Global emergence of Rickettsia felis infections: the hidden threat in pets and their fleas

From its initial detection and characterisation in the 20th Century through to its first isolation in 2001, our understanding of the importance and impact of the emergent zoonotic bacterium Rickettsia felis has, over the last two decades, risen dramatically.^1–3 Taxonomically positioned within the order Rickettsiales, which includes the important animal pathogen genera Anaplasma and Ehrlichia, R. felis shares its genus with a plethora of highly pathogenic species, including Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever and Rickettsia prowazekii, which causes epidemic typhus.^1,4,5 To date, the cosmopolitan cat flea Ctenocephalides felis felis is the only confirmed biological vector of Rickettsia felis and its arthropod reservoir – however, a few other arthropods have been found to carry R. felis DNA (e.g. booklice).^1,6 In humans, infection with R. felis produces the multi-systemic disease flea-borne spotted fever (FBSF) that generates pyrexia, maculopapular rash, headache, myalgia and the formation of a dry dark scab (eschar) at the site of flea bite.^4,7 Nonetheless, the underlying pathophysiology of R. felis remains poorly understood, particularly when compared to better studied species such as R. rickettsii, which causes disease by increasing vascular permeability to generate oedema.⁸ Although FBSF caused by R. felis has typically been characterised as a mild disease, more recent reports have implicated this pathogen in fatal cases of meningoencephalitis as well as a serious case of encephalitis in a pregnant woman.^9,10

Rickettsia felis belongs to the spotted fever group of Rickettsia, with phylogenetic analyses indicating the species is most closely related to sister species such as Rickettsia australis, Candidatus Rickettsia asemboensis and Rickettsia hoogstraalii, among others.^1,11 Interestingly, substantial genetic diversity across key taxonomic barcoding genes from some R. felis isolates has underscored the possibility that R. felis represents a species complex that, to date, remains unresolved.¹

The distribution of R. felis is global, with the pathogen’s epidemiology and transmission intimately tied to that of its vectors and vertebrate hosts.⁴ Despite their name, C. f. felis fleas feed on a wide variety of vertebrate hosts and are frequently found as the dominant ectoparasite infesting dogs and cats (e.g. in Asia).^12,13 Moreover, C. f. felis infected with R. felis have been shown to maintain this pathogen for up to 12 generations by transovarial and transstadial transmission (Fig. 1), meaning that this pathogen is recurrently transmitted from mother to offspring and between flea life cycle stages.¹⁴ The ability of fleas to persist in domestic settings means that fleas can continuously reinfest our pets from an environmental reservoir, thereby further increasing the risks posed by R. felis.¹⁵ Adult fleas are typically the only part of the life cycle observed during infestations; however, they only represent a small proportion (~1–5%) of the local flea population, with the remainder being egg, larval or highly resilient pupal stages that may make flea control more challenging.¹⁵

Fig. 1.

Current understanding of the life cycle and transmission routes of Rickettsia felis. Rickettsia felis can be transmitted vertically to eggs and other life cycle stages of the cat flea Ctenocephalides felis felis, by transovarial and transstadial transmission for up to 12 generations. Horizontal transmission occurs through flea biting and transmission of R. felis to competent mammalian hosts as well as by a potential flea co-feeding route. Canines develop rickettsaemia without outward clinical signs, working to silently amplify R. felis and lead to onward transmission. If humans are bitten by a R. felis infected flea, then the multisystemic disease flea-borne spotted fever can develop. It is unknown if; (i) other mammalian species are competent R. felis reservoirs; and (ii) if arthropod vectors, apart from fleas, are capable of naturally transmitting R. felis.

Horizontal transmission (e.g. through vector co-feeding on a host Fig. 1), is also essential for ecological maintenance of R. felis within a population and, although there is substantial evidence that a wide spectrum of mammals can become infected, a mammalian reservoir remained elusive until 2020.^4,7,16 Critically, at this time, experimental infections of the domestic dog with R. felis were shown to be infectious to C. f. felis fleas and vice versa. Furthermore, after 3–6 days post infection, canine rickettsaemia was observed and found to persist for up to 100 days, demonstrating the role domestic dogs play as an infectious source of R. felis to fleas (Fig. 1).¹⁶ Importantly, dogs experimentally infected with R. felis showed an absence of, or only mild, clinical signs highlighting a potential tolerance of the host towards the pathogen that further demonstrates the role of dogs as a reservoir species for R. felis.¹⁶

Epidemiological surveys of canines have increasingly highlighted their role in the maintenance of R. felis, while also emphasising the risk dogs play in transmission to humans.^16,17 When investigated within the Asia-Pacific region, high levels of both canine exposure, i.e. serologically positive, and active infection, i.e. polymerase chain reaction (PCR) positive, to R. felis have frequently been demonstrated, particularly in countries such as Australia where there has been more investigation.^17–19 For example, in one study conducted by Hii et al. over half of the canines tested in Queensland and the Northern Territory were found seropositive to R. felis, indicative of exposure to this pathogen.¹⁹

Studies exploring R. felis seroprevalence in humans have also found that levels of exposure to this pathogen can be high, particularly in certain demographics.^20,21 For instance, serological studies investigating exposure to this pathogen in ‘high-risk’ cohorts identified a seroprevalence to R. felis in 29% of patients with a suspected case of rickettsiosis and 16% in veterinarians.^20,21 The latter finding underscores an occupational risk for veterinary professionals due to their greater contact with infected animals.²¹

Given the role mammals and fleas play in R. felis maintenance, it is not surprising that there have been well-documented cases of transmission caused by close contact between humans and companion animals.^20–22 In 2009, five members of a family living in Melbourne, Australia, became sick with a rickettsial disease concordant with FBSF, after receiving kittens infested with fleas from a nearby farm.²² The patients were serologically positive for typhus group Rickettsia, whereas fleas collected from the cat family group were found positive for R. felis DNA by PCR.²² These findings are further supported by research that has explicitly looked at risk factors associated with R. felis infection. For example, one study reported that high-risk occupations that entail close contact with domestic animals increase the odds ratio of human infection by almost six times.²³ Given these data, simple measures to reduce flea-burden in companion animals such as the use of ectoparasiticides, regular grooming and pet owner education will likely act to significantly reduce the risk of FBSF in humans.¹⁹ Thankfully, when human R. felis infections do occur, treatment can be simple, with a course of the antibiotic doxycycline established as being highly effective.²⁴

Clinical diagnosis of R. felis in humans is challenging because of the overlap of symptoms of infection with many other rickettsial and non-rickettsial diseases.^1,4,25 This makes the accurate diagnosis of R. felis infections with serological and molecular tools essential.^1,25 Immunofluorescent antibody assays are still largely considered the reference method for detection of most rickettsial infections and can be highly sensitive (Fig. 2).²⁶ Nonetheless, although specific serological tests for R. felis exposure in humans exist, cross reactivity to other Rickettsia, such as Rickettsia typhi has been demonstrated, meaning that definitive diagnosis with such methods may typically require further testing.^3,4,26,27 Moreover, such methods do not provide any information on current infection status, with antibodies to R. felis remaining detectable up to 4 years post-exposure.²⁸

Fig. 2.

Diagnostic techniques and sample types used for the detection of Rickettsia felis and other Rickettsia species.

Considering this, molecular diagnostics for the detection of R. felis in humans offer many advantages over serology due to their greater specificity and ability to detect active infections.^1,26 Numerous conventional PCR (cPCR) and quantitative PCR (qPCR) assays have been developed for the specific detection of R. felis and have been effectively utilised for the identification of this pathogen from vectors, humans and other vertebrate hosts (Fig. 2).^4,26 These assays target genes that are informative for diagnosing Rickettsia infections at the species-level, such as the citrate synthase (gltA) or outer membrane protein B (ompB) genes.^4,26 However, despite the strengths of such approaches they are hampered by challenges associated with intermittent rickettsaemia, meaning that bloodstream-circulating DNA may rapidly wane, precluding PCR-based detection.^4,25 More recently, advanced molecular techniques such as next-generation sequencing (NGS)-based approaches have come to the fore, due to their ability to explore questions that are difficult to address using classical molecular methods (Fig. 2). With NGS, conserved genes found across all bacteria or, more specifically all Rickettsia, can be simultaneously targeted and sequenced in a technique termed ‘metabarcoding’ to provide both sensitive and specific detection.^17,29 Crucially, unlike cPCR, these metabarcoding approaches are not limited to the detection of just one or a few species at a time, meaning that they can easily characterise bacterial coinfections as well as Rickettsia that are potentially novel.^17,29 Metabarcoding has already been used for the accurate detection of rickettsial species, such as R. felis, and shows great promise as a tool for helping us in identifying novel vectors as well as understanding the epidemiology, and transmission dynamics of this important pathogen.^29,30

Rickettsia felis is a complex, globally distributed and emergent zoonotic pathogen of significant importance for human health. However, many elements of its biology and epidemiology are still poorly understood and are at the centre of a large body of ongoing research. Key questions remain to be answered, including:

Continuing research efforts across the 21st Century will undoubtedly work to further unpick the threat posed to us by R. felis and our pets. Improved R. felis detection methods and a better understanding of this pathogen’s biology will provide us with critical insights for more effective control strategies, ultimately safeguarding both human and animal health.