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

Raison, C L; Miller, A H

GNB3 825T produces a shortened splice variant of the guanine nucleotide-binding protein subunit b-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 þ 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-a (IFN-a) 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.