ANATOMY OF THE IMMUNE RESPONSE TO FRANCISELLA TULARENSISLVS INFECTION IN THE LUNGS.

Abstract

Abstract The respiratory mucosa is under constant immune surveillance because of its vulnerability to infectious diseases. Infection of the lungs with the live vaccine strain (LVS) derived from Francisella tularensis (Ft) subspecies holarctica models pulmonary tularaemia-like disease in mice. Current evidence suggest many immune cells and cytokines respond to Ft LVS infection, but how these various immune system components are integrated to mount a protective response remains unclear. Hence, in a transcriptomics study at single cell resolution, we characterized the acute immune landscape in the lungs of C57BL/6 mice at day 0 and day 7 post intranasal inoculation with Ft LVS. Defining features of the immune response include a robust type 1 immune response characterized by the accumulation of inflammatory neutrophils and the expansion of innate-like effector lymphocytes, primarily interferon-γ producing NKT1, NK, and effector CD8 +T cells. Increased accumulation of MAIT17 over MAIT1 cells is another feature, which is in line with previous findings linking MAIT cells and IL-17 to LVS immune response. Surprisingly, a significant proportion of MAIT17 cells either maintained or upregulated type 1 inflammatory markers. Similarly, MAIT1 cells maintained or upregulated Type 3 inflammatory markers. Additionally, a highly active MAIT cell subset has increased Nr4a1 expression, which encodes Nur77, suggesting a T cell receptor-mediated activation. By contrast, NKT1 cells poorly upregulated Nr4a1 expression but induced Il18r1 expression suggesting, a cytokine-mediated activation. Consequently, we predict that unconventional NKT & MAIT cells integrate innate cues to control tularaemia-like disease caused by Ft LVS infection in the mouse. VUSM MSTP NIGMS of the National Institutes of Health T32GM007347 (GDO); IO1 BX001444, BX001610, BX00xxx, IK6 BX004595 & RO1 AI137082; IBX000915A (HMA)