Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

Abstract

Methamphetamine (METH) is a highly addictive psychostimulant that not only affects the brain and cognitive functions but also greatly impacts the host immune system, rendering the body susceptible to infections and exacerbating the severity of disease. Although there is gathering evidence about METH abuse and increased incidence of HIV and other viral infections, not much is known about the effects on the immune system in a chronic viral infection setting. We have used the lymphocytic choriomeningitis virus (LCMV) chronic mouse model of viral infection in a chronic METH environment and demonstrate that METH significantly increases CD3 marker on splenocytes and programmed death-1 (PD-1) expression on T cells, a cell surface signaling molecule known to inhibit T cell function and cause exhaustion in a lymphoid organ. Many of these METH effects were more pronounced during early stage of infection, which are gradually attenuated during later stages of infection. An essential cytokine for T-lymphocyte homeostasis, Interleukin-2 (IL-2) in serum was prominently reduced in METH-exposed infected mice. In addition, the serum pro-inflammatory (TNF, IL12 p70, IL1β, IL-6, and KC-GRO) and Th2 (IL-2, IL-10, and IL-4) cytokine profiles were also altered in the presence of METH. Interestingly CXCR3, an inflammatory chemokine receptor, showed significant increase in the METH treated LCMV infected mice. Similarly, compared to only infected mice, epidermal growth factor receptor (EGFR) in METH exposed LCMV infected mice were up regulated. Collectively, our data suggest that METH alters systemic, peripheral immune responses and modulates key markers on T cells involved in pathogenesis of chronic viral infection.

Trace Amines and Their Receptors

“…The joint regulation of TAAR1 and TAAR2 is important from this aspect, as the chemoattractant response of leukocytes toward TAAR1-selective agonists appears to be dependent on the presence of both TAAR1 and TAAR2, possibly due to the need for heterodimerization of the two (Babusyte et al, 2013). From this perspective, the TAAR1/TAAR2 axis may provide a molecular explanation for the well known immune dysfunction that is associated with amphetamine-like drugs of abuse (Boyle and Connor, 2010;Sriram et al, 2015), many of which are TAAR1 agonists. Indeed, methamphetamine has been reported to increase T-cell TAAR1 expression, an effect that resulted in a decrease in T-cell interleukin 2 levels (Sriram et al, 2016).…”

Methamphetamine and its immune-modulating effects

“…In mice, chronic METH administration reduces the number of CD4 and CD8 T cells in the spleen [20]. In addition, METH significantly increases expression of the inflammatory chemokine receptor CXCR3, suggesting that METH contributes to effector T cell function and migration [12,31]. METH also prolongs the transition from G1 to S phase of T cells [32].…”

“…Overall, a lack of well-rounded knowledge and perception, other than METH's short-term effects, is available on how this drug impacts the immune system long-term. This long-term impact currently remains to be fully explored, and understanding this aspect of METH use in addiction and withdrawal scenarios can help strengthen our current perspective on METH, help inform and guide public policy, notify on The effects of METH on the immune response have yet to be fully determined, however, there is growing evidence that METH suppresses and modulates the immune system [12,13]. Consequently, immune dysregulation through METH abuse could lead to lasting neuropsychiatric conditions [14].…”

“…Consequently, immune dysregulation through METH abuse could lead to lasting neuropsychiatric conditions [14]. METH has significant effects on both the innate and adaptive immune responses [12,15], with reported reductions in the numbers of natural killer (NK) cells and leukocytes [16]. In addition, macrophages stimulated by METH show increased levels of the pro-inflammatory cytokine TNF- [17][18][19].…”

Methamphetamine: Effects on the brain, gut and immune system

“…METH directly activates TAAR1 in vitro and increases the intracellular cAMP levels in human HEK-393 fibroblasts (51). TAAR1 mRNA expression in resting T cells increases in response to METH administration (52). METH increases intracellular cAMP levels in human astrocytes whereas TAAR1 knockout cells have significantly reduced cAMP levels in response to METH administration (53).…”