gms | German Medical Science

In infectious diseases, activation as well as inhibition of the immune response is essential for effective control of the pathogen and to prevent immune pathology. CYLD is a deubiquitinating enzyme which plays a pivotal inhibitory role in immune responses. CYLD downregulates NF-κB activity by the proteolysis of K63-linked ubiquitin from TRAF2, TRAF6, and NEMO. In addition to regulating NF-κB, CYLD also regulates a number of other pathways including cell cycle, MAPK pathways, antiviral, TCR, and calcium signaling. To gain an insight into the function of CYLD in malaria, we infected C57BL/6 Cyld^-/- and wildtype (WT) mice with 20,000 sporozoites (i.v). While all WT mice succumbed to the infection up to day 8 p.i. due to experimental cerebral malaria (ECM), 90% of Cyld^-/- mice survived the infection, indicating that CYLD inhibits protective host responses. The blood parasitemia was significantly reduced in the Cyld^-/- mice compared to WT mice. Histopathological analysis revealed pronounced haemorrhages and enhanced activation of microglia and astrocytes in the WT mice. In addition the Cyld^-/- mice harboured increased numbers of sporozoite-specific CD8⁺ T cells in blood and spleen compared to the WT mice, while the WT mice had higher levels of sporozoite-specific CD8⁺ T cells in the brain. This was in accordance with elevated IFN-γ levels in the brain of WT mice compared to Cyld^-/- mice. Adoptive transfer of Cyld^-/- CD8⁺ T cells cells into WT mice partially protected the mice from ECM, indicating the importance of CD8⁺ T cells in the control of ECM. In conclusion, the absence of CYLD results in increased NF-κB activation, which in turn leads to increased numbers of pathogen-specific CD8⁺ T cells. The increased number of CD8⁺ T cells limits the parasite burden thereby preventing the disruption of the blood brain barrier integrity and impedes the development of ECM.