Figure 5.

The balance of perforin expression may be advantageous to an individual’s fitness. Hypothetical model of perforin’s contribution to pathogen clearance and vascular permeability. Loss of perforin activity in the human due to single deleterious mutation (red cross) or multiple, compounding mutations (yellow crosses) leads to disease FHL 2. In the mouse model, mice lacking perforin cannot clear virus in the CNS but do not experience BBB disruption. Perforin competent mice can clear virus in the CNS but experience lethal BBB disruption. The dashed line and question mark indicate a level of perforin, found in the human population that may mediate BBB disruption but still allow for CNS pathogen control (A). At full perforin activity, CNS viral control is possible, however there is pathologic BBB disruption. At no perforin expression, pathologic BBB disruption is not present, but there is little of CNS viral infection. Non deleterious perforin SNVs that decrease but do not abolish perforin’s activity may provide a balance between these two pathologies (B). The five SNVs listed are purely there as a frame of reference, we do not conclude that these exact polymorphisms play a role in this balance.