Immune-neural connections: how the immune system's response to infectious agents influences behavior

Abstract

Humans and animals use the classical five senses of sight, sound, touch, smell and taste to monitor their environment. The very survival of feral animals depends on these sensory perception systems, which is a central theme in scholarly research on comparative aspects of anatomy and physiology. But how do all of us sense and respond to an infection? We cannot see, hear, feel, smell or taste bacterial and viral pathogens, but humans and animals alike are fully aware of symptoms of sickness that are caused by these microbes. Pain, fatigue, altered sleep pattern, anorexia and fever are common symptoms in both sick animals and humans. Many of these physiological changes represent adaptive responses that are considered to promote animal survival, and this constellation of events results in sickness behavior. Infectious agents display a variety of pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs). These PRR are expressed on both the surface [e.g. Toll-like receptor (TLR)-4] and in the cytoplasm [e.g. nucleotide-binding oligomerization domain (Nod)-like receptors] of cells of the innate immune system, primarily macrophages and dendritic cells. These cells initiate and propagate an inflammatory response by stimulating the synthesis and release of a variety of cytokines. Once an infection has occurred in the periphery, both cytokines and bacterial toxins deliver this information to the brain using both humoral and neuronal routes of communication. For example, binding of PRR can lead to activation of the afferent vagus nerve, which communicates neuronal signals via the lower brain stem (nucleus tractus solitarius) to higher brain centers such as the hypothalamus and amygdala. Blood-borne cytokines initiate a cytokine response from vascular endothelial cells that form the blood-brain barrier (BBB). Cytokines can also reach the brain directly by leakage through the BBB via circumventricular organs or by being synthesized within the brain, thus forming a mirror image of the cytokine milieu in the periphery. Although all cells within the brain are capable of initiating cytokine secretion, microglia have an early response to incoming neuronal and humoral stimuli. Inhibition of proinflammatory cytokines that are induced following bacterial infection blocks the appearance of sickness behaviors. Collectively, these data are consistent with the notion that the immune system communicates with the brain to regulate behavior in a way that is consistent with animal survival.

Fig. 1.

Focusing the innate immune response. Insults to the body, from the outside or from the inside, activate cells of the innate immune system. The immune response transmits this information to the brain to cause physiological and behavioral responses. A mild inflammatory response – such as a low-grade infection, trauma (such as dropping a weight on one’s foot) or even strenuous exercise – results in reversible consequences as they are a result of altered cellular (neuron) function. A severe response induces often irreversible consequences as a result of cell death. In either case, the causal event is initiated by monocytic and dendritic cells with the initiation of an inflammatory response.

Fig. 2.

Classification of Toll-like receptors (TLRs). All TLRs recognize bacteria pathogen-associated molecular patterns (PAMPs) of protein, lipid or nucleotide composition. Approximately half recognize viral PAMPs, either lipids or nucleotides. TLR2/6 and TLR4 recognize fungal PAMPs whereas TLR9 and TLR11 recognize protozoan PAMPs. Several of the TLRs respond to extracellular ligands (1, 2, 4, 5, 6, 9 and 10 not shown) whereas others localize to cellular vesicles and respond to PAMPs that have been internalized by the cell (3, 7, 8, 9 and murine 11; human TLR11 is a pseudogene). Although some of the TLRs also activate proliferation of immune cells through an Akt-dependent pathway (not shown), they all induce the expression and secretion of cytokines. Cytokine production is largely responsible for behavioral changes induced by infection. All TLRs shown (TLR10 cooperates with TLR2 to recognize triacylated lipoproteins but does not activate typical TLR signaling) (Guan et al., 2010), except TLR3, directly induce the expression of TNFα, IL-1β and IFNγ whereas TLR3, 4, 7 and 9 activation results primarily in IFNα and IFNβ expression (Hanke and Kielian, 2011). A brief list of PAMPs or active analogs is shown for each TLR. For definitions, see List of abbreviations.

Fig. 3.

Classification of nucleotide-binding oligomerization domain proteins (Nods). Similar to TLRs, Nod1 and Nod2 are pattern recognition receptors (PRRs) responding to pathogen-associated molecular patterns (PAMPs) of bacterial origin (Newton and Dixit, 2012). Both Nods are localized to the cytoplasm, requiring either phagocytosis of bacteria and subsequent peptidoglycan entry into the cytoplasm or uptake of peptidoglycan by endocytosis, peptide transporters or pore-forming toxins. Nod1 is distributed across tissues and cell types whereas Nod2 is localized principally to leucocytes but can be induced in epithelium (Clarke and Weiser, 2011; Newton and Dixit, 2012). The primary difference between TLRs and Nods (and Nod-like receptors, NLRs) is the identity of the ligand and intracellular pathway. RICK or RIPK/RIP-2 initiate the eventual activation of NF-κB, as compared to MyD88 or TRIF. Similar to TLRs, Nods induce the expression and secretion of cytokines. For definitions, see List of abbreviations.

Fig. 4.

Neural and humoral activation of the brain by the periphery. Peripheral infections alter behavior by communicating with the brain via neural and humoral pathways. The neural pathway occurs via afferent nerves. As an example, the vagal nerve has a proven role in mediating infection-induced behavior. The afferent vagus projects to the nucleus tractus solitaries (NTS) → parabrachial nucleus (PB) → ventrolateral medulla (VLM) before proceeding to the paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus of the hypothalamus (SON), central amygdala (CEA) and bed nucleus of the stria terminalis (BNST). The CEA and BNST, which are part of the extended amygdala, then project to the periaqueductal gray (PAG). By these pathways, activation of the vagus by abdominal or visceral infections influences activity of several brain regions implicated in motivation and mood. The humoral pathway involves delivery of PAMPs or cytokines from the peripheral site of infection directly to the brain. Active transport into the brain across the blood–brain barrier (BBB), volume diffusion into the brain or direct contact with brain parenchymal cells at the choroid plexus (CP) and circumventricular organs [median eminence (ME), organum vasculosum of the laminae terminalis (OVLT, i.e. supraoptic crest), area postrema (AP) and suprafornical organ (SFO)] that lie outside the BBB all transpose the peripheral signal into a central neuroinflammatory response that mirrors the response at the periphery (Dantzer et al., 2008).

Fig. 5.

Cytokine intracellular signaling pathways. Cytokines bind to transmembrane allosterically regulated proteins. Upon ligand binding, the intracellular signaling pathways that are activated correlate to their ability to alter behavior. Three classic proinflammatory cytokines – TNFα, IL-1β and IL-6 – activate cascades leading to NF-κB and MAPK (p38 and JNK) activation. The MAPK cascade is enhanced by parallel signaling pathways that produce ceramide. In contrast, IFNγ, IFNα/β and IL-6 signal primarily through the JAK/STAT pathway. The NF-κB, MAPK and JAK/STAT pathways are considered proinflammatory, inducing a feed-forward cytokine inflammatory response. The ceramide-generating and MAPK pathways have distinct enhancing and inhibitory effects on neuron excitation.

Fig. 6.

Expression of pattern recognition receptors (PRRs) and proinflammatory cytokine receptors in the brain. Although most infections occur at the periphery, the cells of the central nervous system (CNS) are the ultimate mediators of changes in behavior. Receptors within the CNS for pathogen-associated molecular patterns (PAMPs) and proinflammatory cytokines are divided into two categories, intracellular (green boxes) and those that span the plasma membrane. PAMPs reaching the CNS parenchyma can directly activate microglia, which, like other monocyte-derived cells, possess a full complement of TLRs. Thus, microglia are able to respond to PAMPs or peripherally derived cytokines with a central induction of proinflammatory cytokine expression. Astrocytes and neurons have a very limited ability to respond to PAMPs. Neurons only possess intracellular TLRs and Nod2. In contrast, neurons have cell surface receptors for proinflammatory cytokines, TNFα (Bette et al., 2003), IL-1β (French et al., 1999), low expression of IL-6 (Lehtimäki et al., 2003), type I IFNα/β (Paul et al., 2007) and limited (region-specific) expression of the type II IFNγ receptor (Chesler and Reiss, 2002). The absence of most of the bacterial recognition TLRs on neurons indicates that the effects of an extracellular bacterial infection on behavior are secondary to activation of other cells of the CNS, primarily microglia. In contrast, neurons are directly responsive to cytokines.