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Insect immune responses and potential impacts on the nervous system. Insects utilize many different methods to fight off infection, which are reviewed here [37,40]. Briefly, (A) the humoral immune response involves the release of antimicrobial peptides (AMPs) from fat body cells and hemocytes into the hemolymph. AMPs aid in the targeting and destruction of different pathogens (e.g., bacteria and fungi). Intracellular signaling events (e.g., Spätzle/Toll, immune deficiency (IMD), and JAK–STAT signaling) are activated, leading to the synthesis of AMPs and the induction of different immune responses. Recent data have indicated the presence of immune priming in insects, making the insect immune system more adept at fighting off repeat infections than previously believed [43,46]. (B) Cellular responses to infection include, but are not limited to, the induction of processes such as melanization and nodulation, which effectively isolate and neutralize pathogens, and pathogen phagocytosis. Lastly, RNA interference (C) can mediate the degradation of viral genetic material. At present, it remains relatively unclear specifically how these processes (e.g., release of AMPs, alterations in intracellular signaling, phagocytosis, etc.) impact neural and glial cell function and host behavior (as indicated by the question marks). Images created with BioRender.com (accessed on January 15, 2021).
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Many organisms are able to elicit behavioral change in other organisms. Examples include different microbes (e.g., viruses and fungi), parasites (e.g., hairworms and trematodes), and parasitoid wasps. In most cases, the mechanisms underlying host behavioral change remain relatively unclear. There is a growing body of literature linking alterations...
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Citations
... CNS, central nervous system. References: 1, Eberhard (2010b); 2, Kloss et al. (2017); 3, Takasuka (2019); 4, Eberhard and Gonzaga (2019); 5, Dai et al. (2022);6, Cheng et al. (2017); 7, Mohan and Sinu (2022); 8, Kloss et al. (2016); 9, Sawadro et al. (2017); 10, Terashima et al. (2005);11, MacWilliam et al. (2015); 12, Adamo (2019); 13, Moen et al. (2022);14, Herbison (2017); 15, Weinersmith (2019); 16, Yamanaka (2021); 17, Will et al. (2020);18, Hughes et al. (2016); 19, Mangold and Hughes (2021); 20, Will et al. (2023); 21, Roosmalen and de Bekker (2024);22, Hoover et al. (2011). construction of a 'bed' or silk tangle by Theraphosidae spiders, although it was denser than the common moulting web in some cases (Cady et al. 1993, Sýkora et al. 2022); a web constructed by an Amaurobidae spider that initially resembled a pre-moult web but much denser (Sýkora et al. 2022); and a three-dimensional silk structure constructed by Philodromidae spiders parasitized before death by fly larva, which may also be related to egg-laying webs (Kehlmaier et al. 2012, Sýkora et al. 2022. ...
Certain parasites improve their fitness by manipulating their host’s behaviour. Some evidence suggests that parasites exploit innate pathways in the host to manipulate their behaviour. Furthermore, phylogenetically unrelated parasites can generate similar behavioural changes in hosts from the same taxonomic group. Spiders are hosts for several parasites that appear to induce behavioural changes, such as building modified webs that may benefit the parasites. Additionally, some observations on spiders parasitized by Ichneumonidae wasps suggest that the construction of modified webs may merely result from activating the innate ecdysis process. Considering that different parasites may use similar manipulation pathways, we review and examine evidence in the literature that phylogenetically distant parasites (wasps, dipterans, and fungi) may converge on the manipulation mechanism of host spiders through activation of the preexisting mechanism of ecdysis. Also, we suggest that webs built by fungus-infected spiders represent an extended phenotype of these parasites. We conclude that the strategy of behavioural manipulation through activation of innate ecdysis in hosts may have converged in the different spider parasites, which have been favoured over evolutionary time. Therefore, we propose possible pathways for activating this mechanism, and provisions for future investigations to test these hypotheses.
... Neuroinflammation is known to alter synaptic transmission 44 . Neuroinflammation is common in the hosts of parasitic manipulators and may be critical for host manipulation in some systems [45][46][47][48] . ...
The parasitic wasp, Cotesia congregata, manipulates the behaviour of its host, the caterpillar Manduca sexta. The female wasp injects her eggs and a symbiotic virus (i.e. bracovirus, CcBV) into the body of its host. The host’s behaviour remains unchanged until the wasps exit the caterpillar, and then the caterpillar becomes a non-feeding “bodyguard” for the wasp cocoons. Using proteomic, transcriptomic and qPCR studies, we discovered an increase in antimicrobial peptide gene expression and protein abundance in the host central nervous system at the time of wasp emergence, correlating with the change in host behaviour. These results support the hypothesis that the wasps hyperactivate an immune-neural connection to help create the change in behaviour. At the time of wasp emergence, there was also an increase in bracoviral gene expression and proteins in the host brain, suggesting that the bracovirus may also be involved in altering host behaviour. Other changes in gene expression and protein abundance suggest that synaptic transmission may be altered after wasp emergence, and a reduction in descending neural activity from the host’s brain provides indirect support for this hypothesis.
... Neuroin ammation is known to alter synaptic transmission 43 . Neuroin ammation is common in the hosts of parasitic manipulators and may be critical for host manipulation in some systems [44][45][46][47] . ...
The parasitic wasp, Cotesia congregata , manipulates the behaviour of its host, the caterpillar Manduca sexta . The female wasp injects her eggs and a symbiotic virus (i.e. bracovirus, CcBV) into the body of its host. The host’s behaviour remains unchanged until the wasps exit the caterpillar, and then the caterpillar becomes a non-feeding bodyguard for the wasp cocoons. Using proteomic, transcriptomic and qPCR studies, we discovered an increase in antimicrobial peptide gene expression and protein abundance in the host central nervous system at the time of wasp emergence, correlating with the change in host behaviour. These results support the hypothesis that the wasps hyperactivate an immune-neural connection to help create the bodyguard behaviour. At the time of wasp emergence, there was also an increase in bracoviral gene expression and proteins in the host brain, suggesting that the bracovirus may also be involved in altering host behaviour. Other changes in gene expression and protein abundance suggest that synaptic transmission is altered after wasp emergence, and this was supported by a reduction in descending neural activity from the host’s brain. We discuss how a reduction in synaptic transmission could produce bodyguard behaviour.
... Interestingly, our work is the first to establish a correlation between SOD1 mutations and AMPs that are instead known to be up-regulated in Drosophila models of neurodegeneration/neuroinflammation such as ataxia telangiectasia [78], Alzheimer's Disease [79], and traumatic brain injury [80]. Thus, our results now introduce attacin, cecropin, diptericin, drosocin, defensin, drosomycin and metchnikowin as novel biological mediators/markers of the neuroimmune-glia signaling and of the early evolution of the SOD1-ALS phenotype [81]. Confirming our results, pan-neuronal or motor neuronal overexpression of human TAR DNA-binding Protein 43 (TDP-43), a major pathological protein in ALS, leads to up-regulation of attacin and diptericin, and to a minor extent also of cecropin and drosocin [82]. ...
Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients’ death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration.
To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1A4V or hSOD1G85R).
We demonstrate that pan-neuronal expression of the hSOD1A4V or hSOD1G85R pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected.
The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.
... Microbes can shape how insects respond to a stimulus [54]. Although most of the studies addressing this focus on the implications of specific symbionts, entire microbial populations are also linked to diverse roles in the physiology and behaviour of insects such as Drosophila. ...
Microbes can be an important source of phenotypic plasticity in insects. Insect physiology, behaviour, and ecology are influenced by individual variation in the microbial communities held within the insect gut, reproductive organs, bacteriome, and other tissues. It is becoming increasingly clear how important the insect microbiome is for insect fitness, expansion into novel ecological niches, and novel environments. These investigations have garnered heightened interest recently, yet a comprehensive understanding of how intraspecific variation in the assembly and function of these insect-associated microbial communities can shape the plasticity of insects is still lacking. Most research focuses on the core microbiome associated with a species of interest and ignores intraspecific variation. We argue that microbiome variation among insects can be an important driver of evolution, and we provide examples showing how such variation can influence fitness and health of insects, insect invasions, their persistence in new environments, and their responses to global environmental changes.
... However, in contrast to behavior-manipulating trematodes and viruses (termed neuroparasites; Hughes and Liebersat 2018), hypocrealean fungi do not invade the CNS of the living host (Fredericksen et al. 2017), whereas recent evidence suggests that entomophthorelean species can infiltrate the CNS tissue while the host is still alive (Elya et al. 2018(Elya et al. , 2023. This all suggests that similar behaviors may be regulated by different underlying mechanisms across parasite phyla (Mangold and Hughes 2021). ...
Parasite-induced modification of host behavior increasing transmission to a next host is a common phenomenon. However, field-based studies are rare, and the role of environmental factors in eliciting host behavioral modification is often not considered. We examined the effects of temperature, relative humidity (RH), time of day, date, and an irradiation proxy on behavioral modification of the ant Formica polyctena (Förster, 1850) by the brain-encysting lancet liver fluke Dicrocoelium dendriticum (Rudolphi, 1819). This fluke induces ants to climb and bite to vegetation by the mandibles in a state of temporary tetany. A total of 1264 individual ants expressing the modified behavior were observed over 13 non-consecutive days during one year in the Bidstrup Forests, Denmark. A sub-set of those ants (N = 172) was individually marked to track the attachment and release of infected ants in relation to variation in temperature. Infected ants primarily attached to vegetation early and late in the day, corresponding to low temperature and high RH, presumably coinciding with the grazing activity of potential herbivorous definitive hosts. Temperature was the single most important determinant for the induced phenotypic change. On warm days, infected ants altered between the manipulated and non-manipulated state multiple times, while on cool days, many infected ants remained attached to the vegetation all day. Our results suggest that the temperature sensitivity of the infected ants serves the dual purpose of exposing infected ants to the next host at an opportune time, while protecting them from exposure to high temperatures, which might increase host (and parasite) mortality.
... 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 [23]. 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 [24]. ...
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. They support insects in the elimination of viral infections. AMPs participate in the regulation of brain-controlled processes, e.g., sleep and non-associative learning. By influencing neuronal health, communication, and activity, they can affect the functioning of the insect nervous system. Expansion of the AMP repertoire and loss of their specificity is connected with the aging process and lifespan of insects. Moreover, AMPs take part in maintaining gut homeostasis, regulating the number of endosymbionts as well as reducing the number of foreign microbiota. In turn, the presence of AMPs in insect venom prevents the spread of infection in social insects, where the prey may be a source of pathogens.
... Likewise, in mammalian hosts, the protozoan parasite Toxoplasma gondii appears to manipulate the behavior of its intermediate hosts through changes in dopaminergic signaling [41] in ways that augment predation by felines, its final host [42]. In general, however, it can be challenging to determine the extent to which these behavioral changes represent direct manipulation by the parasites, neuroimmune interactions, or both [43,44]. ...
... For example, rats that were infected with Escherichia coli as neonates exhibited memory impairment (measured as responsiveness to context-dependent shock conditioning) after given LPS injections as adults, potentially because glial activation in early development alters cytokine responses to subsequent immune challenges [61]. Although we do not fully understand the mechanisms by which glial activation impacts neural function in vertebrate or invertebrate systems [44], it is hypothesized that glial activation compromises synaptic efficiency and causes neural damage [62]. ...
Infectious disease is linked to impaired cognition across a breadth of host taxa and cognitive abilities, potentially contributing to variation in cognitive performance within and among populations. Impaired cognitive performance can stem from direct damage by the parasite, the host immune response, or lost opportunities for learning. Moreover, cognitive impairment could be compounded by factors that simultaneously increase infection risk and impair cognition directly, such as stress and malnutrition. As highlighted in this review, however, answers to fundamental questions remain unresolved, including the frequency, duration, and fitness consequences of infection-linked cognitive impairment in wild animal populations, the cognitive abilities most likely to be affected, and the potential for adaptive evolution of cognition in response to accelerating emergence of infectious disease.
... In addition, the host's immune and nervous system are undeniably connected (100)(101)(102). Immune responses against invading pathogens result in the release of factors that affect neural function. ...
Transmission is a crucial step in all pathogen life cycles. As such, certain species have evolved complex traits that increase their chances to find and invade new hosts. Fungal species that hijack insect behaviors are evident examples. Many of these "zombie-making" entomopathogens cause their hosts to exhibit heightened activity, seek out elevated positions, and display body postures that promote spore dispersal, all with specific circadian timing. Answering how fungal entomopathogens manipulate their hosts will increase our understanding of molecular aspects underlying fungus-insect interactions, pathogen-host coevolution, and the regulation of animal behavior. It may also lead to the discovery of novel bioactive compounds, given that the fungi involved have traditionally been understudied. This minireview summarizes and discusses recent work on zombie-making fungi of the orders Hypocreales and Entomophthorales that has resulted in hypotheses regarding the mechanisms that drive fungal manipulation of insect behavior. We discuss mechanical processes, host chemical signaling pathways, and fungal secreted effectors proposed to be involved in establishing pathogen-adaptive behaviors. Additionally, we touch on effectors' possible modes of action and how the convergent evolution of host manipulation could have given rise to the many parallels in observed behaviors across fungus-insect systems and beyond. However, the hypothesized mechanisms of behavior manipulation have yet to be proven. We, therefore, also suggest avenues of research that would move the field toward a more quantitative future.
... The molecular basis of this process involves the expression of genes coding for proteins that influence the behavior of the host or the pathogen. Here, Mangold and Hughes review specific situations where the behavioral phenotype of various insect hosts is manipulated by different microbes and parasites; they analyze the mechanisms responsible for these effects, and explain how they impact distinct aspects of the innate immune response [4]. The authors connect this information to neuroinflammation and its relationship to innate immune signaling and neural mechanisms. ...
The insect innate immune system is under strong selection pressure to evolve resistance to pathogenic infections [...]
