Rickettsial infections of the central nervous system

Abstract

As a result of migrations and globalization, people may face a possible increase in the incidence of central nervous system rickettsial infections (CNS R). These diseases, caused by Rickettsia species and transmitted to humans by arthropod bites, are putatively lethal. However, the diagnosis of CNS R is challenging and often delayed due to their nonspecific clinical presentation and the strict intracellular nature of rickettsiae. Furthermore, transfer of rickettsiae to the brain parenchyma is not yet understood. The aim of this review is to analyze and summarize the features and correlated findings of CNS R in order to focus attention on these intriguing but frequently neglected illnesses. We also incorporated data on CNS infections caused by Rickettsia-related microorganisms.

Fig 1. Phylogenetic tree of Rickettsia species inferred from the comparison of concatenated sequences from the gltA and sca4 genes.

Rickettsia species are distributed into 4 groups: SFG, TRG, TG, and AG. SFG rickettsiae are mostly associated with ticks; TG rickettsiae with human body lice (R. prowazekii) and rat fleas (R. typhi); TRG rickettsiae with ticks, cat fleas, or mites; and AG rickettsiae with ticks. Asterisks mark pathogenic species, and bold letters indicate species causing CNS infections. AG, ancestral group; CNS, central nervous system; SFG, spotted fever group; TG, typhus group; TRG, transitional group.

Fig 2. Developmental cycle and host range of Rickettsia-infected ticks.

Ticks are the main vectors and constitute a threat of rickettsial infection regardless of their development stage (larvae, nymphs, or adults). Many factors play a role in the epidemiology of tick-borne rickettsioses, including the prevalence and species diversity of rickettsiae in mammals [–153] and the dispersion of infected ticks by migratory birds [154].

Fig 3. Body lice as the cause of typhus reemergence.

R. prowazekii is classified as a category B bioterrorism agent. It is stable in dried louse feces and can be transmitted through aerosols. Detection of the pathogen in body lice is crucial for monitoring the transmission risk to humans. However, Brill–Zinsser disease, a relapsing form of epidemic typhus that may develop as sporadic cases up to 40 years after the initial acute infection, is unrelated to louse infestation but to stress or a waning immune system that initiates the reactivation of an earlier and latent infection. Patients developing Brill–Zinsser disease may, in turn, be the source of new outbreaks when conditions facilitate louse infestation and transmission [155]. The mechanism of R. prowazekii latency has not been established. Brill–Zinsser disease should be considered as a possible diagnosis for acute fever in any patient who has lived in an area where epidemic typhus was endemic [156].

Fig 4. Mechanisms of bacterial penetration through the blood–brain barrier.

(A) Intercellular or paracellular, described in extracellular pathogens. The physical barrier formed by endothelial tight junctions is disturbed by bacterial penetration. (B) Transcellular, passing through cells, e.g., direct invasion of endothelial cells. In this scenario, blood-borne bacteria directly invade CNS endothelial cells. (C) By leukocytes, within infected macrophages, named “Trojan horse” mechanism. Infected leukocytes adhere to endothelial cells, allowing the spread of bacteria or, alternatively, leukocytes can transmigrate and deliver bacteria to the CNS parenchyma. CNS, central nervous system.