The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)

Raison, C L; Miller, A H

immune function, and the Cav1.2 channel in particular contributes to the function of a variety of immune cell types, including dendritic cells, CD4 þ and CD8 þ 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-a 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 CAC-NA1C, 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