Recently, the expression of two AMPs belonging to defensins, i.e., galiomicin and gallerimycin, has been detected in the brains of G. mellonella larvae after injection of Habrobracon hebetor venom or topical application of the entomopathogenic nematode Steinernema carpocapse. However, the role of these peptides in the G. mellonella nervous system has not been investigated yet [16]. In this study, the upregulation of the sericotropin gene and peptide was also detected in the brains of challenged larvae. Sericotropin functions in lepidopteran insects as a stimulator of silk production. It has been demonstrated that synthetic peptides derived from the N- and C-terminal parts of sericotropin exhibited antibacterial activity against Xenorhabdus spp. bacteria, i.e., symbionts of S. carpocapse, suggesting an antimicrobial role of sericotropin expressed in the G. mellonella brain [16]. In the brains of the honeybee A. meliffera infected with deformed wing virus (DWV), transcriptomic and metabolomic analyses revealed overexpression of genes encoding proline-rich AMPs, abaecin and apidaecin, as well as hymenoptaecin and an increased level of these peptides [17]. Results obtained in a study on the response of the central nervous system (CNS) of Locusta migratoria manilensis infected with the fungus Metarhizium acridum also indicated an important cross-talk between the CNS and the immune system. The expression patterns in the CNS responded rapidly to the infection and changed as the infection proceeded. Many differentially expressed genes, directly involved in immune function and regulation, were identified, including genes encoding defensin and diptericin, which were up-regulated in the CNS of M. acridum-challenged locusts [18].
The use of Drosophila models of Alzheimer’s disease (AD), traumatic brain injury (TBI), and ataxia-telangiectasia (AT) revealed a role of the Toll and Imd signaling pathways in neurodegeneration [19][20][21][22][23]. Although Toll signaling is engaged in proper development of the brain in Drosophila, it was demonstrated that suppression of Toll signaling protected against neurodegeneration. Moreover, Drosophila mutants in the negative regulator of the Imd pathway, dnr1 (defense repressor 1), had increased expression of AMP genes (Cec, Dpt, Att, drosomycin (Drs), Mtk), which was correlated with progressive age-dependent neuropathological changes and a shortened lifespan. It has also been demonstrated that neurodegeneration is dependent on the transcription factor Relish, and bacterial infection in the brain can trigger neurodegeneration through the neurotoxic effects of AMPs. On the other hand, Relish mutations inhibited upregulation of innate immune response genes and neurodegeneration in AT Drosophila mutants, whereas overexpression of active Relish in glial cells resulted in neurodegeneration [20][24]. Similar effects as those caused by mutations in dnr1 were observed in flies with mutations in other negative regulators of the Imd signaling pathway: zfh1 (transcription factor Zn finger homeodomain 1), Pirk (poor Imd response upon knock-in), trbd (deubiquitinase Trabid), and tg (Transglutaminase), strengthening the evidence for the negative role of AMPs in the development of diseases [25][26]. Moreover, the overexpression of Dro, AttC, and CecA1 in neurons or glia was accompanied not only by a shortened lifespan but also by early appearance of locomotor defects in comparison with controls, suggesting a causative relationship between high levels of AMPs and neurodegeneration in Drosophila [26]. In turn, Barati et al. studied the effect of amyloid-β 42 (Aβ42) and tau on the Imd pathway and neuroinflammation gene expression in a Drosophila model. They showed that the expression of genes involved in the Imd pathway, such as Relish and AMPs (AttA, DptB), increased with age in the W1118 control flies and in the embryonic nervous system of AD transgenic flies Aβ42, tauWT, or tauR406W, but the level of AMPs in glia remarkably decreased compared to W1118. The decline was higher in both tau flies compared to Aβ42 transgenic flies. The overexpression of AMPs in Drosophila leads to brain neurodegeneration and neuroinflammation [27]. Another example connecting overexpression of AMPs with neurodegeneration was provided by research on the role of the Yorkie transcription factor in polyglutamine (PolyQ)-mediated neurotoxicity (involved in Huntington’s disease in humans) in Drosophila. It was found that PolyQ expansion increased the expression of CecA, Att, Dpt, Dro, and Drs. It was postulated that upregulation of AMPs can participate in PolyQ-mediated neurotoxicity in Drosophila [28].
An important role of one of the AMPs, metchnikowin, in acute and chronic outcomes of TBI was demonstrated by Swanson et al. in a Drosophila TBI model. In an analysis of null mutations in 10 AMP genes (AttA, AttB, AttC, AttD, defensin (Def), Dro, Drs, Mtk, DptA, DptB), it was found that Mtk mutant flies exhibited reduced acute behavioral deficits and only the mutation in the Mtk gene protected flies from early mortality after TBI in different diet conditions. These results indicate that Mtk plays an infection-independent role in the nervous system and can promote neuropathological changes in the brain following TBI [29]. In another study conducted in a Drosophila Closed Head Injury (dCHI) model, an acute broad-spectrum immune response was detected in glia cells, where many AMP genes were up-regulated 24 h after TBI (Att, Cec, Def, Dpt, Dro, Drs, Mtk, listericin). It was found that the deletions of most of these AMPs shortened insect survival after TBI. In contrast, loss of Def extended survival, indicating that the Drosophila immune response to TBI, including the induction of AMP expression, may result in different effects. Moreover, in this research, a link between the immune response and sleep in flies was demonstrated, as loss of Relish protected against impaired control of sleep and movement after TBI [11].
Progress of neurodegenerative processes is correlated in time with an age-dependent increase in AMP expression in the head tissue of Drosophila [26]. Using a transgenic Drosophila model of AD, Wang et al. provided evidence for distinct expression profiles of AMP genes in an aging model and in wild-type flies. Whole transcriptome profiles of wild-type Drosophila heads revealed upregulation of 12 AMP genes: AttA, AttB, AttC, AttD, CecA2, CecC, DptA, DptB, Drs, Def, Dro, and Mtk. A gradual increase in expression of these AMPs was observed in the wild-type flies during the normal aging process, whereas an initial decrease and a subsequent increase in the expression levels was found during aging of the AD flies. Interestingly, significant correlations between the abnormal amyloid β (Aβ) peptide concentration and abnormal expression of AttB, AttC, CecA, Drs, Mtk, and LysS were detected, suggesting contribution of AMP dysregulation to AD progression by inducing deposition of Aβ peptide aggregates [30]. However, in other studies, lysozyme was demonstrated to be beneficial in different Drosophila models of AD. For example, co-expression of human lysozyme rescued the rough eye phenotype indicative of toxicity in flies that expressed Aβ1-42 in the eyes. Moreover, lysozyme binding with Aβ1-42 in the Drosophila eye was detected, suggesting that such an interaction prevented from the toxic effects of Aβ1-42 [31]. Interestingly, antimicrobial activity of the Aβ peptide was reported, suggesting that it is an AMP in the nervous system and that neurodegenerative Alzheimer’s disease may be partially an infectious disease [32]. Increased activation of innate immunity mechanisms reflected by overexpression of AMP genes was also postulated as a cause of long-term deleterious effects leading to neurological deficits, persistent cell death in brains, and premature aging in a Drosophila model of radiation-induced neurotoxicity. In this study, upregulation of Drs, DroA, Dpt, AttC, Cec, and Mtk was detected in brains of 5-day- and 15-day-old adult flies after radiation exposure during larval development (late third larval instar), indicating contribution of persistent activation of immune signaling pathways to neurological deficits in adult flies [33].
The connection between immunity and nervous system is also evident at the level of neuropeptides. Among human neuropeptides, antimicrobial activity has been reported for enkelytin, substance P, neuropeptide Y, bombesin, adrenomedullin, vasoactive intestinal peptide, and pituitary adenylate cyclase activating polypeptide (PACAP) [34][35]. Besides regulation of neurodevelopment, emotion, and certain stress responses, the PACAP neuropeptide acts as an antimicrobial agent. Although its antimicrobial function was demonstrated in mammals, the phylogenetic analysis predicted antimicrobial properties of eleven PACAP homologs, including PACAP from the cockroach Periplaneta americana [36].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24065753

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