ABSTRACT
Historically, the fields of ecoimmunology, psychoneuroimmunology and disease ecology have taken complementary yet disparate theoretical and experimental approaches, despite sharing critical common themes. Researchers in these areas have largely worked independently of one another to understand mechanistic immunological responses, organismal level immune performance, behavioral changes, and host and parasite/disease population dynamics, with few bridges across disciplines. Although efforts to strengthen and expand these bridges have been called for (and occasionally heeded) over the last decade, more integrative studies are only now beginning to emerge, with critical gaps remaining. Here, we briefly discuss the origins of these key fields, and their current state of integration, while highlighting several critical directions that we suggest will strengthen their connections into the future. Specifically, we highlight three key research areas that provide collaborative opportunities for integrative investigation across multiple levels of biological organization, from mechanisms to ecosystems: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors. By building new bridges among these fields, and strengthening existing ones, a truly integrative approach to understanding the role of host immunity on individual and community fitness is within our grasp.
Introduction: Where have we been? The origins and evolution of immunology-related fields
The immune system, once studied almost exclusively within the field of immunology, has in the last several decades become an important area of focus among a broader range of scientists, including physiologists, ecologists and behavioral neuroscientists. Today, several related fields exist that aim to understand immune system function; these include psychoneuroimmunology, ecological immunology (ecoimmunology) and disease ecology (Fig. 1). The field of psychoneuroimmunology was born from (1) seminal studies in the 1980s revealing that immune responses were susceptible to classic conditioning, and (2) the identification of key connections among psychological processes and the immune, nervous and endocrine systems (Ader and Cohen, 1981; Ader et al., 2001). Disease ecology has its roots in epidemiology, with the development of mathematical models to understand direct and indirect (via hosts) parasite spread in populations (Kermack et al., 1927; Ross, 1911, 1915). Important goals of this discipline are to explain how pathogens affect host populations, and how they are transmitted spatially and temporally, while considering ecological and evolutionary drivers of those processes (Kilpatrick and Altizer, 2010). More recently, an appreciation of environmental influences on immune system function has occurred within the fields of ecology and evolutionary biology, leading to the emergence of ecological immunology (Folstad and Karter, 1992; Sheldon and Verhulst, 1996).
The field of ecoimmunology aims to understand immune system function within an integrative organismal context, but also through an ultimate, evolutionary lens. To accomplish this, ecological immunology, like psychoneuroimmunology, combines diverse approaches from evolution, ecology and life history theory on the one hand, with endocrinology, neurobiology, molecular biology and behavior on the other (Demas and Carlton, 2015; Schulenburg et al., 2009). Another exciting avenue of research that broadens the ecoimmunological perspective is its integration with disease ecology (Hawley and Altizer, 2011). Areas of synergy between ecoimmunology and disease ecology include: (1) potential immune mechanisms underlying host heterogeneity in disease susceptibility, (2) environmental influences (e.g. seasonality, climate change) on host susceptibility and pathogen dynamics, and (3) the effects of infection by taxonomically and functionally distinct groups of parasites that elicit different immune responses by the host. Just as there is considerable natural variation in immunity among organisms, there is also variation in individual infection status over time. Psychoneuroimmunologists have shown us that infection and immune activation influence the neuroendocrine system and vice versa. Gaining a greater understanding of the environmental and neuroendocrine factors that affect the immune system dynamics of both infection and coinfection will undeniably expand our understanding of human and wildlife disease dynamics. For example, in the case of coinfection, major gaps remain with respect to how the immune and neuroendocrine systems interact and influence the dynamics of multiple infections in natural systems (e.g. Rynkiewicz et al., 2015; Viney and Graham, 2013).
Despite the relative importance of the fields of psychoneuroimmunology, ecoimmunology and disease ecology, much of the research within each field remains predominantly focused narrowly on only a single level of analysis with little overlap. Although there has clearly been increasing integration and synthesis in recent years (e.g. simulated immune and sickness studies in free-living animals testing ecoimmunological outcomes), more work remains to be done. The primary goal of this Centenary Commentary is to identify and briefly discuss the critical next steps that will strengthen connections among these related disciplines, and to highlight some key research questions that will provide opportunities for continued integration across multiple levels of organization (Fig. 1). By strengthening the bridges among these fields, we can build a critical integrative framework within which we can begin to understand the central role of host immunity on individual, community and ecosystem fitness.
Acute phase response
Systemic immune reaction of an organism in response to infection or tissue injury.
Allogrooming
A behavior involving an individual grooming other members of the same species.
Gnotobiotic
Colonized by a specific community of known microorganisms or lacking any microorganisms (i.e. germ-free).
Humoral immunity
A type of acquired immunity involving the generation of specific antibodies by B lymphocytes to neutralize antigens.
Innate immunity
Non-specific immunity present at birth that provides the first line of defense in response to a pathogen.
Immune priming
Increased host immunity in response to an initial exposure to a pathogen, providing increased immune defenses following a subsequent infection by the same or similar pathogen.
Microbe-associated molecular patterns (MAMPs)
Patterns of molecules or parts of molecules having structures or chemical patterns unique to specific microbes, allowing them to be identified as foreign; these include lipopolysaccharide, bacterial lipoprotein and flagellin.
Mitogen
Substance that stimulates cellular mitosis, including leukocytes, thereby non-specifically stimulating immune cells.
Peyer's patches
Small clusters of lymphatic tissue located throughout the gastrointestinal tract that regulate intestinal bacteria populations.
Probiotics
Live microorganisms typically introduced into an organism with the goal of improving health.
Psychosocial factors
An array of factors related to an individuals' psychological state and social environment that have the potential to influence that individual.
Pyrogens
Substances that induce a fever response when introduced into the blood.
Where are we going? The future of ecoimmunology, psychoneuroimmunology and disease ecology
Despite the historic disconnect among the related fields of psychoneuroimmunology, ecoimmunology and disease ecology, there are several current research areas making strides towards integration of these areas. Because of the brevity of this Centenary Commentary, we cannot afford to cover all of the exciting avenues at the level of detail they deserve. Instead, we have chosen to highlight three examples of areas where progress is being made in filling the remaining gaps among psychoneuroimmunology, ecoimmunology and disease ecology (Fig. 2). These areas include: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors.
Parental effects
Infection induces immune stimulation of parents, and can thereby influence offspring phenotype, including immunity, through transgenerational effects (Grindstaff et al., 2006). This area of research can therefore connect disease ecology (studies of infection in the parents), ecoimmunology (testing immune outcomes and fitness consequences) and psychoneuroimmunology (identifying physiological changes in parents that influence offspring). Other physiological changes that occur during immune activation of parents can also have lasting consequences for offspring; these include metabolic changes, temperature changes (e.g. fever), induction of the stress response and production of free radicals (Costa et al., 2020; Garbett et al., 2012; Glover, 2015; Howerton and Bale, 2012; Parolini et al., 2019).
The mechanisms by which parental infection affects developing offspring differ depending on both the type of infection and the mode of reproduction. For example, in viviparous species, there is a prolonged potential for exposure to maternal effects owing to development taking place inside the mother. However, many of these species also benefit from placental buffering that can limit exposure to certain maternal influences (including steroid hormones) during development (Painter et al., 2002). Conversely, oviparous species primarily influence their offspring during yolk deposition. However, hormones that may be elevated during immune challenges and infection can be transferred to eggs in the oviduct, even post-shelling (Ensminger et al., 2018).
Regardless of reproductive mode, transgenerational effects seemingly occur through multiple different pathways following infection, including through: (1) factors directly associated with inflammation (e.g. cytokines, prostaglandins, antibodies), (2) the associated activation of the hypothalamic–pituitary–adrenal axis, (3) modulation of the hypothalamic–pituitary–gonadal axis (Kentner and Pittman, 2010; Romero-Haro and Alonso-Alvarez, 2020), (4) changes in incubation temperature associated with maternal fever or even hypothermia during infection (French et al., 2013) and (5) altered oxidative stress owing to immune-induced oxidative bursts (Sorci and Faivre, 2009), which produces reactive oxygen species (ROS), known to have important roles in developing offspring (Parolini et al., 2019; Possenti et al., 2018). We discuss examples of these pathways in more detail below in the following paragraph.
Elevated maternal glucocorticoids are transferred to developing offspring (Merlot et al., 2008; Miltiadous and Buchanan, 2021), and can alter offspring physiology (Haussmann et al., 2012). Likewise, specific cytokines that are elevated during maternal immune activation result in neuroendocrine-immune effects: elevated levels of the cytokine interleukin-6 (IL-6) in offspring results in both transcriptional and behavioral changes (Smith et al., 2007). One key product of the action of certain cytokines during inflammation is fever, which can change incubation temperature for embryos; the relevant cytokines are pyrogens (see Glossary), including interleukin (IL)-1, IL-6, IL-8, macrophage-inflammatory protein-1β and interferon-γ. Any change in maternal temperature is significant because developing embryos are especially sensitive to temperature (Costa et al., 2020; Du and Shine, 2015; Edwards et al., 2003). However, in some instances, animals respond to infection with hypothermia (Romanovsky and Székely, 1998); this tends to occur when animals are in an energy deficit (MacDonald et al., 2014; Romanovsky and Székely, 1998), receive relatively larger immune challenges (e.g. higher dose of mitogen; see Glossary) (French et al., 2013) or, in the case of zebra finches, receive immune challenges during different times of the day (Sköld-Chiriac et al., 2015). This may explain why females demonstrate suppressed febrile responses during reproduction, a life-history event that incurs a significant energy cost (Martin et al., 1995; Zurovsky et al., 1987); alternatively, perhaps preventing hyperthermia during pregnancy is an adaptive response to protect developing embryos.
Studies investigating either experimentally induced or natural infections can help to elucidate mechanisms from parasite infection/disease processes to immunological responses, and ultimately to psychoneuroimmunological mechanisms that can affect multiple generations. For example, depending on the magnitude of the challenge, maternal immune stimulation using a simulated bacterial infection in Siberian hamsters (Phodopus sungorus) results in either fever (low-magnitude challenge) or hypothermia (high-magnitude challenge), reduced pregnancy success and litter size, and elevated endocrine stress responses in offspring (French et al., 2013). Additionally, maternal immune responses in viviparous species are known to affect offspring immunity in a sex-specific manner (French et al., 2016). This is also the case in oviparous species, where activation of the immune system with lipopolysaccharide (LPS) in pregnant (i.e. vitellogenic) female side-blotched lizards (Uta stansburiana) reduces the deposition of reactive oxygen metabolites in developing eggs (Virgin et al., 2023), thus altering their oxidative status, a factor that is known to alter offspring phenotype (Romero-Haro and Alonso-Alvarez, 2020). There is also a vast literature in invertebrates showing that parental pathogen exposure induces offspring resistance to pathogens, changes in immunity or both (reviewed in Tetreau et al., 2019).
Many, though not all, maternal effects are thought to be beneficial, priming the offspring for the environment into which it will be born (Estes and McAllister, 2016; Grindstaff et al., 2003; Parker and Douglas, 2010). These preparations include maternal factors that are transferred to offspring (e.g. antibodies to specific pathogens, lysozymes and antimicrobial peptides) and even altered offspring condition and size (Boonyarittichaikij et al., 2018; Grindstaff, 2008). For example, maternal antibodies provide offspring protection against infection with a specific strain of Lyme disease, which is spread through tick bites in bank voles (Myodes glareolus; Gomez-Chamorro et al., 2019). Similarly, desert tortoise (Gopherus agassizii) mothers transmit antibodies against Mycoplasma agassizii, which causes a serious respiratory illness, to their offspring (Schumacher et al., 1999), and pied flycatchers (Ficedula hypoleuca) exposed to bacterial antigens prior to laying produce offspring with enhanced humoral immune responses (Grindstaff et al., 2006). Invertebrates also show examples of immune priming (see Glossary); there are both maternal and paternal contributions, but the effects of these parental contributions vary (Zanchi et al., 2011). For example, in yellow mealworm beetles (Tenebrio molito), all offspring from mothers challenged with a bacteria-like infection have enhanced general immunity, but offspring immune priming from paternal contributions only occurs in a limited window early in the reproductive process (Zanchi et al., 2011).
It is important to highlight that maternal exposure to parasites is not always beneficial for the next generation. For example, in side-blotched lizards, adult females with more mites show greater bacterial killing responses, but maternal mite burden is inversely related to yolk bacterial killing ability of eggs, suggesting that there is a trade-off between the immune response of the mother and reproductive investment (Virgin et al., 2023). Moreover, mothers with greater bacterial killing ability and higher levels of reactive oxygen metabolites have smaller clutches in terms of mass (Virgin et al., 2022). Thus, the maternal environment – including both parasites and microbes – and psychoneuroimmunological responses to infection have important influences on offspring immune development, and may ultimately affect offspring survival and fitness.
Finally, direct transmission of parasites and microbes via the mother can alter offspring physiology and phenotype (Clayton and Tompkins, 1994; Stewart et al., 2005). This process provides an opportunity to further explore the connections between disease ecology, ecoimmunology and psychoneuroimmunology. The maternal transmission of Toxoplasma, a common parasite in endotherms, is well documented (Hide et al., 2009), and can have detrimental effects for offspring. There is also evidence for the vertical transmission of Hepatozoon blood parasites in the ovoviviparous terrestrial garter snake (Thamnophis elegans; Kauffman et al., 2017) and in multiple vole species (Microtus; Tołkacz et al., 2023), yet the health effects in these instances are less clear. There is even recent evidence of direct maternal transmission of nematodes from oviparous female common wall lizards (Podarcis muralis) to the brains of their offspring (Feiner et al., 2020). Interestingly, some social invertebrates demonstrate not only vertical transmission of pathogens, but also horizontal transmission across individuals, leading to colony immunization (Konrad et al., 2012; Masri and Cremer, 2014). These examples of maternal and colony parasite transmission provide direct links between disease ecology, ecoimmunology and psychoneuroimmunology through maternal effects. More research is needed to understand how early and prolonged parasite (or microbial) exposure during development – combined with maternal effects associated with infection – may affect offspring. In particular, a focus on how the vertical transfer of microbes alters offspring immune function and phenotype would be fruitful.
Overall, the connections among parental immune activation and offspring changes are apparent; however, the underlying mechanisms regulating these offspring effects remain unclear and deserve future attention. Moving forward requires integrating the fields of disease ecology to understand the infection dynamics in the parents, ecoimmunology to test immune outcomes in parents and offspring, and psychoneuroimmunology to test underlying mechanisms.
Microbiome–immune interactions
The mucosal surfaces of virtually all organisms host a complex ecological community composed of commensal, symbiotic and pathogenic bacteria, archaea, fungi and viruses, called the ‘microbiota’ (their genes are collectively referred to as the ‘microbiome’). The microbiota of humans, for example, is estimated to contain nearly 100 trillion microorganisms and over 1000 distinct bacterial species alone (Sender et al., 2016). For most animals, the microbiome plays a critical role in survival (Mueller et al., 2020; Williams et al., 2020). By aiding in nutrient acquisition and digestion (Hooper et al., 2001), directing development (Erny et al., 2015; Heijtz et al., 2011), modulating social behaviors (Brucker and Bordenstein, 2013; Cusick et al., 2021; Dinan et al., 2015) and affecting host immune system function (Chung et al., 2012; Sylvia and Demas, 2018), the microbiome connects many physiological systems (e.g. the neuroendocrine and immune systems; Garcia-Reyero, 2018; Sylvia and Demas, 2018) and can directly affect host fitness (Suzuki, 2017). Given this array of functions, the microbiome has received more integrative attention from the fields of psychoneuroimmunology, disease ecology and ecological immunology, as outlined below.
Microbiota are present throughout the body, often in largely discrete communities within an individual (e.g. Rojas et al., 2020). Because most of the host's microbiome is found within the gastrointestinal tract (i.e. gut; Wallace et al., 2011; Williams et al., 2020), much of the empirical work has focused on the ‘gut microbiome’. There are fewer investigations into the function of the microbiome associated with other body sites (e.g. skin, vagina, oral cavity), but these are crucially needed, as microbes on other body sites are likely to also affect the behavior and physiology of the host (Rojas et al., 2020). Through both direct (e.g. vagus nerve) and indirect (e.g. cytokines) mechanisms, an individual's microbiome affects several body systems, including the immune, neuroendocrine and nervous systems. Consequently, the microbiome plays a critical role in modulating host physiology and behavior. In addition, the gut microbiome develops in tandem with the neonatal central nervous system through the transmission of signals from the vagus nerve, the major nerve of the parasympathetic nervous system, to the gastrointestinal tract. This ‘gut–immune–brain axis’ serves as a bidirectional pathway facilitating communication between gut microbes and the immune and nervous systems (Morais et al., 2021).
Much of our understanding of the connections between the microbiome and the host immune system comes from studies employing ‘germ-free’ mice – mice that lack microbes entirely (Hooper et al., 2012). By employing this model, we have begun to appreciate the importance of gut bacterial communities for an organism's phenotype. Further, new knowledge about how different microbes work together with the host's immune system to mediate both innate (see Glossary) and humoral responses, in health and disease contexts, was made possible by studies supplementing germ-free mice with specific commensal and pathogenic bacteria (e.g. Hooper et al., 2012). The gut also possesses its own immune system, which serves to protect against pathogenic bacteria and to create a dynamic environment for beneficial bacteria (Ichinohe et al., 2011). For example, immune responses to influenza (e.g. antibodies and T-cell responses) are significantly decreased in antibiotic-treated relative to control mice, owing to antibiotics altering their gut microbes (Ichinohe et al., 2011). Further, the commensal bacteria of the gut (e.g. Lactobacillus and Enterobacter) may play a particularly important role in supporting the immune system in response to influenza (Ichinohe et al., 2011). Conversely, host immunity serves to relay information to the gut to maintain homeostasis, and it may be especially critical in supporting the microbiome in times of disruptions to homeostasis, such as during exposure to stressors or changes in diet or following antibiotic treatment (Sylvia and Demas, 2018).
Although the precise means by which microbes communicate with the brain to influence behavior are still being uncovered, we know that the immune system is likely to play a particularly important role in this crosstalk (Lee and Mazmanian, 2010). For example, germ-free rats have altered development of various features of the immune system, including fewer, smaller and inactive lymph nodes and Peyer's patches (see Glossary), preventing the immune system from responding appropriately to immune challenges (Hoshi et al., 1992). Crosstalk between various microbial-associated molecular patterns (MAMPs; see Glossary) within the gut microbiome may be possible. These molecules (and probably others) activate specific aspects of the immune system (e.g. macrophages) and influence the production of pro-inflammatory cytokines, which leads to alterations in physiology and behavior (reviewed in Sampson and Mazmanian, 2015). Although the gut has specific mechanisms to prevent the activation of the immune system by MAMPs, in times of prolonged immune activation (e.g. during long-term inflammation), the gut lining can become more vulnerable (i.e. ‘leaky’) and thus release endotoxins systemically, often leading to disease. Thus, while we continue to accrue a considerable amount of information about how the brain, immune system and microbiome interact in the context of both health and disease, there is still much to be learned, especially with respect to non-model species.
Microbial–immune interactions are becoming an active area of research within non-mammalian taxa as well (Bodawatta et al., 2022). With respect to avian microbiome–immune interactions, a growing body of research has focused on poultry as a model system. In poultry, a critical role for gut bacterial symbionts in immune system development has been demonstrated in young chicks by studying gnotobiotic individuals (see Glossary) compared with wild-type animals (Broom and Kogut, 2018a). As with development of mammalian immunity, crosstalk between gut bacteria and innate (e.g. Toll-like receptor and mucin genes) and adaptive (major histocompatibility complex MHC-I and MHC-II genes) immunity is critical for avian development (Broom and Kogut, 2018b). Furthermore, the administration of probiotics (see Glossary) reduces the prevalence and abundance of specific avian pathogens (e.g. Salmonella, Escherichia and avian influenza; reviewed in Bodawatta et al., 2022). In reptiles, evidence to support the frequent crosstalk between the microbiome and immune system has also amassed (reviewed in Siddiqui et al., 2022); vertical transmission of microbes in lizards is important to protect developing eggs from fungal infections and promote egg survival (Bunker et al., 2021). Most knowledge on the fish microbiome currently comes from species used in aquaculture (Luna et al., 2022).
Aside from the small amount of work on lizards discussed above, few non-mammalian studies have investigated microbiome–immune crosstalk outside of agriculturally relevant poultry and fish species. Thus, the field is ripe for studies across a broader array of species. Based on the emerging research within poultry, such studies should pursue field (or laboratory) manipulations of specific symbionts within gut microbiomes, combined with experimental infection studies to identify how specific bacteria can alter host fitness, either by directly attacking environmental pathogens or by altering host immunity. In amphibians, work of this kind is demonstrating that certain types of skin microbiota can reduce mortality and morbidity upon infection with the fungal pathogen Batrachochytrium dendrobatidis (Bd; reviewed in Walke and Belden, 2016). Bd is decimating amphibian populations worldwide and, therefore, understanding the protective potential of the skin microbiota has major conservation implications.
To complement field studies, in vitro experiments can employ the use of specific gut bacteria combined with individual pathogens to directly determine how elements of the microbiome help to reduce or prevent infections from environmental pathogens (Bodawatta et al., 2022). Field and laboratory-based studies employing combinations of antibiotic and probiotic administration, along with measures of immune and neuroendocrine function and assessments of pathogen resistance, will begin to identify specific mechanisms within the gut–immune–brain axis underlying disease resistance or susceptibility to infections. Because these physiological systems do not work in isolation, it is critical to focus on how their connections work together to create an organismal phenotype (e.g. Sylvia and Demas, 2018). Finally, because early-life experiences, including immune activation (see ‘Sickness behaviors’, below), diet and environmental stressors, can influence species-typical behavioral and physiological responses, and thus have the potential to affect an individual's fitness later in adulthood, it will be important to examine these influences in the context of the gut–immune–brain axis. It is obvious from this discussion that continued collaboration among immunologists, microbiologists, physiologists and disease ecologists (among others) will be critical for future progress in this area.
Sickness behaviors
Sickness behaviors provide another area of study that is ideal for exploring bridges between psychoneuroimmunology, ecological immunology and disease ecology. Sickness behavior is the term used to characterize the range of behavioral symptoms induced in response to many infections (Hart, 1988). These behaviors are one of the components of the acute phase response (Adelman and Martin, 2009), and they are triggered by the early steps of the inflammatory cascade (Dantzer, 2004). Sickness behaviors generally include reduced eating, drinking, locomotion, exploratory, sexual and social behavior, increased sleepiness, and increased thermal and pain sensitivity, as well as changes in thermoregulatory behavior (reviewed in Lopes et al., 2021). Because the manner and frequency with which animals interact with one another, as well as the way in which animals use space and common resources (such as food and water), are key determinants of infectious parasite spread, these major changes in host behavior are important for disease ecology (Stockmaier et al., 2021). For example, using a population of wild house mice, researchers showed that a simulated bacterial infection led to hosts drastically reducing their social contacts (Lopes et al., 2016). Disease models using data from social interactions of mice in this population predicted that those host-driven changes in behavior would have led to parasite spread being reduced to very few animals in the population, relative to scenarios where the host expressed no sickness behaviors (Lopes et al., 2016). Although this study illustrates the importance of sickness behaviors for disease transmission, research in the fields of psychoneuroimmunology and ecological immunology has shown that the extent to which sickness behaviors are expressed is highly contextual, depending on aspects such as the season, ambient temperature, age, sex, social status and social environment (Lopes, 2014). A deeper understanding of when and how context affects behavioral responses to an infection will lead to more precise models of disease spread. Therefore, this is one place where bridges between ecoimmunology, disease ecology and psychoneuroimmunology need to be strengthened.
In addition to sickness behaviors altering social contacts and space use of the infected host, they also provide cues of sickness to other animals. These cues can then lead other animals to alter their behaviors in ways that change social contacts and, thus, disease transmission. For example, many animals show avoidance of diseased groupmates (Lopes et al., 2022). Conversely, in certain species of social insects, allogrooming (see Glossary) of infected groupmates increases, which can help remove ectoparasites or fungal spores (Cremer et al., 2007). In extreme cases (e.g. advanced infection), however, social insects may attack, evict or even cannibalize infected nestmates (Baracchi et al., 2012; Davis et al., 2018; Drum and Rothenbuhler, 1985).
Bridges between psychoneuroimmunology, ecological immunology and disease ecology could help improve our understanding of: (1) what sickness cues are important for disease detection, (2) at what stage of progression diseases can be detected, and (3) how the cues are interpreted and used to trigger the types of groupmate behaviors discussed above. This improved understanding could ultimately lead to better predictions of when disease cues lead to altered social contact and disease spread in animal groups and populations. The feedback between the behavior of infected hosts and that of non-infected animals has become easier to explore owing to the emergence of more sophisticated, faster and more powerful behavioral tracking tools and software. For example, using high-resolution video tracking, (Jolles et al., 2020) showed that Schistocephalus solidus-infected sticklebacks move slower than uninfected individuals, and that this change in behavior covaries with parasite load and drives changes in collective behavior. Using automated tracking of Lasius niger ants in their colony, Stroeymeyt et al. (2018) also showed behavioral changes in both pathogen-exposed ants and their nestmates, leading to colony social network changes that helped contain the disease to fewer individuals. Combining experimental manipulation of different disease cues with these types of tracking tools could help us to link within-host with between-host processes.
Owing to its biomedical relevance, for decades there has been interest in understanding the precise ways in which the immune system and the brain communicate to elicit sickness behaviors (Dantzer and Kelley, 2007). The explosion of ‘-omics’ tools, particularly the rapid advances in spatial transcriptomics techniques providing unprecedented spatial resolution information on changes in transcripts (Larsson et al., 2021; Tian et al., 2023), combined with continued advances in chemogenetic (Atasoy and Sternson, 2018; Sternson and Roth, 2014), optogenetic (Deisseroth, 2015; Kim et al., 2017) and genome editing (Heidenreich and Zhang, 2016) tools, has recently allowed for more precise explorations of the neural mechanisms and neural populations involved in producing sickness behaviors. For example, using a combination of single nucleus RNA-sequencing and chemogenetic techniques, two recent laboratory studies identified the neuronal populations involved in the control of different aspects of sickness behaviors (Ilanges et al., 2022; Osterhout et al., 2022). Interestingly, differences in the findings between these two studies highlight the importance of integrating knowledge from the fields of ecological immunology and disease ecology into these types of mechanistic within-host studies. Even using very similar experimental settings (Table S1), in one study, mice responded with fever (Osterhout et al., 2022), whereas in the other study, mice responded with hypothermia (Ilanges et al., 2022). Most critically, the main brain region identified and characterized by Ilanges et al. (2022) – the nucleus of the solitary tract (NTS) – showed no differences in terms of neural activation in Osterhout et al. (2022). These differences are likely to stem from factors known in disease ecology and ecological immunology to affect physiological and behavioral responses to infection. For instance, differences in the time of day when the injections were administered and outputs quantified could affect some of the responses measured (Baxter and Ray, 2020). In addition, psychosocial factors (Lasselin, 2021) and the social environment (Lopes, 2014) are known to dramatically affect sickness behaviors. For example, a recent study demonstrated that the social environment can rapidly change how the brain responds to an LPS challenge (Lopes et al., 2023). Therefore, vocalizations or odors from females housed in the same room could have affected the neural responses observed. Non-mutually exclusive possibilities would be technical differences between the studies, such as the dose and type of LPS used (Horan et al., 1989; Lopes, 2016). Given that sex affects both the physiological and behavioral responses to an infection (Avitsur and Yirmiya, 1999; Lasselin et al., 2018; Lopes, 2014), it will also be crucial to include sex as a biological variable in these types of studies. Although it is more expensive and complex, it is perhaps relevant, therefore, to study animals in more naturalistic environments. Neural populations that are differently activated between sick and control animals under noisier but more realistic settings might be the ones that are most fundamental/essential for the control of sickness behaviors. Neural populations that are only activated under very specific circumstances (such as illustrated by the difference in NTS activation in the studies discussed) might be responsible for additive or compensatory effects. A combination of the types of behavioral tracking tools alluded to above (more used by ecoimmunologists and disease ecologists) with rapidly developing ‘-omics’ tools (more traditionally used by the field of psychoneuroimmunology) will permit researchers to increase studies in natural or semi-natural environments and in non-traditional study systems, while precisely measuring changes in behavior and physiology in response to infections. This knowledge is of interest to all three fields of study discussed in this Commentary. The importance of understanding these types of responses in wild animals is greatly illustrated by recent spillover events, such as the COVID-19 pandemic, and by reports that predict that those events will continue to increase in frequency owing to anthropogenic effects on the environment (e.g. Carlson et al., 2022).
Conclusions: immunology into the future
The overarching goal of this Centenary Commentary was to provide a brief historical perspective on the emergence of research areas within the field of immunology, with a critical eye toward the future: which directions they can take to make significant impacts within the next decade. By highlighting just three key areas of integrative immunological research, we have attempted to convey the strong potential for continued synthesis and integration across multiple levels of biological organization, from mechanisms to ecosystems. The three areas highlighted (parental effects, microbiome and sickness behaviors) draw attention to the myriad factors influencing how organisms respond to infection, which is a central question for psychoneuroimmunology, ecoimmunology and disease ecology. For example, the study of the microbiome underlines the idea that infection-like processes (such as gut colonization by micro-organisms) do not always lead to negative (pathogenic) outcomes. What characteristics of host and invading organisms dictate when these relationships will be beneficial, neutral or negative? How do ontology and context (physiological, social and environmental) affect infection outcomes, as illustrated in one or more of the three areas highlighted? Integrating a host-focused physiological perspective (characteristic of psychoneuroimmunology and ecoimmunology) with a pathogen-focused transmission perspective (used in disease ecology), while accounting for the effects of the environment on host and parasite biology (more common in ecoimmunology and disease ecology), will help answer these fundamental questions (Fig. 3).
More broadly, our goal was to illustrate how combining approaches from each of the three fields produces more transformative insights into infectious and immune processes; the integrative approach to studying the immune system has been, and will continue to be, an extremely productive strategy. Collaborative research areas that truly integrate fields and address critical linkages, from molecular mechanisms to whole-organism immune responses, behavioral outcomes, and parasite and host population dynamics that could affect ecosystems, have the potential to revolutionize the field. By building new bridges among psychoneuroimmunology, ecoimmunology and disease ecology, while continuing to strengthen existing ones, a truly integrative approach to understanding the effects of host immunity on individual and community fitness can be achieved (Figs 2 and 3).
Acknowledgements
We thank Charlotte Rutledge and anonymous reviewers for their constructive feedback on earlier versions of this paper.
Footnotes
Funding
This work was supported in part by National Science Foundation (NSF) grants IOS-1752908 to S.S.F., IOS-1656414 to G.E.D. and IOS-2232190 to P.C.L.
References
Competing interests
The authors declare no competing or financial interests.