Chronic Alcoholism and HHV-6 Infection Synergistically Promote Neuroinflammatory Microglial Phenotypes in the Substantia Nigra of the Adult Human Brain

Abstract

Both chronic alcoholism and human herpesvirus-6 (HHV-6) infection have been identified as promoters of neuroinflammation and known to cause movement-related disorders. Substantia Nigra (SN), the dopaminergic neuron-rich region of the basal ganglia, is involved in regulating motor function and the reward system. Hence, we hypothesize the presence of possible synergism between alcoholism and HHV-6 infection in the SN region and report a comprehensive quantification and characterization of microglial functions and morphology in postmortem brain tissue from 44 healthy, age-matched alcoholics and chronic alcoholics. A decrease in the perivascular CD68+ microglia in alcoholics was noted in both the gray and white matter. Additionally, the CD68+/Iba1− microglial subpopulation was found to be the dominant type in the controls. Conversely, in alcoholics, dystrophic changes in microglia were seen with a significant increase in Iba1 expression and perivascular to diffuse migration. An increase in CD11b expression was noted in alcoholics, with the Iba1+/CD11b− subtype promoting inflammation. All the controls were found to be negative for HHV-6 whilst the alcoholics demonstrated HHV-6 positivity in both gray and white matter. Amongst HHV-6 positive alcoholics, all the above-mentioned changes were found to be heightened when compared with HHV-6 negative alcoholics, thereby highlighting the compounding relationship between alcoholism and HHV-6 infection that promotes microglia-mediated neuroinflammation.

Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

“…Although the underlying mechanism is still unknown, based on the history of viral inflammatory diseases, it is expected that dysregulation of the adaptive immune response [157,158] could be one critical component of disease progression. Activation of CD4 + Th1 cells upon SARS-CoV2 infection and subsequent production of anti-viral cytokine IFN-γ might be beneficial (25) for initial virus killing; however, prolonged activation of these T cells might result in the development of a pathological inflammatory response (Fig. 5) including an elevated production of chemokines and cytokines released activated macrophages and microglia.…”

“…One potential mechanism could be the escape of persistently infected CD4 + T cells from the above-mentioned acute apoptotic pathway that potentially stimulate an inflammatory response in macrophages and glial cells. A recent report also suggests that HHV6A directly stimulates the inflammation and migration of microglial cells via activation of TREM2 and ApoE [ 24 ].Therefore, active HHV6 infection, but not an acute immunosuppressive event, may be directly responsible for responsible for the microglial activation [ 25 ], and possible demyelination [ 26 ]. Furthermore, a recent study [ 27 ] identified that patients with demyelination in CNS displayed HHV6-immunoreactive oligoclonal bands in their cerebrospinal fluid indicating a potential link between multiple sclerosis (MS)-like encephalopathy and HHV6-infection.…”

Human Herpes Virus-6 (HHV-6) infectious encephalitis in an immunocompetent adult

“…The high HHV-6 DNA load in patients with ciHHV-6 can sometimes lead to misdiagnosis due to the assumption of active HHV-6 infection but in this patient the clinical picture was consistent with HHV-6 infection with improvement on appropriate treatment. While elevated HHV-6 levels can be seen in settings such as alcoholism and use of immunosuppressives, clinical correlation is needed to establish a cause and effect relationship while looking for other possible etiologies for patient’s symptoms [20] .…”

Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach

“…Both chronic alcoholism and human herpesvirus-6 (HHV-6) infection may cause movement-related disorders and promote neuroinflammation. Jain et al [19] observed decreased perivascular CD68 + /Iba1 + microglia in the postmortem brain from alcoholic individuals as compared to the dominant CD68 + /Iba1 − microglial subpopulation in the control brains. All the control brains were HHV-6 negative.…”