Methamphetamine (METH) is a highly addictive psychostimulant that not only affects

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. 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, IL1, 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. use of amphetamines, including METH, affects immune function with a significant suppression of IL-2 (Potula et al., 2010), but not IL-4 production by T-lymphocytes, as well as a suppression of B-lymphocyte proliferation; however, this occurred only at the highest amphetamine concentrations (Steinkellner et al., 2011; Kwack et al., 2014). Considerable evidence exists linking drug abuse to immune dysregulation and enhanced susceptibility to the progression of chronic infections, such as HIV-1(Ellis et al., 2003; Mantri et al., 2014). METH use is associated with high-risk sexual behavior and high rates of HIV acquisition and progression (Jamieson et al., 1997; Ellis et al., 2003). In this report, we have used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to study the effects of METH on T cell immune responses. Although LCMV is a relatively simple virus, encoding only four gene products, it has proven to be one of the best experimental systems for analyzing cellular immune responses (Zhou et al., 2012). Several studies have reported that acute infections induce remarkably high levels of antiviral T cells, while protracted Rabbit Polyclonal to Synaptophysin or chronic infections are associated with both functional impairment and deletion of virus-specific CD8 T cells (Khanolkar et al., 2002). T cell exhaustion has a major role in failure to control chronic infection. Expression of inhibitory receptors, including PD-1, an inhibitory receptor of the CD28CCTLA-4 family are up regulated considerably in chronic viral infection (Barber et al., 2006). This along with the inability to sustain functional T cell responses contribute to exhaustion. CD4 Th cells are central orchestrators of the immune response and differentially activate diverse branches of innate and adaptive immunity to guide the SKI-606 appropriate response to an invading pathogen (Penaloza-MacMaster et al., 2014). CD4 Th1 immunity is critical to sustain residual CD8 T-cell activity to control infection during persistent infection and is characterized in CD4 T cells by the secretion of IFN-, TNF-, and IL-2 (Matloubian et al., 1994). So far no study has addressed the role of METH in the context of SKI-606 chronic viral infection to analyze the effects on T cell immune responses. In this report, we have systematically analyzed the classic responses of CD4 and CD8 T cells in secondary lymphoid organ namely spleen during chronic LCMV infection in mice that have been exposed to chronic METH and the peripheral responses by measuring the serum cytokines. Our findings indicate that METH administered in a s.c. route altered T cells responses with important consequences, in a chronic LCMV infection model. METH effects on CD4 and CD8 cell percentages were modest although the expression of important markers of LCMV infection and T cell exhaustion SKI-606 such as PD-1 was greatly increased. Many of the METH effects were more pronounced by day 14 but normalized as infection progressed up to 56 days. Serum cytokine analysis revealed reduction of IL-2 production at all time points in METH-exposed infected mice than without. The serum pro-inflammatory (TNF, IL12p70, IL1, 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, suggesting that METH modulates the migratory properties of T cells during infection thus affecting immune activation. We also found another interesting up regulation of epidermal growth factor receptor (EGFR) in METH exposed LCMV infected mice at later times of infection, suggesting that signaling through EGFR may enable to establish persistent infection. Materials and methods Mice Male.

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