RESUMEN
How intracellular bacteria subvert the major histocompatibility complex (MHC) class I pathway is poorly understood. Here, we show that the obligate intracellular bacterium Orientia tsutsugamushi uses its effector protein, Ank5, to inhibit nuclear translocation of the MHC class I gene transactivator, NLRC5, and orchestrate its proteasomal degradation. Ank5 uses a tyrosine in its fourth ankyrin repeat to bind the NLRC5 N-terminus while its F-box directs host SCF complex ubiquitination of NLRC5 in the leucine-rich repeat region that dictates susceptibility to Orientia- and Ank5-mediated degradation. The ability of O. tsutsugamushi strains to degrade NLRC5 correlates with ank5 genomic carriage. Ectopically expressed Ank5 that can bind but not degrade NLRC5 protects the transactivator during Orientia infection. Thus, Ank5 is an immunoevasin that uses its bipartite architecture to rid host cells of NLRC5 and reduce surface MHC class I molecules. This study offers insight into how intracellular pathogens can impair MHC class I expression.
Asunto(s)
Antígenos de Histocompatibilidad Clase I , Péptidos y Proteínas de Señalización Intracelular , Orientia tsutsugamushi , Orientia tsutsugamushi/metabolismo , Orientia tsutsugamushi/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Animales , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Citoplasma/metabolismo , Células HEK293 , Proteolisis , Tifus por Ácaros/inmunología , Tifus por Ácaros/microbiología , Tifus por Ácaros/metabolismo , Ratones , Ubiquitinación , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
Objectives: Scrub typhus is the most common rickettsial disease in India, caused by Orientia tsutsugamushi and transmitted by chigger mites. Previously prevalent in South India, a resurgence of scrub typhus cases has recently affected Eastern India. This study aimed to estimate the prevalence and describe the clinico-laboratory profile of scrub typhus in paediatric patients (1-12 years old) living in Eastern India. Methods: This prospective observational study was conducted from January to December 2019 at the Dr B C Roy Post Graduate Institute of Paediatric Sciences, Kolkata, India. All acute undifferentiated cases of febrile illness, in patients aged between 1-12 years, were tested using scrub typhus serology by ELISA. Demographic details, clinical features, laboratory findings, complications and treatment outcomes of these scrub typhus patients were extracted and analysed. Results: Out of 1,473 patients with acute febrile illness, 67 (4.5%) children were diagnosed with scrub typhus. The mean age of the selected patients was 5.22 ± 3.05 years, and the majority (64.2%) had been running a fever since the preceding 7-14 days. Gastrointestinal symptoms such as vomiting (43.3%) and abdominal pain (32.8%) were most frequently observed. Major clinical signs of scrub typhus were hepatomegaly (41.8%) and splenomegaly (31.3%). Complications were observed in 74.6% of patients, with thrombocytopenia (40.3%) and meningoencephalitis (29.9%) occurring more frequently. The case fatality rate of the study sample was 1.5%. Conclusion: Classical eschar was absent in three-fourth of the studied patients. Hence, this study advocates laboratory scrub typhus tests for all suspected cases in the endemic region (Eastern India). Prompt treatment with doxycycline and/or azithromycin could prevent complications such as thrombocytopenia/meningoencephalitis and reduce mortality.
Asunto(s)
Tifus por Ácaros , Centros de Atención Terciaria , Humanos , Tifus por Ácaros/epidemiología , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , India/epidemiología , Estudios Prospectivos , Niño , Preescolar , Masculino , Femenino , Prevalencia , Centros de Atención Terciaria/organización & administración , Centros de Atención Terciaria/estadística & datos numéricos , Lactante , Orientia tsutsugamushi/patogenicidadRESUMEN
The prevalence of tick-borne pathogens (TBP), Orientia tsutsugamushi, Rickettsia and Borrelia spp. in wild small animals, namely wild rodents, is now widely investigated. This study is to present the prevalence and distribution of O. tsutsugamushi, Rickettsia and Borrelia spp. in wild small animals and ticks collected from Gyeonggi and Gangwon provinces, Republic of Korea (ROK) in 2014. A total of 131 wild small animals, rodents and shrews, and 2,954 ticks were collected from Gyeonggi and Gangwon provinces from May to November 2014. The wild small animals (KR1-9) and ticks (K1-17) were grouped in accordance with capture dates and locations. Among the wild small animals, a total of 393 tissues and blood samples were extracted from six selected small animal series (KR1-3, KR6-8). Also, each date and location-grouped ticks were identified for its species and pooled according to the stage of development. Molecular identification for Rickettsia, Orientia, and Borrelia species was performed using polymerase chain reaction (PCR). To detect TBPs among wild small animals and ticks, primer sets targeting the 56 kDa protein encoding gene of Orientia spp., outer membrane protein B gene (OmpB) of Rickettsia spp., and 5S-23S intergenic spacer region (IGS) gene of Borrelia spp. were used. Of the 393 wild small animals' blood and tissue samples, 199 (50.6%) were positive for Orientia spp., 158 (40.2%) were positive for Borrelia spp., and 55 (14.0%) were positive for Rickettsia spp. Moreover, a total of 14 tick pools (n = 377) was positive for Rickettsia spp. (n=128, 34.0%) and Borrelia spp. (n=33, 8.8%). High prevalence of Orientia spp. and Rickettsia spp. in rodents and shrews were observed. This study presents significant insights by presenting data collected in 2014 that the prevalence of TBP was already high in mid 2010s. This study highlights the sustainable routine surveillance model for TBP.
Asunto(s)
Borrelia , Orientia tsutsugamushi , Rickettsia , Roedores , Musarañas , Garrapatas , Animales , Musarañas/parasitología , Musarañas/microbiología , Roedores/microbiología , Roedores/parasitología , Rickettsia/aislamiento & purificación , Rickettsia/genética , República de Corea/epidemiología , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/aislamiento & purificación , Borrelia/aislamiento & purificación , Borrelia/genética , Garrapatas/microbiología , Enfermedades por Picaduras de Garrapatas/epidemiología , Enfermedades por Picaduras de Garrapatas/microbiología , Enfermedades por Picaduras de Garrapatas/veterinaria , Reacción en Cadena de la Polimerasa , Animales Salvajes/microbiología , Animales Salvajes/parasitología , Tifus por Ácaros/epidemiología , Tifus por Ácaros/veterinaria , Tifus por Ácaros/microbiologíaRESUMEN
Spotted fever group (SFG) rickettsia, the causative agent of SFG rickettsiosis, is predominantly carried by ticks, whereas Orientia tsutusgamushi, the causative agent of scrub typhus, is primarily transmitted by chigger mites in Japan. In this study, we attempted to isolate intracellular eubacteria from Leptotrombidium scutellare, a major vector of O. tsutsugamushi; moreover, we isolated an SFG rickettsia using a mosquito-derived cell line. Draft genome sequences of this unique isolate, by applying criteria for species delimitation, classified this isolate as a novel strain, proposed as "Rickettsia kedanie." Further genetic analysis identified conserved virulence factors, and the isolate successfully propagated in mammalian cells, suggesting its ability to cause diseases in humans. The presence of SFG rickettsia in unfed larvae implies potential dual-pathogen carriage and reflects a symbiotic relationship similar to that between the mites and O. tsutsugamushi, indicating possibility of its transovarial transmission from female adults. Furthermore, conserved genomic similarity of the novel isolate to known SFG rickettsia suggests potential multiple hosts, including chiggers and ticks. In the natural environment, ticks, chigger mites, and wild animals may carry new isolates, complicating the infection cycle and increasing the transmission risks to humans. This discovery challenges the conventional association of SFG rickettsia with ticks, emphasizing its implications for research and disease control. However, this study was confined to a particular species of chigger mites and geographic area, underscoring the necessity for additional studies to comprehend the ecological dynamics, host interactions, and health implications linked to this newly identified SFG rickettsia.
Asunto(s)
Larva , Rickettsia , Rickettsiosis Exantemáticas , Trombiculidae , Animales , Rickettsia/genética , Rickettsia/clasificación , Rickettsia/aislamiento & purificación , Trombiculidae/microbiología , Larva/microbiología , Rickettsiosis Exantemáticas/microbiología , Genoma Bacteriano , Humanos , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/clasificación , Orientia tsutsugamushi/aislamiento & purificación , Femenino , Filogenia , Japón , Factores de Virulencia/genética , Tifus por Ácaros/microbiología , Tifus por Ácaros/transmisión , Línea CelularRESUMEN
Scrub typhus, a prevalent tropical infection, may sometimes manifest with unusual complications. Here, we present the case of a young man who was admitted to our facility with a fever for the past 3 days and passage of dark-coloured urine since that morning. On investigation, we identified intravascular haemolytic anaemia. Through meticulous examination, a black necrotic lesion (eschar) was discovered on his right buttock, a pathognomonic sign of scrub typhus infection. Treatment was initiated with oral doxycycline 100 mg two times a day. Subsequently, diagnosis of scrub typhus was confirmed through positive results from scrub typhus IgM via ELISA and PCR analysis from the eschar tissue. The patient responded well to oral doxycycline and his symptoms resolved within the next few days. This case highlights severe intravascular haemolysis associated with scrub typhus infection.
Asunto(s)
Antibacterianos , Doxiciclina , Tifus por Ácaros , Humanos , Tifus por Ácaros/complicaciones , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , Masculino , Doxiciclina/uso terapéutico , Antibacterianos/uso terapéutico , Anemia Hemolítica/etiología , Anemia Hemolítica/diagnóstico , Adulto , Orientia tsutsugamushi/aislamiento & purificaciónRESUMEN
OBJECTIVES: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. We aimed to provide the first comprehensive review on the seroprevalence, incidence, mortality of and risk factors for scrub typhus. METHODS: We searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases. Trended incidence and median mortality were calculated and pooled seroprevalence and risk factors for scrub typhus were evaluated using the random-effects meta-analysis. RESULTS: We included 663 articles from 29 countries/regions. The pooled seroprevalence was 10.73% (95%CI 9.47-12.13%) among healthy individuals and 22.58% (95%CI: 20.55%-24.76%) among febrile patients. Mainland China reported the highest number of cases and South Korea and Thailand had the highest incidence rates. Median mortalities were 5.00% (range: 0.00-56.00%) among hospital inpatients, 6.70% (range: 0.00-33.33%) among patients without specified admission status and 2.17% (range: 0.00-22.22%) among outpatients. The significant risk factors included agricultural work, specific vegetation exposure, other outdoor activities, risky personal health habits, and proximity to rodents, livestock, or poultry. CONCLUSIONS: Our comprehensive review elucidates the significant yet variable burden of scrub typhus across different regions, underscoring its emergence as a critical public health concern globally.
Asunto(s)
Tifus por Ácaros , Tifus por Ácaros/epidemiología , Tifus por Ácaros/mortalidad , Humanos , Estudios Seroepidemiológicos , Factores de Riesgo , Incidencia , Orientia tsutsugamushi/inmunología , Salud Global , AnimalesRESUMEN
BACKGROUND: Scrub typhus, caused by Orientia tsutsugamushi, rarely leads to central nervous system involvement. Although intracerebral bleeding is rare due to endemicity and a significant proportion of underdiagnoses, it should be considered a noteworthy differential diagnosis in endemic regions in patients with relevant history and clinical findings. CASE PRESENTATION: We present the case of a 40-year-old Nepali woman who visited the emergency department with complaints of left-sided weakness for 6 hours and an acute febrile illness with an eschar for 7 days and was diagnosed with scrub typhus by immunoglobulin M enzyme-linked immunosorbent assay of the serum. Imaging revealed a right-sided frontotemporal hematoma, and further examination revealed pulmonary edema with multiple organ dysfunction syndrome. The patient was mechanically ventilated and was treated with antibiotics, steroids, vasopressors, and antipyretics. However, the hematoma was treated conservatively, with ongoing neurological recovery at the 6-month follow-up. CONCLUSION: Although neurological complications and intracranial hemorrhage are uncommon, physicians must be cautious when making differential diagnoses and initiating appropriate therapies to avoid serious or fatal complications.
Asunto(s)
Antibacterianos , Accidente Cerebrovascular Hemorrágico , Tifus por Ácaros , Humanos , Tifus por Ácaros/complicaciones , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , Femenino , Adulto , Accidente Cerebrovascular Hemorrágico/diagnóstico , Antibacterianos/uso terapéutico , Diagnóstico Diferencial , Orientia tsutsugamushi , Tomografía Computarizada por Rayos XRESUMEN
Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.
Asunto(s)
Anticuerpos Antibacterianos , Inmunoglobulina G , Inmunoglobulina M , Orientia tsutsugamushi , Tifus por Ácaros , Tifus por Ácaros/epidemiología , Tifus por Ácaros/inmunología , Humanos , India/epidemiología , Estudios Seroepidemiológicos , Nepal/epidemiología , Inmunoglobulina G/sangre , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Orientia tsutsugamushi/inmunología , Inmunoglobulina M/sangre , Incidencia , Adulto , Masculino , Femenino , Tailandia/epidemiología , Adolescente , Adulto Joven , Teorema de Bayes , Persona de Mediana EdadRESUMEN
A 64-year-old male, working at a mountain site in Taitung County, suffered from primary open angle glaucoma (POAG) post trabeculectomy with well-controlled intraocular pressure (IOP) in both eyes (OU). He presented with headache accompanied by red eyes (OU) for 10 days. Physical examination revealed fever up to 38.2°C, neck stiffness, one eschar at the left forearm and another at the left ankle. Abnormal laboratory data indicated bacterial infection with central nervous system involvement. Ophthalmic examination showed elevated IOP, moderate conjunctival congestion, subconjunctival hemorrhage, anterior uveitis, cotton-wool spots on the retina and multiple white dots on the temporal retina (OU). Under the impression of uveitis in tsutsugamushi disease with atypical meningitis, oral doxycycline, anti-glaucoma and anti-inflammation eye drugs were prescribed. IOP returned to 12 mmHg and anterior uveitis subsided. The lesions of cotton-wool spots on the retina disappeared within 2 weeks, but multiple white dots remained persistently on the temporal retina.
Asunto(s)
Infecciones Bacterianas del Ojo , Glaucoma de Ángulo Abierto , Presión Intraocular , Tifus por Ácaros , Humanos , Masculino , Persona de Mediana Edad , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/microbiología , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Presión Intraocular/fisiología , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , Tifus por Ácaros/microbiología , Tifus por Ácaros/complicaciones , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/microbiología , Antibacterianos/uso terapéutico , Orientia tsutsugamushi/aislamiento & purificación , Doxiciclina/uso terapéutico , Uveítis Anterior/microbiología , Uveítis Anterior/diagnóstico , Uveítis Anterior/tratamiento farmacológico , TrabeculectomíaRESUMEN
RATIONALE: Scrub typhus is a naturally occurring acute febrile disease caused by Orientia tsutsugamushi. Although it can cause multiple organ dysfunction, central nervous system infections are uncommon. PATIENT CONCERNS: A 17-year-old male presented with a 5-day history of fever and headaches. The MRI of the head revealed thickness and enhancement of the left temporal lobe and tentorium cerebelli, indicating potential inflammation. DIAGNOSES: The patient was diagnosed with a central nervous system infection. INTERVENTIONS: Ceftriaxone and acyclovir were administered intravenously to treat the infection, reduce fever, restore acid-base balance, and manage electrolyte disorders. OUTCOMES: Despite receiving ceftriaxone and acyclovir as infection therapy, there was no improvement. Additional multipathogen metagenomic testing indicated the presence of O tsutsugamushi infection, and an eschar was identified in the left axilla. The diagnosis was changed to scrub typhus with meningitis and the therapy was modified to intravenous doxycycline. Following a 2-day therapy, the body temperature normalized, and the fever subsided. CONCLUSIONS: The patient was diagnosed with scrub typhus accompanied by meningitis, and doxycycline treatment was effective. LESSION: Rarely reported cases of scrub typhus with meningitis and the lack of identifiable symptoms increase the chance of misdiagnosis or oversight. Patients with central nervous system infections presenting with fever and headache unresponsive to conventional antibacterial and antiviral treatment should be considered for scrub typhus with meningitis. Prompt multipathogen metagenomic testing is recommended to confirm the diagnosis and modify the treatment accordingly.
Asunto(s)
Antibacterianos , Tifus por Ácaros , Humanos , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , Tifus por Ácaros/complicaciones , Masculino , Adolescente , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Doxiciclina/uso terapéutico , Doxiciclina/administración & dosificación , Orientia tsutsugamushi/aislamiento & purificación , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/tratamiento farmacológico , Meningitis Bacterianas/microbiologíaRESUMEN
During evolution Orientia tsutsugamushi became a smarter obligate bacterium to establish as intracellular pathogens. O. tsutsugamushi is a human pathogenic bacterium responsible for 1 billion infections of scrub typhus. Several novel mechanisms make this bacterium unique (cell wall, genetic constitutions, secretion system, etc.). In 2007, O. tsutsugamushi Boryong was pioneer strain for whole-genome sequencing. But the fundamental biology of this bacterial cell is a mystery till date. The unusual biology makes this organism as model for host cell interaction. Only a few antibiotics are effective against this intracellular pathogen but emergence of less susceptibility toward antibiotics make the situation alarming. The review was captivated to highlight the unusual aspects of adaptation, antibiotics, and drugs beyond antibiotics.
Asunto(s)
Antibacterianos , Orientia tsutsugamushi , Tifus por Ácaros , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/efectos de los fármacos , Tifus por Ácaros/microbiología , Tifus por Ácaros/tratamiento farmacológico , Antibacterianos/farmacología , Humanos , Adaptación Fisiológica , AnimalesRESUMEN
This study aimed to assess the molecular prevalence of mite-borne zoonotic pathogen O. tsutsugamushi in household rats of South India through nested polymerase chain reaction amplification of O. tsutsugamushi 47-kDa htrA gene and to determine the most suitable sample type for screening of O. tsutsugamushi in rats. Out of 85 rats trapped in Tamil Nadu, Karnataka, and Puducherry regions, 47 rats were found positive for the O. tsutsugamushi genome with prevalence of 55.29â¯%. Among different sample types screened, faecal samples exhibited the highest positivity rate, followed by liver, spleen, kidney, and blood samples. Agreement between faecal and spleen samples of rats for the presence of O. tsutsugamushi was the highest. Principal component analysis revealed a positive correlation between the spleen, liver, and faeces and a negative correlation between blood and faeces for the presence of O. tsutsugamushi genome. These findings underscore the varied distribution of O. tsutsugamushi among different samples and indicate that the faecal and liver samples of rats are an ideal choice of samples for epidemiological studies. This is the first study to report a high level of presence of O. tsutsugamushi in faecal samples of rats.
Asunto(s)
Heces , Orientia tsutsugamushi , Tifus por Ácaros , Bazo , Animales , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/aislamiento & purificación , India/epidemiología , Tifus por Ácaros/epidemiología , Tifus por Ácaros/microbiología , Ratas , Heces/microbiología , Estudios Transversales , Prevalencia , Bazo/microbiología , Hígado/microbiología , Enfermedades de los Roedores/epidemiología , Enfermedades de los Roedores/microbiología , Reacción en Cadena de la Polimerasa , ADN Bacteriano/genéticaRESUMEN
Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-ß. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.
Asunto(s)
Interferón gamma , Orientia tsutsugamushi , Tifus por Ácaros , Transducción de Señal , Animales , Ratones , Modelos Animales de Enfermedad , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Orientia tsutsugamushi/inmunología , Tifus por Ácaros/inmunología , Tifus por Ácaros/microbiología , Piel/microbiología , Piel/patología , Piel/inmunología , Factor de Transcripción STAT1/metabolismo , Receptor de Interferón gamma/genética , Receptor de Interferón gamma/metabolismoRESUMEN
Background: Scrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar. Case presentation: We obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly. Conclusion: The unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.
Asunto(s)
Linfohistiocitosis Hemofagocítica , Orientia tsutsugamushi , Tifus por Ácaros , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/complicaciones , Humanos , Femenino , Niño , Orientia tsutsugamushi/aislamiento & purificación , Orientia tsutsugamushi/genética , Linfohistiocitosis Hemofagocítica/diagnóstico , China , Masculino , Doxiciclina/uso terapéuticoRESUMEN
Scrub typhus, a neglected disease, is a significant health concern in the Tsutsugamushi triangle of the Asia-Pacific and has raised global concerns due to recent cases occurring outside this region. To estimate the global prevalence of scrub typhus, we conducted a systematic review and meta-analysis. We conducted a systematic search of PubMed, Scopus, and Embase databases for observational studies on scrub typhus. Using a random-effects model, we combined the prevalence estimates with inverse-variance weights while also evaluating heterogeneity and publication bias. Among 3551 reports screened, we identified 181 studies with 1,48,251 samples for inclusion in our synthesis. The overall pooled seroprevalence (95% confidence intervals) of scrub typhus infections was 24.93% (23.27-26.60). Gender-wise pooled prevalence was estimated to be 50.23% (47.05-53.40) for males and 48.84% (45.87-51.80) for females. Eschar prevalence was observed to be 30.34% (22.54-38.15) among the positive cases. One-fourth of all the samples tested positive for scrub typhus and eschar was present in one-third of these total positive cases, encompassing regions beyond the Tsutsugamushi triangle. This estimation underlines the importance of this neglected disease as a public health problem. Strengthening surveillance and implementing disease control measures are needed in the affected regions.
Asunto(s)
Tifus por Ácaros , Tifus por Ácaros/epidemiología , Humanos , Estudios Seroepidemiológicos , Femenino , Masculino , Prevalencia , Orientia tsutsugamushi/inmunología , Salud GlobalRESUMEN
Scrub typhus, a potentially life-threatening infectious disease, is attributed to bacteria Orientia tsutsugamushi (O. tsutsugamushi). The transmission of this illness to humans occurs through the bite of infected chiggers, which are the larval forms of mites belonging to the genus Leptotrombidium. In this research, we developed a subunit vaccine specifically designed to target outer membrane proteins. Immunodominant cytotoxic T-lymphocytes (CTLs), B- lymphocytes (BCLs), and major histocompatibility complex (MHC)- II epitopes were identified using machine learning and bioinformatics approaches. These epitopes were arranged in different combinations with the help of suitable linkers like AAY, KK, GPGPG and adjuvant (cholera toxin B) that resulted in a vaccine construct. Physiochemical properties were assessed, where the predicted solubility (0.571) was higher than threshold value. Tertiary structure was predicted using I-TASSER web server and evaluated using Ramachandran plot (94 % residues in most favourable region) and z-score (-6.04), which had shown the structure to have good stability and residue arrangement. Molecular docking with immune receptors, Toll-like receptor (TLR)-2 and -4 showed good residue interaction with 13 and 5 hydrogen bonds respectively. Molecular dynamics simulations of receptor-ligand complex provided the idea about the strong interaction having 1.524751 × 10-5 eigenvalue. Amino acid sequence of vaccine was converted to nucleotide sequence and underwent codon optimization. The optimized codon sequence was used for in-silico cloning, which provided idea about the possibility of synthesis of vaccine using E. coli as host. Overall, this study provided a promising blueprint for a scrub typhus vaccine, although experimental validation is needed for confirmation. Furthermore, it is crucial to acknowledge that while bioinformatics provides valuable insights, in-vitro and in-vivo studies are imperative for a comprehensive evaluation of vaccine candidate. Thus, the integration of computational predictions with empirical research is essential to validate the efficacy, safety, and real-world applicability of the designed vaccine against Scrub Typhus. Nevertheless, the findings are good to carry forward for in-vitro and in-vivo investigations.
Asunto(s)
Epítopos de Linfocito B , Epítopos de Linfocito T , Orientia tsutsugamushi , Tifus por Ácaros , Vacunas de Subunidad , Tifus por Ácaros/inmunología , Tifus por Ácaros/prevención & control , Orientia tsutsugamushi/inmunología , Humanos , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/inmunología , Vacunas de Subunidad/inmunología , Simulación del Acoplamiento Molecular , Vacunas Bacterianas/inmunología , Simulación por Computador , Biología Computacional/métodos , Linfocitos T Citotóxicos/inmunología , Aprendizaje Automático , Linfocitos B/inmunología , Receptor Toll-Like 2/inmunologíaRESUMEN
BACKGROUND: Globally, India has a high zoonotic disease burden and lacks surveillance data in humans and animals. Rodents are known reservoirs for many zoonotic diseases and their synanthropic behavior poses a great public health threat. METHODS: In this study, trapped rodents/shrews from randomly selected villages within Puducherry, India, and their ectoparasites were screened for zoonotic pathogens, namely, Orientia tsutsugamushi, other pathogenic rickettsiae, Leptospira spp., Cryptosporidium spp., Coxiella burnetii and methicillin-resistant Staphylococcus aureus (MRSA) using conventional PCR. A total of 58 rodents/shrews were trapped from 11 villages. The species trapped were Suncus murinus (49/58, 84.48%), Rattus rattus (8/58, 13.79%) and Rattus norvegicus (1/58, 1.72%). All ectoparasites collected were identified as mites and its infestation rate was 46.55% (27/58). RESULTS: Real-time PCR targeting the 47 kDa gene of O. tsutsugamushi revealed positivity in one rodent and one shrew (3.45%) and two mite pools (7.41%). Conventional PCR targeting the 56 kDa gene revealed positivity in one shrew and two mite pools and the phylogenetic analysis of all three amplicons indicated the circulation of the Gilliam-related serotype. MRSA was detected in the alimentary tract of a shrew (1/32, 3.13%). Leptospira spp., Rickettsia, Cryptosporidium spp. and Co. burnetii tested negative. CONCLUSIONS: The detection of zoonotic pathogens within reservoir hosts and vectors poses a risk of transmission to humans. This study signifies the need for zoonotic pathogen surveillance in synanthropic rodents/shrews.
Asunto(s)
Coxiella burnetii , Reservorios de Enfermedades , Staphylococcus aureus Resistente a Meticilina , Salud Pública , Roedores , Zoonosis , Animales , India/epidemiología , Zoonosis/transmisión , Zoonosis/epidemiología , Humanos , Coxiella burnetii/aislamiento & purificación , Coxiella burnetii/genética , Reservorios de Enfermedades/microbiología , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/genética , Roedores/parasitología , Roedores/microbiología , Rickettsia/aislamiento & purificación , Rickettsia/genética , Musarañas/parasitología , Musarañas/microbiología , Ratas , Orientia tsutsugamushi/aislamiento & purificación , Orientia tsutsugamushi/genética , Cryptosporidium/aislamiento & purificación , Cryptosporidium/genética , Leptospira/aislamiento & purificación , Leptospira/genética , Ácaros/microbiología , Enfermedades de los Roedores/epidemiología , Enfermedades de los Roedores/microbiología , Enfermedades de los Roedores/parasitología , Enfermedades de los Roedores/transmisiónRESUMEN
Scrub typhus, caused by Orientia tsutsugamushi, is a re-emerging zoonotic disease in the tropics with considerable morbidity and mortality rates. This disease, which is mostly prevalent in rural areas, remains underdiagnosed and underreported because of the low index of suspicion and non-specific clinical presentation. Limited access to healthcare, diagnostics, and treatment in rural settings further makes it challenging to distinguish it from other febrile illnesses. While easily treatable, improper treatment leads to severe forms of the disease and even death. As there is no existing public health program to address scrub typhus in India, there is an urgent need to design a program and test its effectiveness for control and management of the disease. With this backdrop, this implementation research protocol has been developed for a trial in few of the endemic "pockets" of Odisha, an eastern Indian state that can be scalable to other endemic areas of the country, if found effective. The main goal of the proposed project is to include scrub typhus as a differential diagnosis of fever cases in every tier of the public health system, starting from the community level to the health system, for the early diagnosis among suspected cases and to ensure that individuals receive complete treatment. The current study aimed to describe the protocol of the proposed Scrub Typhus Control Program (STCP) in detail so that it can receive valuable views from peers which can further strengthen the attempt.
Asunto(s)
Diagnóstico Precoz , Orientia tsutsugamushi , Salud Pública , Tifus por Ácaros , Tifus por Ácaros/diagnóstico , Humanos , India , Orientia tsutsugamushi/aislamiento & purificaciónRESUMEN
BACKGROUND: Trombiculid mites are globally distributed, highly diverse arachnids that largely lack molecular resources such as whole mitogenomes for the elucidation of taxonomic relationships. Trombiculid larvae (chiggers) parasitise vertebrates and can transmit bacteria (Orientia spp.) responsible for scrub typhus, a zoonotic febrile illness. Orientia tsutsugamushi causes most cases of scrub typhus and is endemic to the Asia-Pacific Region, where it is transmitted by Leptotrombidium spp. chiggers. However, in Dubai, Candidatus Orientia chuto was isolated from a case of scrub typhus and is also known to circulate among rodents in Saudi Arabia and Kenya, although its vectors remain poorly defined. In addition to Orientia, chiggers are often infected with other potential pathogens or arthropod-specific endosymbionts, but their significance for trombiculid biology and public health is unclear. RESULTS: Ten chigger species were collected from rodents in southwestern Saudi Arabia. Chiggers were pooled according to species and screened for Orientia DNA by PCR. Two species (Microtrombicula muhaylensis and Pentidionis agamae) produced positive results for the htrA gene, although Ca. Orientia chuto DNA was confirmed by Sanger sequencing only in P. agamae. Metagenomic sequencing of three pools of P. agamae provided evidence for two other bacterial associates: a spirochaete and a Wolbachia symbiont. Phylogenetic analysis of 16S rRNA and multi-locus sequence typing genes placed the spirochaete in a clade of micromammal-associated Borrelia spp. that are widely-distributed globally with no known vector. For the Wolbachia symbiont, a genome assembly was obtained that allowed phylogenetic localisation in a novel, divergent clade. Cytochrome c oxidase I (COI) barcodes for Saudi Arabian chiggers enabled comparisons with global chigger diversity, revealing several cases of discordance with classical taxonomy. Complete mitogenome assemblies were obtained for the three P. agamae pools and almost 50 SNPs were identified, despite a common geographic origin. CONCLUSIONS: P. agamae was identified as a potential vector of Ca. Orientia chuto on the Arabian Peninsula. The detection of an unusual Borrelia sp. and a divergent Wolbachia symbiont in P. agamae indicated links with chigger microbiomes in other parts of the world, while COI barcoding and mitogenomic analyses greatly extended our understanding of inter- and intraspecific relationships in trombiculid mites.