Chronic Viral Infection and Exacerbates Polymicrobial Sepsis Increases Susceptibility

نویسندگان

  • Thomas S. Griffith
  • Vladimir P. Badovinac
  • Stephanie A. Condotta
  • Shaniya H. Khan
  • Deepa Rai
چکیده

Patients who survive sepsis display suppressed immune functions, often manifested as an increased susceptibility to secondary infections. Recently, using a cecal-ligation and puncture (CLP) model of sepsis, we showed that sepsis induces substantial and long-lasting changes in the available naive CD8 + T cell repertoire affecting the capacity of the host to respond to newly encountered acute infections. However, the extent to which sepsis changes the host susceptibility to chronic infection and affects CD8 + T cell responses is currently unknown. In this study, we demonstrate that inbred and outbred mice recovering from a septic event are more susceptible to lymphocytic choriomeningitis virus (LCMV) clone-13 infection exhibited by mortality and viral burden. Primary virus-specific CD8 + T cells in LCMV clone-13–infected septic mice displayed exacerbated CD8 + T cell exhaustion illustrated by increased inhibitory molecule expression (e.g., programmed cell death 1, lymphocyte-activation gene 3, and 2B4) and diminished Ag-driven cytokine production (e.g., IFN-g, TNF-a) compared with similarly infected sham-treated mice. Importantly , therapeutic inhibitory molecule dual blockade (anti–PD-L1 and anti–lymphocyte-activation gene 3) increased the number of circulating LCMV-specific CD8 + T cells, and improved CD8 + T cell function and pathogen control in chronically infected septic mice. Together, these results illustrate that polymicrobial sepsis compromises the overall health of the host leading to increased vulnerability to chronic infection and exacerbated CD8 + T cell exhaustion. Collectively, our findings suggest that septic survivors may be more susceptible and at greater risk for developing exhaustible CD8 + T cells upon encountering a subsequent chronic infection. I n the United States, septicemia is the cause of .1.6 million hospital cases with an in-hospital mortality rate of ∼16% (1, 2). A septic event triggers massive apoptosis of immune cells, including T cells, resulting in an initial hyperinflammatory phase followed by a prolonged hypoinflammatory immunosup-pressive state (3–8). Septic patients exhibit immunoparalysis manifested by the inability to control and eradicate infections that are normally cleared with functioning CD8 + T cell–mediated immunity (3, 6, 7, 9). Furthermore, viral reactivation of latent viruses can occur after a septic event (5, 10–13), and sepsis survivors have an increased risk for death from nonseptic causes years after the initial septic insult; for example, increased heart, lung, renal, and liver disease, infection, and hematologic disorders experienced in the preceding year are factors associated with increased risk for death in sepsis survivors (14). CD8 + T cells play a crucial role …

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تاریخ انتشار 2015