Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness

Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.