Mediterranean Spotted Fever: Current Knowledge and Recent Advances

Abstract

Mediterranean spotted fever (MSF) is an emerging tick-borne rickettsiosis of the spotted fever group (SFG), endemic in the Mediterranean basin. By virtue of technological innovations in molecular genetics, it has been determined that the causative agent of MSF is Rickettsia conorii subspecies conorii. The arthropod vector of this bacterium is the brown dog tick Rhipicephalus sanguineus. The true nature of the reservoir of R. conorii conorii has not been completely deciphered yet, although many authors theorize that the canine population, other mammals, and the ticks themselves could potentially contribute as reservoirs. Typical symptoms of MSF include fever, maculopapular rash, and a characteristic eschar ("tache noire"). Atypical clinical features and severe multi-organ complications may also be present. All of these manifestations arise from the disseminated infection of the endothelium by R. conorii conorii. Several methods exist for the diagnosis of MSF. Serological tests are widely used and molecular techniques have become increasingly available. Doxycycline remains the treatment of choice, while preventive measures are focused on modification of human behavior and vector control strategies. The purpose of this review is to summarize the current knowledge on the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of MSF.

Keywords: Mediterranean spotted fever; Rhipicephalus sanguineus; Rickettsia conorii; Rickettsiales; tick-borne disease.

Figure 1

Rhipicephalus sanguineus can be infected with Rickettsia conorii conorii through three main routes: when ticks feed on infected mammals (horizontal transmission), transovarially (vertical transmission), and transstadially (vertical transmission). The transovarial and transstadial transmission of R. conorii conorii within the tick population could suggest the potential role of the tick as a reservoir. The true nature of the reservoir of R. conorii conorii is not yet fully comprehended, while many authors theorize that the canine population, as well as other mammals, could potentially contribute as reservoirs. The transmission of R. conorii conorii to humans is achieved through infected ticks, which are transferred to the human habitat via the canine population.

Figure 2

(A) Rickettsia conorii mediates cellular entry by coordinated interactions between outer-membrane protein A (OmpA) with α₂β₁ integrin, surface cell antigen 2 (Sca2) with an unknown receptor, and outer-membrane protein B (OmpB) with Ku70; (B) binding of OmpB to Ku70 triggers a host-signaling cascade that involves the activation of c-Cbl and the ubiquitination of Ku70. The distal arm of this pathway activates the actin related 2/3 (Arp2/3) complex which results in actin activation and bacterial internalization; (C) the bacteria use membranolytic enzymes, possibly phospholipase D and hemolysin C, to achieve phagosomal escape and gain access to host cytosol; (D) bacterial RickA activates the Arp2/3 complex which leads to host cell actin polymerization and the formation of a network of long actin filaments; (E) the bacteria can then move to the extracellular space and the adjacent endothelial cells.