Effect of Interleukin-15 Complex Therapy on Splenic Natural Killer Cell Activity and Germinal Center Formation during Severe Malaria
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection causing up to 90% of malaria-related deaths. Experimental cerebral malaria (ECM) is a well-characterized mouse model of Plasmodium berghei ANKA (PbA) infection involving secretion of pro-inflammatory cytokines and remodeling of brain endothelial cell tight junctions, leading to blood brain barrier disruption and death. Previous studies show that treatment of PbA-infected mice with interleukin-15 complex (IL-15C), an engineered cytokine complex, prevents the development of ECM by inducing expression of immunosuppressive and anti-inflammatory IL-10 by natural killer (NK) cells. Recurrence of malaria infection is relatively common, potentially because severe malaria inhibits the establishment of germinal centers (GCs), structures in the spleen where the proliferation and differentiation of memory B cells and antibody-secreting plasma cells occurs. Specifically, malarial inflammation impairs naïve CD4 T cell differentiation into follicular helper T (TFH) cells in the spleen, which are essential cells for further B cell proliferation and GC establishment. As IL-10 plays a role in dampening the inflammatory pathways during PbA infection in the brain, we aimed to investigate the potential role that IL-10 plays in the humoral immune response in the spleen. This study examines the effects of treatment with IL-15C on splenic architecture and immune cell populations in an ECM mouse model. I utilized three experimental conditions: uninfected mice (UI group), mice infected with Plasmodium berghei ANKA (PbA group), and mice infected with PbA and treated with interleukin-15 complex (PbA + IL-15C group). It was hypothesized that infected mice treated with IL-15C would have more splenic GC B cells and TFH cells and improved GC architecture at day 13 post infection (p.i.) compared to untreated mice. IL-15C-treated mice did have a seemingly slight increase in frequency and number of splenic GC B cells, although this finding was not found significant, thus warranting further study.