Vascular Permeability Mechanisms as Adjunct Therapies for Rickettsial Infections

Many microbial infections, such as those caused by viruses, bacteria, fungi and protozoan parasites are associated with microvascular endothelial cell (MEC) dysfunction. Rickettsiae such as R. rickettsii and R. parkeri as well as Ehrlichia or Anaplasma spp. cause febrile illness often characterized by severe complications including death owing to compromise of MEC barrier permeability. Defining mechanisms and developing a therapeutic strategy directed at diminishing or reversing pathogen-associated MEC barrier dysfunction by targeting shared host molecular/cellular pathways to provide more favorable clinical outcomes is both a reasonable and testable goal. We target the three most important tick-borne rickettsial diseases for which information regarding pathogen-microvascular function is available and easily within our expertise. Our studies will use lab-based bioassays of human MEC barriers that mimic flow through blood vessels in human tissues to identify drugs or groups of drugs that reduce leakiness or stabilize blood vessels. These drug agents or other in their drug classes will be tested in mouse models of tick-borne rickettsial diseases with the hope that they could be repurposed into new therapeutics with improved qualities to circumvent serious and fatal complications of rickettsial disease.