Rickettsia Research Articles

Serological profile of patients suspected with non-scrub typhus rickettsioses

BackgroundRickettsial pathogens are Gram-negative, obligate intracellular bacteria. They are transmitted by arthropods and are responsible for a wide variety of disease, from minor to life-threatening, which have a global effect on human health. Limited data are available on the prevalence of rickettsial diseases from India, and the disease epidemiology is not fully described. This study aimed to diagnose non-scrub typhus rickettsioses including spotted fever and typhus group of Rickettsia in clinically suspected patients by using standard serological tests and recognition of common epidemiological conditions and clinical manifestations. MethodsDuring the study period, a total of 700 patients of all ages with acute febrile illness were enrolled. Patients were screened for rickettsial infection using IgM Enzyme-linked immunosorbent assay (ELISA) and Immunofluorescence assay (IFA) was performed to confirm the ELISA positive results. The relevant demographic, clinical, and laboratory details of patients were documented and analyzed. ResultsOf 700 samples tested, 141 (20.2%) were found to be positive for IgM antibodies against rickettsioses using ELISA and IFA. SFGR was positive in 15 (2.2%), TGR was positive in 112 (16%) and 14 (2%) samples were positive for both groups. 20 (14.2%) patients required admission to the intensive care unit (ICU), and 24 (17%) in-hospital deaths occurred. ConclusionsThe prevalence of rickettsioses in India appears to be underestimated; therefore, increased awareness and improved diagnostic testing could facilitate early detection of cases, pathogen-targeted appropriate treatment, and improved outcomes for patients. Despite the fact that Rickettsiae can be isolated or detected using molecular techniques in clinical specimens, serology still remains the most commonly used diagnostic method for rickettsioses around the world. Our study helps bridge the gap of limited data on Rickettsia in north India and could be useful for future epidemiological investigation of rickettsial diseases and outbreaks.

Orientia tsutsugamushi: A life between escapes.

The life cycle of the mite-borne, obligate intracellular pathogen Orientia tsutsugamushi (Ot), the causative agent of human scrub typhus, differs in many aspects from that of other members of the Rickettsiales order. Particularly, the nonlytic cellular exit of individual Ot bacteria at the plasma membrane closely resembles the budding of enveloped viruses but has only been rudimentarily studied at the molecular level. This brief article is focused on the current state of knowledge of escape events in the life cycle of Ot and highlights differences in strategies of other rickettsiae.

Current Status of Vector-Borne Diseases in Croatia: Challenges and Future Prospects.

Different vector-borne pathogens are present or have (re-)emerged in Croatia. Flaviviruses tick-borne encephalitis (TBEV), West Nile (WNV), and Usutu (USUV) are widely distributed in continental regions, while Toscana virus (TOSV) and sandfly fever viruses are detected at the Croatian littoral. Recently, sporadic clinical cases of Tahyna orthobunyavirus (TAHV) and Bhanja bandavirus infection and seropositive individuals have been reported in continental Croatia. Acute infections and serologic evidence of WNV, TBEV, USUV, and TAHV were also confirmed in sentinel animals and vectors. Autochthonous dengue was reported in 2010 at the Croatian littoral. Lyme borreliosis is the most widely distributed vector-borne bacterial infection. The incidence is very high in northwestern and eastern regions, which correlates with numerous records of Ixodes ricinus ticks. Acute human Anaplasma phagocytophilum infections are reported sporadically, but there are many records of serologic evidence of anaplasmosis in animals. Mediterranean spotted fever (Rickettsia conorii) and murine typhus (Rickettsia typhi) are the main rickettsial infections in Croatia. Human leishmaniasis is notified sporadically, while serologic evidence of leishmaniasis was found in 11.4% of the Croatian population. After the official eradication of malaria in 1964, only imported cases were reported in Croatia. Since vector-borne diseases show a growing trend, continuous monitoring of vectors is required to protect the population from these infections.

Pathogenic Rickettsia, Anaplasma, and Ehrlichia in Rhipicephalus microplus ticks collected from cattle and laboratory hatched tick larvae.

The order Rickettsiales contains a group of vector-borne gram-negative obligate intracellular bacteria, which often cause human emerging infectious diseases and economic losses for dairy and meat industries. The purpose of this study is to investigate the distribution of the pathogens including Rickettsia spp., Anaplasma spp., and Ehrlichia spp. in the order Rickettsiales in ticks from Yueyang, a prefecture-level city of Hunan Province in Sothern China, and assess the potentiality of transovarial transmission of these rickettsial organisms. Ticks were collected from cattle in a farm in Yueyang City and the tick DNA was used as template to amplify the htrA, rrs, gltA, ompA and ompB genes of Rickettsia as well as rrs and groEL genes of Anaplasma and Ehrlichia. All ticks (465) collected were the cattle tick, Rhipicephalus microplus. PCR showed the minimum infection rate (MIR) was 1.5% (7/465) for Candidatus Rickettsia xinyangensis, 1.9% (9/465) for C. Anaplasma boleense, 1.3% (6/465) for Anaplasma platys, 0.6% (3/465) for A. marginale, and 1.17% (2/465) for each of A. bovis, Ehrlichia minasensis, and a non-classified Ehrlichia sp. A human pathogen, C. Rickettsia xinyangensis and A. platys were detected in 100% (3/3) and 33.3% (2/6) laboratory-hatched larval pools from infected females respectively. Our study revealed a diversity of pathogenic rickettsial species in R. microplus ticks from Hunan Province suggesting a threat to people and animals in China. This study also provided the first molecular evidence for the potential transovarial transmission of C. Rickettsia xinyangensis and A. platys in R. microplus, indicating that R. microplus may act as the host of these two pathogens.

Purpura Fulminans Secondary to Indian Tick Typhus of Spotted Fever Group of Rickettsial Infections: A Case Report

Rickettsia is a group of vector-borne organisms that beget acute febrile illnesses throughout the world. While the clinical presentation of rickettsial infection is analogous, the causative species and epidemiology can vary depending upon the region. Purpura fulminans (PF) is a rare pattern of intravascular thrombosis and haemorrhagic infarction of the skin that is fleetly progressive and is accompanied by vascular collapse and disseminated intravascular coagulation. We report a case of 11 month old male child presented with high grade fever and necrotic skin lesion over lower limbs. The child was diagnosed with acute contagious PF secondary to Indian tick typhus of spotted fever group of rickettsial infections. Underdiagnosed and misdiagnosed rickettsial infections are an important public health problem leading to an increased morbidity and mortality in cases with PF.

Seroprevalence of Orientia tsutsugamushi and Rickettsia typhi in water buffaloes (Bubalus bubalis) from Southern Thailand.

Scrub typhus and murine typhus are globally distributed zoonoses caused by the intracellular Gram-negative bacteria Orientia tsutsugamushi and Rickettsia typhi, respectively. Numerous studies have been undertaken on rickettsial illnesses in humans and animals, including arthropod vectors, in Thailand. However, the reports on the seroprevalence of antibodies to O. tsutsugamushi and R. typhi in buffaloes is extremely rare. Thus, this study aimed to estimate the seroprevalence of both rickettsial infections in water buffaloes (Bubalus bubalis) in Phatthalung Province, southern Thailand. From February to March 2023, a total of 156 serum samples were collected from 156 water buffaloes on 29 farms in Phatthalung province. The sera were screened for antibodies against O. tsutsugamushi and R. typhi using an indirect immunofluorescence assay. The seroprevalence of antibodies against O. tsutsugamushi and R. typhi in individual water buffaloes was 4.49% (95% confidence interval [CI]: 2.19%-8.97%) and 3.85% (95% CI: 1.77%-8.14%), respectively, whereas 31% (9/29) of the herds had buffaloes with antibodies. The number of buffaloes with scrub typhus infection and ectoparasite infestation was statistically significant (p < 0.05; odds ratio = 6.25 [95% CI: 1.19-33.33]). Intriguingly, the prevalence of scrub typhus antibodies in buffaloes that were not infested with ectoparasites was much higher than those that were. This is the first report of O. tsutsugamushi and R. typhi antibodies in water buffalo sera in Southern Thailand. Two serum samples showed a high antibody titer against O. tsutsugamushi. Seroprevalence mainly occurred in non-ectoparasite-infested buffaloes, especially for O. tsutsugamushi antibodies. At the herd level, one-third of the studied farms showed seroprevalence. Additional research on the occurrence of these pathogens in vectors and in other animal reservoirs is necessary.

Historical epidemics of scrub typhus in Queensland and Papua New Guinea.

Undifferentiated febrile diseases (e.g., Mossman fever) from northern Queensland were eventually partially attributed to mite-transmitted rickettsial infections known as scrub typhus or tsutsugamushi fever. Scrub typhus became a major medical threat to military operations in Papua New Guinea during the Second World War and killed more Australian soldiers than malaria in the pre-antibiotic era. Further investigations showed scrub typhus to be an occupational disease of rural workers in north Queensland especially around Cairns and Innisfail. Occasional small epidemics of scrub typhus still occur during military exercises in Queensland, but as scrub typhus is not a reportable disease, its presence in the civilian community is largely unknown. Increased use of serological testing in patients with fever and rash illnesses after exposure in northern Queensland is likely to show that scrub typhus is a modern infection that remains treatable with antibiotics once it is identified.

Clinical Presentation of Dengue Fever among Bangladeshi Children: A Study of 100 Cases

Background: Dengue is a common tropical disease in Bangladesh. It is prevalent in our country during and just after the rainy season. The symptoms and signs are similar to many other diseases. Objective: The objective of the study is to observe the pattern of dengue fever in this institution for better care of the patients and also comparing with follow-up studies. Methodology: This cross-sectional study was conducted in the Department of Pediatrics at Holy Family Red Crescent Medical College Hospital, Dhaka, Bangladesh from May 2019 to August 2019. A total number of 100 patients were enrolled for this study. They were selected form the inpatient admission. Results: Most commonly children from the 5 to 10 years’ age group were affected with slight preponderance of girls. 90% patients presented with fever with chills and rigor. About 38.18 % children had uncomplicated dengue fever. Most common bleeding manifestation was melena (12.0%). About 21 patients had associated rickettsia infections. About 11 patients developed shock after admission only 22 patients had respiratory distress and 15 patients had pleural effusion. Six patients had neurological symptoms. Conclusions: Classical DF is most common form of the disease. This is followed by other two manifestations. Bangladesh Journal of Infectious Diseases, June 2022;9(1):25-30

Serologic Testing for Rocky Mountain Spotted Fever in a Low-Incidence Region.

Tick-borne diseases have grown in incidence over recent decades. As a result, diagnostic testing has become more common, often performed as broad antibody-based panels for multiple tick-transmitted pathogens. Rocky Mountain spotted fever (RMSF) is rare in our region yet may cause severe morbidity, leading to diagnostic screening in low-risk patients. We sought to describe trends in RMSF diagnostic testing, rate of IgG seropositivity, and clinical features of those tested. We performed a retrospective chart review of patients ≤21 years old undergoing testing for RMSF and/or with an ICD-9/10 code for RMSF. Patients were categorized by infection likelihood based on clinical and laboratory criteria adapted from Centers for Disease Control and Prevention's (CDC) case definition of spotted fever rickettsioses. Clinical data were collected and analyzed with descriptive statistics. One hundred and seventy patients were included. 5.8% met CDC criteria for rickettsial infection, 6.5% had an elevated IgG titer but lacked suggestive symptoms, and 87.6% had a negative IgG titer. Many patients tested were unlikely to have RMSF, including 50% lacking fever, 20% lacking any RMSF "classic triad" symptoms, 13% without acute illness, and 22% tested during months with low tick activity. Convalescent serology was performed in 7.6% of patients and none underwent Rickettsia rickettsii polymerase chain reaction (PCR) testing. Diagnostic testing was frequently performed in patients unlikely to have RMSF. We identified many opportunities for improving test utilization. Reserving testing for those with higher pretest probability, performing convalescent serology, and utilizing PCR may improve the accuracy of RMSF diagnosis and reduce clinical challenges stemming from inappropriate testing.

Typical and Atypical Manifestation of Scrub Typhus in Children

Introduction: Scrub typhus is grossly under-diagnosed or lately diagnosed in India because of its non-specific clinical presentation, a limited awareness about the disease, a low index of suspicion among clinicians, and a lack of diagnostic facilities. Absence of typical features may create diagnostic dilema among physicians thereby delaying the diagnosis which may lead to complications &amp; high mortality. Material and method: A hospital based Cross sectional study which was conducted in the Department of Paediatrics, PRM Medical College, Baripada, Odisha from July 2021 to December 2021. Children from 1 month to 14 years of age presenting with fever in whom rickettsia infection is suspected included. All children who are found to be Elisa or IgM positive for scrub typhus even if admitted for other disease included. All fever cases with rash /oedema/ pallor/icterus/lymphadenopathy/hepatosplenomegaly and or any other systemic features with or without eschar was included. Results: The laboratory parameters of the cases are shown in Table 4. The total leukocyte count was elevated in 30.6% of the cases. An elevated serum creatinine level or a change in the serum creatinine level greater than 0.3 mg/dl, which is a diagnostic of AKI, was observed in 20% of cases. Hyponatremia was found in 6.9% of the cases. The serum CPK level (total and MB fraction) was elevated in 8.9% of cases. Conclusion: Pediatric scrub typhus is a common infection and should be suspected in cases with fever for more than 5 days and non-specific signs and symptoms. Early detection and timely management lead to a higher recovery rate. Hypotension, hypoxia, azotemia, altered sensorium, and bleeding manifestations on admission were associated with unfavorable outcomes.

Multiplex PCR for detection of Anaplasma marginale, A. bovis and A. platys in cattle.

Anaplasma genus has been classified under the family Anaplasmataceae of order Rickettsiales, which contains the spp. Anaplasma marginale, Anaplasma bovis, Anaplasma centrale, Anaplasma platys and Anaplasma phagocytophilum is accountable for a broad range of diseases in both man and animal medicine around the globe. A multiplex PCR procedure was designed to identify A. marginale, A. bovis, and A. platys simultaneously by employing species-specific primers targeting the msp4 (Anaplasma marginale), 16S rRNA (Anaplasma bovis), and groEL (Anaplasma platys) genes. The sensitivity of the assay was ascertained by tenfold dilutions of DNA obtained from cattle blood infected with A. marginale, A. bovis, and A. platys was used to evaluate the test sensitivity. A total of 31 Anaplasma genus positive samples were subjected to mPCR by using species specific primers for simultaneous detection of all the three species. All the 31 samples showed amplification of 753bp fragment specific for A. marginale and 61.29% of the samples showed amplification of 547bp fragment specific for A. bovis. The 470bp DNA fragment specific for A. platys was found in 96.7% of samples. The lower limit of detection of the method for A. platys, A. marginale and A. bovis was found to be 4.4, 0.44 and 0.044ng/µl, respectively.

Identification of common sequence motifs shared exclusively among selectively packed exosomal pathogenic microRNAs during rickettsial infections.

We previously reported that microRNA (miR)23a and miR30b are selectively sorted into exosomes derived from rickettsia-infected endothelial cells (R-ECExos). Yet, the mechanism remains unknown. Cases of spotted fever rickettsioses have been increasing, and infections with these bacteria cause life-threatening diseases by targeting brain and lung tissues. Therefore, the goal of the present study is to further dissect the molecular mechanism underlying R-ECExos-induced barrier dysfunction of normal recipient microvascular endothelial cells (MECs), depending on their exosomal RNA cargos. Infected ticks transmit the rickettsiae to human hosts following a bite and injections of the bacteria into the skin. In the present study, we demonstrate that treatment with R-ECExos, which were derived from spotted fever group R parkeri infected human dermal MECs, induced disruptions of the paracellular adherens junctional protein VE-cadherin, and breached the paracellular barrier function in recipient pulmonary MECs (PMECs) in an exosomal RNA-dependent manner. We did not detect different levels of miRs in parent dermal MECs following rickettsial infections. However, we demonstrated that the microvasculopathy-relevant miR23a-27a-24 cluster and miR30b are selectively enriched in R-ECExos. Bioinformatic analysis revealed that common sequence motifs are shared exclusively among the exosomal, selectively-enriched miR23a cluster and miR30b at different levels. Taken together, these data warrant further functional identification and characterization of a monopartition, bipartition, or tripartition among ACA, UCA, and CAG motifs that guide recognition of microvasculopathy-relevant miR23a-27a-24 and miR30b, and subsequently results in their selective enrichments in R-ECExos.

Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series

Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Quantifying the direct and indirect effects of sika deer (Cervus nippon) on the prevalence of infection with Rickettsia in questing Haemaphysalis megaspinosa: A field experimental study

Sika deer (Cervus nippon) are important hosts for all life stages of Haemaphysalis megaspinosa, a suspected Rickettsia vector. Because some Rickettsia are unlikely to be amplified by deer in Japan, the presence of deer may decrease the prevalence of Rickettsia infection in questing H. megaspinosa. As sika deer decrease vegetation cover and height and thereby indirectly cause changes in the abundance of other hosts, including reservoirs of Rickettsia, the prevalence of Rickettsia infection in questing ticks can also change. We investigated these possible effects of deer on the prevalence of infection with Rickettsia in questing ticks in a field experiment in which deer density was manipulated at three fenced sites: a deer enclosure (Deer-enclosed site); a deer enclosure where deer had been present until 2015 and only indirect effects remained (Indirect effect site); and a deer exclosure in place since 2004 (Deer-exclosed site). Density of questing nymphs and the prevalence of infection with Rickettsia sp. 1 in questing nymphs at each site were compared from 2018 to 2020. The nymph density at the Deer-exclosed site did not significantly differ from that at the Indirect effect site, suggesting that the deer herbivory did not affect the nymph density by reducing vegetation and increasing the abundance of other host mammals. However, the prevalence of infection with Rickettsia sp. 1 in questing nymphs was higher at the Deer-exclosed site than at the Deer-enclosed site, possibly because ticks utilized alternative hosts when deer were absent. The difference in Rickettsia sp. 1 prevalence between the Indirect effect and Deer-exclosed sites was comparable to that between the Indirect effect and Deer-enclosed sites, indicating that the indirect effects of deer were as strong as the direct effects. Examining the indirect effects of ecosystem engineers in the study of tick-borne diseases may be more important than previously recognized.

Type 1 secretion system and effectors in Rickettsiales.

Obligate intracellular bacteria in the order Rickettsiales are transmitted by arthropod vectors and cause life-threatening infections in humans and animals. While both type 1 and type 4 secretion systems (T1SS and T4SS) have been identified in this group, the most extensive studies of Rickettsiales T1SS and associated effectors have been performed in Ehrlichia. These studies have uncovered important roles for the T1SS effectors in pathobiology and immunity. To evade innate immune responses and promote intracellular survival, Ehrlichia and other related obligate pathogens secrete multiple T1SS effectors which interact with a diverse network of host targets associated with essential cellular processes. T1SS effectors have multiple functional activities during infection including acting as nucleomodulins and ligand mimetics that activate evolutionarily conserved cellular signaling pathways. In Ehrlichia, an array of newly defined major immunoreactive proteins have been identified that are predicted as T1SS substrates and have conformation-dependent antibody epitopes. These findings highlight the underappreciated and largely uncharacterized roles of T1SS effector proteins in pathobiology and immunity. This review summarizes current knowledge regarding roles of T1SS effectors in Rickettsiales members during infection and explores newly identified immunoreactive proteins as potential T1SS substrates and targets of a protective host immune response.

Anaplasma Species in Africa-A Century of Discovery: A Review on Molecular Epidemiology, Genetic Diversity, and Control.

Anaplasma species, belonging to the family Anaplasmataceae in the order Rickettsiales, are obligate intracellular bacteria responsible for various tick-borne diseases of veterinary and human significance worldwide. With advancements in molecular techniques, seven formal species of Anaplasma and numerous unclassified species have been described. In Africa, several Anaplasma species and strains have been identified in different animals and tick species. This review aims to provide an overview of the current understanding of the molecular epidemiology and genetic diversity of classified and unclassified Anaplasma species detected in animals and ticks across Africa. The review also covers control measures that have been taken to prevent anaplasmosis transmission on the continent. This information is critical when developing anaplasmosis management and control programs in Africa.

Innate immunity in rickettsial infections.

Rickettsial agents are a diverse group of alpha-proteobacteria within the order Rickettsiales, which possesses two families with human pathogens, Rickettsiaceae and Anaplasmataceae. These obligate intracellular bacteria are most frequently transmitted by arthropod vectors, a first step in the pathogens' avoidance of host cell defenses. Considerable study of the immune responses to infection and those that result in protective immunity have been conducted. Less study has focused on the initial events and mechanism by which these bacteria avoid the innate immune responses of the hosts to survive within and propagate from host cells. By evaluating the major mechanisms of evading innate immunity, a range of similarities among these bacteria become apparent, including mechanisms to escape initial destruction in phagolysosomes of professional phagocytes, those that dampen the responses of innate immune cells or subvert signaling and recognition pathways related to apoptosis, autophagy, proinflammatory responses, and mechanisms by which these microbes attach to and enter cells or those molecules that trigger the host responses. To illustrate these principles, this review will focus on two common rickettsial agents that occur globally, Rickettsia species and Anaplasma phagocytophilum.

Recent outbreaks of Marburg virus in Africa: an urgent call for public concern

Recent outbreaks of Marburg virus in Africa: an urgent call for public concern

Diversity of Rickettsiales bacteria in five species of ticks collected from Jinzhai County, Anhui Province, China in 2021-2022.

The order Rickettsiales in the class Alphaproteobacteria comprises vector-borne pathogens of both medical and veterinary importance. Ticks, as a group, are second only to mosquitoes as vectors of pathogens to humans, playing a critical role in the transmission of rickettsiosis. In the present study, 880 ticks collected from Jinzhai County, Lu'an City, Anhui Province, China in 2021-2022 were identified as belonging to five species from three genera. DNA extracted from individual ticks was examined using nested polymerase chain reaction targeting the 16S rRNA gene (rrs), and the gene fragments amplified were sequenced to detect and identify Rickettsiales bacteria in the ticks. For further identification, the rrs-positive tick samples were further amplified by PCR targeting the gltA and groEL gene and sequenced. As a result, 13 Rickettsiales species belonging to the genera Rickettsia, Anaplasma, and Ehrlichia were detected, including three tentative species of Ehrlichia. Our results reveal the extensive diversity of Rickettsiales bacteria in ticks from Jinzhai County, Anhui Province. There, emerging rickettsial species may be pathogenic and cause under-recognized diseases. Detection of several pathogens in ticks that are closely related to human diseases may indicate a potential risk of infection in humans. Therefore, additional studies to assess the potential public health risks of the Rickettsiales pathogens identified in the present study are warranted.

Rickettsia Deregulates Genes Coding for the Neurotoxic Cell Response Pathways in Cerebrocortical Neurons In Vitro.

Rickettsial infections of the central nervous system (CNS) are manifested by severe neurological symptoms and represent a serious life-threatening condition. Despite the considerable health danger, only a few studies have been conducted focusing on the pathogenesis induced by Rickettsia sp. in CNS. To investigate the signaling pathways associated with the neurotoxic effects of rickettsiae, we employed an experimental model of cerebrocortical neurons combined with molecular profiling and comprehensive bioinformatic analysis. The cytopathic effect induced by Rickettsia akari and Rickettsia slovaca was demonstrated by decreased neuronal viability, structural changes in cell morphology, and extensive fragmentation of neurites in vitro. Targeted profiling revealed the deregulation of genes involved in the neuroinflammatory and neurotoxic cell response pathways. Although quantitative analysis showed differences in gene expression response, functional annotation revealed that the biological processes are largely shared between both Rickettsia species. The identified enriched pathways are associated with cytokine signaling, chemotaxis of immune cells, responses to infectious agents, interactions between neurons, endothelial and glial cells, and regulation of neuronal apoptotic processes. The findings of our study provide new insight into the etiopathogenesis of CNS infection and further expand the understanding of molecular signaling associated with neuroinvasive Rickettsia species.