Pathogen Host Defense (PATHOS-D) theory of depression:
|(1) Depression should be associated with increased inflammation and inflammatory activation should induce depression.
|(2) Allelic variants that increase the risk for major depressive disorder (MDD) should enhance host defense mechanisms in general and innate immune inflammatory responses in particular.
|(3) Environmental risk factors for MDD should be associated with increased risk of infection and attendant inflammatory activation.
|(4) On the whole, patterns of increased immune activity associated with MDD should have decreased mortality from infection in ancestral environments.
|(5) Depressive symptoms should enhance survival in the context of acute infection and in situations in which risk of infection from wounding is high.
Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations.
These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia.
By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.
Major depression is so detrimental to survival and reproduction that it is hard to understand why allelic variants that promote the disorder have not been culled from the human genome, why in fact—far from being culled—genes that promote depression are so common and numerous and appear to have actually increased in prevalence during recent human evolution.1 To address this issue, we have developed a novel theoretical framework positing that risk alleles for depression originated and have been largely retained in the human genome because these alleles encode for an integrated suite of immunological and behavioral responses that promote host defense against pathogens. This enhanced pathogen defense is accomplished primarily via heightened innate immune system activation, which results in reduced death from infectious causes,2, 3, 4, 5 especially in infancy when selection pressure from infection is strongest,6 and the adaptive immune system is not yet fully operational.6, 7, 8, 9 A vast literature has associated depressive symptoms and/or major depressive disorder (MDD) with increased innate immune inflammatory responses,10 with meta-analyses reporting the most consistent findings for increased plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein and haptoglobin.11, 12, 13 Recent longitudinal studies extend these cross-sectional observations by reporting that increased inflammatory markers in nondepressed individuals predict the later development of depression.14, 15, 16 Because infection has been the primary cause of early mortality and hence reproductive failure across human evolution,9, 17, 18, 19, 20, 21 it would be expected that if depressive symptoms were an integral part of a heightened immunological response, allelic variants that support this response would have undergone strong positive selection pressure and thus would be both numerous and prevalent, as they appear to be. However, because the survival benefits of inflammatory processes are tempered by their costs in terms of increased mortality from septic shock,22, 23 pathogen manipulation,21, 24 long-term tissue damage and chronic disease,10 these alleles would not be predicted to go to fixation (that is, 100% prevalence) but would be expected to manifest an intermediate prevalence reflecting the benefit of enhanced host defense in any given environment minus attendant costs. Again, this is consistent with current findings in the genetics of depression.
It should be noted that this Pathogen Host Defense (PAThos HOSt Defense=PATHOS-D) hypothesis is not the first theory to associate depression with protection from infection. Indeed, similar to PATHOS-D, at least one previous hypothesis has envisioned depression as a behavioral response that helps the immune system combat existing infections while avoiding additional pathogen exposure.25 However, prior theoretical articulations have envisioned depressive symptoms as adaptive primarily because they compensate for various types of immune system vulnerabilities.25 PATHOS-D suggests something qualitatively different and more far-reaching; specifically that depressive symptoms were integral components of immune-mediated host defense against pathogens in the ancestral environment. In this model, depressive symptoms are inextricably intertwined with—and generated by—physiological responses to infection that—on average—have been selected as a result of reducing infectious mortality across mammalian evolution (Figure 1). Thus, it is proposed that the alleles for depression, rather than having coevolved with immunological alleles that support pathogen defense, are in fact one in the same as those alleles, and therefore genes associated with depression would be predicted to be the same genes that are associated with successful host immune responses.
To fully elaborate this hypothesis, this article is structured to evaluate the foundations of the PATHOS-D theory (Table 1) by first examining the immune relevance of previously identified depression risk alleles, followed by an exploration of relationships among environmental risk factors for depression, inflammation and pathogen host defense. The role of depression-associated immune changes in promoting survival during infection is reviewed next, followed by an examination of the potential utility of depressive symptoms in host defense. We conclude with a consideration of the potential limitations of—and challenges to— the PATHOS-D theory.
Risk alleles for MDD and host defense:
The failed promise of genome-wide association studies (GWASs) to unambiguously identify genetic risk variants for MDD has led increasingly to the suggestion that depression and other major psychiatric conditions arise not from common allelic variants with small effect sizes, but rather from an array of highly nonadaptive genetic variants too rare to be identified by GWASs that nonetheless have large effect sizes.26, 27 Confirmation of this would effectively preclude the possibility that depressive risk alleles conferred any selective advantage during human evolution.28 However, an alternative possibility is that differences in common allelic variants between depressed and nondepressed individuals might be more apparent/consistent if the unit of analysis was extended from single genes to groupings of genes that form functional units. In the context of the PATHOS-D theory, this suggests that small allelic differences between depressed and nondepressed groups should not be randomly distributed across the genome, but rather should be largely localized to genes with host defense functions, and that the effect sizes for differences in individual host defense alleles should be additive (that is, positive epistasis), so that large effect size differences should emerge when functionally related host defense-enhancing alleles are evaluated as a unit. Support for this possibility comes from a recent network analysis of candidate genes for MDD. Although this analysis only interpreted findings in terms of potential central nervous system (CNS) effects,29 from a PATHOS-D perspective, it is striking that pathways identified as central to the best-supported MDD gene networks all have well-documented inflammatory and/or anti-inflammatory effects.
To be fully consistent with the PATHOS-D theory, allelic risk variants should meet three criteria. They should (1) be located in genes with known immune effects; (2) increase signaling in inflammatory/host defense pathways; and (3) increase survival in the context of infection. Although a number of candidate gene studies have identified depression risk alleles that are associated with inflammatory processes,30, 31, 32, 33, 34 to evaluate in the most conservative manner whether putative risk alleles meet the three criteria above, we have limited our examination to candidate genes confirmed either by GWASs or meta-analysis and to alleles identified in meta-analyses of GWAS data.
Candidate genes confirmed by GWASs
Currently, only two candidate single-nucleotide polymorphisms (SNPs; rs12520799 in DCNP1 (dendritic cell nuclear protein-1) and rs16139 in NPY (neuropeptide Y)) and one candidate gene for MDD (TNF–α), smallest P-value for rs76917) have been confirmed by GWASs.35 It is striking that each of these genes plays an important role in processes central to host defense, including proinflammatory cytokine signaling (TNF), antigen presentation (DCNP1) and T helper type 1 cell differentiation and function (NPY). Of these SNPs, functionality has only been established for rs16139 in NPY. Although NPY has numerous and contrasting effects on innate and adaptive immune functioning, its primary actions appear to be anti-inflammatory in both the brain and periphery.36, 37, 38 Given this, the PATHOS-D theory predicts that MDD should be characterized by reduced NPY activity and that the depression risk T allele at rs16139 should be associated with reduced NPY production. Significant data support both predictions.39, 40, 41, 42, 43
Unlike NPY, the functionality of rs76917 in TNF is currently unknown. A clear prediction of PATHOS-D theory is that this SNP should be associated with increased TNF-α production, given that TNF-α is increased in MDD and appears to be especially relevant to enhanced survival from infection in the types of pathogen-dense environments that were normative during human evolution. A separate SNP (−308G/A) in the promoter region for TNF is worthy of comment in this regard. Although not found to be significant by GWASs,35 several studies have associated the high-production A allele at −308 (ref. 44) with depression and related states such as anger.33, 34, 45 As predicted by PATHOS-D theory, the −308A allele has also been associated with reduced risk for infection with a number of pathogens, including Mycobacterium tuberculosis, parvovirus B19 and hepatitis B virus (HBV),46, 47, 48 and with an increased likelihood of survival in critically ill hospitalized patients.49 On a population level, Canadian First Peoples who are highly susceptible to tuberculosis have a markedly reduced prevalence of the A allele compared with Caucasians.50
DCNP1 was initially considered to be unique to dendritic cells,51 although it has subsequently been identified in neurons.52 The rs12520799 T allele, which is associated with MDD, codes for a truncated version of the protein. No data are available regarding the effect of this allele on either inflammatory signaling or infection outcomes, but given strong patterns of comorbidity between asthma/atopy and MDD, it is intriguing that the allele has been associated with increased levels of immunoglobulin E for common specific antigens in individuals with asthma.53
Candidate genes confirmed by meta-analysis
Although findings on candidate genes for depression have proven remarkably difficult to replicate,35 a recent meta-analysis provides at least some additional support for several allelic variants being risk factors for MDD, including GNB3 825T, MTHFR 677T, APOE ε2, SLC6A3 40 bpVNTR 9/10 genotype and SLC6A4 44 bp ins/del short allele.54 Although not traditionally considered as primarily immune related, each of these genes has well-documented immunological effects and hence meets the first of the three criteria for consistency with the PATHOS-D theory. In addition, each to a varying degree has some evidence consistent with either the second or third criterion.
GNB3 825T produces a shortened splice variant of the guanine nucleotide-binding protein subunit β-3 (GNB3) that has enhanced signal transduction properties.55 Also, 825T has been reported to enhance in vitro cellular immune responses to recall antigens and IL-2 stimulation, to increase neutrophil chemotaxis in response to IL-8 and to increase both lymphocyte chemotaxis and the number of circulating CD4+ T cells.55, 56 These immune-enhancing effects come at the price of increased rates of microalbunemia, hypertension and cardiovascular disease in T allele carriers.57, 58 However, as predicted by the PATHOS-D theory, these effects also appear to translate into improved host defense, given associations between the T allele and reduced death from infection in infancy and evidence of positive selection for the T allele in geographical areas with high rates of infectious pathology.59, 60 Also consistent with enhanced host defense responses, the T allele is associated with improved antiviral responses following interferon-α (IFN-α) treatment for hepatitis C virus and highly active retroviral treatment for human immunodeficiency virus.61, 62, 63 In addition, following HBV booster vaccination, the T allele increases in vitro lymphocyte proliferative responses to HBV surface antigen.64
The MTHFR 677T allele produces a version of the methylenetetrahydrofolate reductase (MTHFR) enzyme with reduced activity,65 leading to elevations in plasma concentrations of homocysteine and other markers of inflammation.66, 67, 68, 69, 70, 71, 72 Animal and human data suggest that this reduced MTHFR activity and concomitant increase in inflammatory tone may enhance host defense in at least some situations. For example, in a mouse model, MTHFR deficiency protects against cytomegalovirus infection,65 and in pregnant females, increased MTHF is associated with the presence of a sexually transmitted disease and bacterial vaginosis.73 Directly supporting a protective role for the T allele are data demonstrating that the allele protects against HBV infection in African populations.72 Moreover, the hyperhomocysteinemia associated with reduced MTHFR activity has been posited as protective against malaria and has been suggested as a selection factor for the T allele in sub-Saharan Africa.74 Interestingly, however, the prevalence of the T allele is actually far lower in sub-Saharan populations than in other ethnic/geographical groups despite these potential benefits, likely because homozygosity for the allele is lethal in situations of low folate availability such as pertain throughout much of the region.72 On the other hand, given the array of disease states that has been associated with MTHFR 677T,75, 76, 77, 78, 79, 80 as well as reduced fertility,81 its increased prevalence in environments of ready folate availability may reflect more substantial benefits for host defense than are currently recognized.
Apolipoprotein E (APOE), a glycoprotein central to lipid transport and metabolism, has been implicated as a risk and/or protective factor in a wide range of illnesses. The APOE gene has three primary alleles, termed ε2, ε3 and ε4, with ε3 being the most common worldwide, but with significant data suggesting that ε4 is the ancestral human allele.82, 83, 84, 85 APOE affects immune functioning in complex and apparently contradictory ways, with both immune-enhancing and immune-suppressing effects reported. The depression-protective ε2 allele does not appear to be associated with reduced inflammation per se, as PATHOS-D theory would predict, but may meet the third criteria required by PATHOS-D by being a risk factor for diseases known to have exerted significant selection pressure on humans, including tuberculosis and malaria.86 Conversely, the ε4 allele, which increases the risk for MDD when compared with ε2, is associated with increases in many measures of inflammation and related processes such as oxidative stress,82, 83, 84, 85 and has been reported to protect against the development of childhood diarrhea in high-pathogen environments.
Dopamine and serotonin are pivotal neurotransmitters in mood regulation, and yet like other factors linked to depression, these monoamines both affect, and are affected by, the immune system. The bulk of available evidence suggests that MDD is best characterized as a condition of low dopamine availability, at least in CNS regions linked to motivation and reward.87, 88, 89, 90 The possibility that reduced dopamine availability in MDD may serve host defense purposes is suggested by animal studies showing that hyperdopaminemia is associated with reductions in both innate and adaptive T helper 1-type cellular immunity, with resultant increased susceptibility to infection.91, 92 That dopamine transporter activity in particular may be important for host defense in humans is suggested by findings from two recent genome-wide linkage analyses of risk factors for tuberculosis in geographic areas in which the disease is endemic. Both studies localized a genetic protective factor to a locus of chromosome 15.93, 94 Fine mapping of this locus identified a SNP (rs250682) within the dopamine transporter gene (SLC6A3) as conferring the strongest protective effect.93 The G allele of rs250682 was found to be associated with reduced skin reactions to the tuberculin test, which predicts reduced risk of later active disease in endemic areas.93 However, no data were found indicating that rs250682 is in linkage disequilibrium with the SLC6A3 40 bpVNTR that has been associated with MDD. Nor do any data address whether the 9 repeat allele of the VNTR has immunological effects that would enhance host defense. Indeed, even the question of whether this putative depression risk allele is a gain-of-function or loss-of-function variant for the dopamine transporter remains to be definitively clarified.95, 96
The SLC6A4 44 bp ins/del polymorphism (often referred to as 5HTTLPR) is by far the most extensively studied, and debated, genetic risk factor for MDD. Significant data suggest that the ‘short’ allele of this serotonin transporter polymorphism (which is less efficient in the reuptake of serotonin) increases the risk for developing depression in response to psychosocial adversity, both during development and in adulthood. Less well known, but consistent with PATHOS-D predictions, the short allele has also been shown to protect against sudden infant death syndrome, a condition often associated with unrecognized infectious morbidity.97, 98, 99, 100 Given the PATHOS-D prediction that stress should activate inflammation as a prepotent protection against the risk of wounding (see below), it is intriguing that the 5HTTLPR short allele is associated with an increase in the ratio of circulating proinflammatory to anti-inflammatory cytokines (for example, IL-6/IL-10) following a psychosocial stressor.101 Further supporting a role for SLC6A4 in host defense is the recent finding that the gene might account for 10% of the correlation between depressive symptoms and circulating levels of IL-6 in a group of medically healthy adults.102 Finally, the prevalence of the short allele in cultures around the world is strongly correlated with historical burden of disease-causing pathogens in these cultures,103 consistent with the possibility that the short allele has undergone positive selection as a result of enhancing host defense.104
Alleles identified by meta-analyses of GWAS data
Far less is known about the general functionality of alleles identified in GWASs, let alone which physiological effects may be relevant to MDD. Therefore, it should not be surprising that limited data are available regarding whether these potentially depressogenic SNPs affect immunity to enhance host defense. On the other hand, it is intriguing that associations with immune/inflammatory function or other aspects of host defense against pathogens have been demonstrated for 8 of the top 10 genes (or their very close homologs) identified in the largest GWAS meta-analysis of MDD conducted to date (Table 2).105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 Many other depression-relevant genes identified in earlier large GWASs (as well as meta-analyses of these studies), including PBRM1, GNL3, ATP6V1B2, SP4, AK294384, LY86, KSP37, SMG7, NFKB1, LOC654346, LAMC2, ATG7, CUGBP1, NFE2L3, LOC647167, VCAN, NLGN1, BBOX1, ATF3, RORA, EIF3F, CDH13, ITGB1 and GRM8, have also been linked to immune system and/or host defense functions (see Supplementary Table S1 for additional information/relevant references).
An exception to the general lack of knowledge regarding GWAS-identified depression risk alleles is provided by the rs1006737 SNP in the CACNA1C gene, which codes for the α1 subunit of the L-type voltage-gated calcium channel (Cav1.2).29 CACNA1C has been identified as a potential depression risk gene in several GWASs,105, 141, 142 and convergent validity for its role in depression is provided by data demonstrating that carriers of the risk A allele have changes in brain function and morphology relevant to MDD.143, 144, 145
An examination of the immune effects of CACNA1C highlights both the promise and complexities of a PATHOS-D perspective. Calcium signaling pathways play central and essential roles in multiple aspects of immune function, and the Cav1.2 channel in particular contributes to the function of a variety of immune cell types, including dendritic cells, CD4+ and CD8+ T cells, mast cells and macrophages.146, 147, 148, 149, 150, 151, 152, 153, 154 Consistent with an overall proinflammatory effect for Cav1.2, agents that block this calcium channel have been repeatedly observed to have anti-inflammatory properties.155 Given these findings, the PATHOS-D theory predicts that the depressogenic A allele at rs1006737 should be a gain-of-function variant with an overall proinflammatory effect. In support of this, the A allele has been associated with reduced activation of the anti-inflammatory intracellular messenger Akt,156 which is known from in vitro studies to downregulate TNF-α and inducible nitric oxide synthase production in response to challenge with bacterial endotoxin.157 Moreover, if Cav1.2 activation promotes host defense via activation of inflammatory processes, one would predict that the A allele should be associated with increased CACNA1C protein production. Although this has yet to be confirmed, data from post-mortem brain tissue indicate that carriers of the A allele have increased CACNA1C mRNA production in the CNS.144
These data suggest that the A allele of CACNA1C meets the first two criteria for consistency with a PATHOS-D perspective (that is, located in a gene with known immune effects and associated with increased signaling in inflammatory/host defense pathways). The finding that Cav1.2 activation is necessary for T-cell defense against Leishmania major infection is consistent with the third criteria,148 given that the A allele appears to be a gain-of-function variant. However, other lines of circumstantial evidence undermine any straightforward association between allelic variants that increase Cav1.2 function and enhanced host defense. In fact, the opposite appears to be the case, given that Timothy Syndrome, caused by a rare gain-of-function variant in CACNA1C,158 is associated with a strikingly increased risk of infection.154 Similarly, activation of Cav1.2 channels appears to actually impede host defense against M. tuberculosis by reducing the bactericidal activity of dendritic cell-activated T cells.149 These results appear paradoxical given that calcium influx into immune cells is essential for eradication of M. tuberculosis, and significant data indicate that L-type voltage-gated channels play an important role in this regard.150 However, conflicting data suggest that L-type calcium channels may actually downregulate overall calcium influx, given that blocking these channels increased calcium signaling and bactericidal activity in M. tuberculosis-infected macrophages.149 These findings are consistent with the observation that bacterial endotoxin acutely downregulates L-type calcium channel mRNA, as would be expected if Cav1.2 has an anti-inflammatory function.159
These considerations introduce a critically important complication into our discussion of the immune effects of depressogenic gene variants. Up to this point we have proceeded as though pathogen host defense is a monolithic process, which is a simplification exposed by the bivalent effects of L-type intracellular calcium signaling on infectious outcomes. Because calcium signaling activates multiple facets of the immune system, it is not surprising that this signaling has been shown to contribute to the antipathogen capacities of a variety of cell types. For example, macrophages rely on L-type calcium channel activation in response to Chlamydia pneumonia lipopolysaccharide to kill the microorganism.160 However, other microbes have evolved to manipulate this host defense system to their own benefit, such as Legionella pneumophila, which requires L-type calcium signaling to replicate within infected host cells.161 These examples demonstrate that the same physiological process can enhance host defense to one pathogen, while simultaneously increasing vulnerability to another.
Infection, inflammation and environmental risk factors for MDD
If depressogenic alleles contribute to protection against pathogen invasion, the circumstances in which such invasion was likely or already a fait accompli should be especially potent activators of these genes, and hence especially likely to induce depression. Moreover, if these alleles heighten host defense in large part by increasing inflammation, inflammatory mediators released in response to environments rife with pathogen danger would be expected to induce depressive symptoms. These predictions are borne out by many studies demonstrating the depressogenic effects of inflammatory mediators,10, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 as well as the remarkably diverse array of conditions that activate inflammatory processes and also increase the risk for depression.174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221
Psychosocial stress may be especially relevant in this regard. Stress is a universal and powerful risk for the development of depression both during development and adulthood.222, 223, 224, 225 This squares nicely with social theories of depression, and at first glance appears to challenge host defense perspectives. But if we consider that the vast majority of stressors in mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or fighting conspecifics in dominance hierarchies for reproductive access/status, it is not surprising that these states are also circumstances in which the risk of pathogen invasion—and subsequent death from infection—was greatly increased as a result of traumatic opening of the protective skin barrier from wounding.226 Such wounding is common in social species and was a significant source of morbidity and mortality among humans in the ancestral environment, and indeed well into the historical period.227, 228, 229 Given this, it is not surprising that—to quote Firdaus Dhabhar—‘stress perception by the brain may serve as an early warning signal to activate the immune system in preparation for a markedly increased likelihood of subsequent infection’.230 And although chronic stress is best known to suppress immune function,231 the types of acute and/or psychosocial stressors most likely to be associated with immediate risk of wounding and hence infection activate both innate and adaptive immunity.232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242 And while suppressing certain measures of adaptive immunity, chronic stress (whether experienced during childhood or as an adult) has been repeatedly associated with increased peripheral inflammatory biomarkers.233, 243, 244, 245, 246, 247, 248
From a PATHOS-D perspective, then, psychosocial stress may increase the risk for depression, at least in part, because it activates host defense mechanisms that reliably induce depressive symptoms. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution, operating by the so-called ‘smoke detector’ principle,249 favored organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often in vain. This perspective provides a parsimonious explanation for why psychosocial stressors reliably induce depression, even though depressive reactions to stressors often appear so patently maladaptive. Across evolutionary time, the benefit that depressive symptoms (and their underlying physiology) conferred in terms of host defense in situations of high infectious danger (including most psychosocial adversities) outweighed their cost in terms of any social impairment they incurred in these same contexts. A clear prediction of this hypothesis is that genes promoting inflammatory responses to psychosocial stress should decrease in prevalence over time in human societies in which the association between stressors and subsequent infection has been weakened by factors such as modern health practices. Consistent with this possibility, the prevalence of the short allele of the serotonin transporter gene, which has been associated with increased inflammatory responses to psychosocial stress, is lower in societies with reduced rates of historical infectious mortality.104
In addition to providing a novel explanation for why stress is a primary risk factor for developing depression, the PATHOS-D theory offers a unifying perspective on why many other facets of modern life are also depressogenic, a perspective not readily provided by theories focused more exclusively on the social realm. Indeed, if the adaptive value of depression is to be found primarily in its effects on social functioning, it is hard to understand why so many risks for depression, including obesity, sedentary lifestyle, dietary factors, diminished sleep and smoking, are at least partially nonsocial in nature. On the other hand, these conditions are all associated with increased inflammation (for reviews see refs. 207, and 250, 251, 252), suggesting that they may be depressogenic because they tap into pathways that initially evolved to fight infection.
Patterns of immune activation in MDD and protection from infectious mortality in ancestral environments
The hypothesis that patterns of immune activity associated with MDD should have decreased mortality from infection in ancestral environments appears to face a challenge from data indicating that depression worsens outcome in a number of infectious processes253, 254, 255, 256, 257, 258, 259, 260 and is associated with impairments in adaptive immune mechanisms important for protection against both viruses and bacteria.13, 261, 262 To address this challenge, we have first to inquire whether innate immune inflammatory processes that are increased in MDD produce the patterns of infectious vulnerability and adaptive immune impairment that are apparent in depression. Surprisingly, the answer is yes.263, 264 Although essential for activating adaptive immunity in response to pathogen invasion, chronic inflammation can actually suppress T- and B-cell function through various mechanisms.263, 264, 265, 266, 267, 268, 269, 270 Consistent with this, rates of infection are often increased—not decreased—in autoimmune conditions characterized by chronic inflammation.271 However, PATHOS-D theory requires only that across evolutionary time the survival benefits of enhanced inflammatory activity characteristic of depression outweighed any costs imposed by associated reductions in other aspects of immune functioning. Several lines of evidence support this possibility.
One such line of evidence comes from Ghana, a country in which some regions rely for drinking water on heavily contaminated rivers and other regions obtain clean water from boreholes. As would be expected, death rates from infection are higher in river-drinking regions than in areas where borehole-obtained water is available. Consistent with the prediction that increased inflammatory signaling is protective in the type of high-infection environments common during human evolution (and especially common since the origin of agriculture and the rise of cities),272 a haplotype of the IL-10 gene associated with increased inflammation was found to be significantly more prevalent in populations that relied on river water than in populations that drank from boreholes—suggesting positive selection driven by enhanced pathogen protection.2 Consistent with this possibility, during a 5-year follow-up period, the high-inflammation IL-10 haplotype was associated with increased survival in populations that drank from rivers, but reduced survival in individuals who drank from boreholes.2 These results are consistent with the observation that cytokine-stimulated production of TNF-α declines with age in the Netherlands, a country with a low infectious burden, but does not decline with age in Ghana, a country with high rates of infection (that is, 85% of Ghanan study participants were infected with malaria),273 again suggesting that increased proinflammatory cytokine production—as observed in MDD—promotes survival under conditions of high pathogen burden.274
Multiple facets of modernity have reconfigured our relationship with the microbial/parasitic world in ways that have reduced the benefits of inflammation and increased its costs.274, 275 Nonetheless, even in an environment so different from that in which humans evolved, multiple studies have identified associations between patterns of increased inflammation observed in MDD and improved outcome in the context of infection,3, 4, 5, 50, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290 as shown in Table 3.
Survival-promoting elements of depressive/ sickness symptoms in response to infection