Febrile Illness In Humans Research Articles

Seroprevalence of Rickettsia Spp. and Orientia tsutsugamushi in Indigenous Populations from the Sierra Nevada de Santa Marta, Colombia.

Background: Rickettsia spp. are vector-borne zoonotic pathogens that cause febrile illness in humans. Rickettsioses is not included in the Colombian national surveillance system and is subsequently expected to be underreported. This cross-sectional study aimed to determine the seroprevalence of Rickettsia spp. and the closely related Orientia tsutsugamushi in two indigenous populations residing in the Sierra Nevada de Santa Marta, Colombia. Materials and Methods: Serum samples (n = 539) were collected from the Wiwa and Koguis people between 2021 and 2022. Serum samples were screened for spotted fever group (SFG) and typhus group (TG) Rickettsia spp. using the Fuller laboratories Rickettsia IgG IFA kit and for O. tsutsugamushi with the Scrub Typhus Detect™ IgG ELISA. Results: We observed an overall seroprevalence of 26.2% (95% confidence interval [CI] 22.5-30.1] for Rickettsia spp. of the SFG, 5.4% (95% CI 3.6-7.6) for Rickettsia spp. of the TG and 4.3% (95% CI 2.7-6.3) for O. tsutsugamushi. Common risk factors for zoonotic disease infections were assessed for 147 of the Wiwa participants. Increased odds of seropositivity for SFG Rickettsia spp. were observed for Wiwa participants who cared for livestock, including assisting with the birth of cattle (odds ratio [OR] = 8.85; 95% CI 1.54-50.90; p = 0.015) and goats (OR = 7.60; 95% CI 1.70-33.90; p = 0.008). Conclusions: These results highlight a notable exposure to Rickettsia spp., especially the SFG, in rural Colombia. Together with recent reports of high mortality for Rocky Mountain Spotted Fever in nearby regions of South America, more detailed investigations focusing on improving knowledge and awareness as well as "One Health" and "causes-of-fever" studies are needed. The characterization of Rickettsia spp. infections in humans, livestock, and tick vectors with their potential transmission routes could make a high impact on these easily treatable diseases.

First detection of Jingmen tick virus in Corsica with a new generic RTqPCR system

Jingmen tick virus (JMTV) is a recently discovered segmented RNA virus, closely related to flaviviruses. It was identified for the first time in 2014, in China and subsequently in Brazil. Following this discovery, JMTV-related sequences have been identified in arthropods, vertebrates (including humans), plants, fungus, and environmental samples from Asia, America, Africa, Europe, and Oceania. Several studies suggest an association between these segmented flavi-like viruses, termed jingmenviruses, and febrile illness in humans. The development of rapid diagnostic assays for these viruses is therefore crucial to be prepared for a potential epidemic, for the early detection of these viruses via vector surveillance or hospital diagnosis. In this study, we designed a RT-qPCR assay to detect tick-associated jingmenviruses, validated it and tested its range and limit of detection with six tick-associated jingmenviruses using in vitro transcripts. Then, we screened ticks collected in Corsica (France) from different livestock species, in order to determine the distribution of these viruses on the island. In total, 6269 ticks from eight species were collected from 763 cattle, 538 horses, 106 sheep, and 218 wild boars and grouped in 1715 pools. We report the first detection of JMTV in Corsica, in Rhipicephalus bursa, Hyalomma marginatum and R. sanguineus ticks collected from cattle and sheep. The highest prevalence was found in the Rhipicephalus genus. The complete genome of a Corsican JMTV was obtained from a pool of Rhipicephalus bursa ticks and shares between 94.7% and 95.1% nucleotide identity with a JMTV sequence corresponding to a human patient in Kosovo and groups phylogenetically with European JMTV strains. These results show that a Mediterranean island such as Corsica could act as a sentinel zone for future epidemics.

Aetiologies of bacterial tick-borne febrile illnesses in humans in Africa: diagnostic limitations and the need for improvement.

Tick-borne febrile illnesses caused by pathogens like Anaplasma spp., Bartonella spp., Borrelia spp., Ehrlichia spp., Coxiella burnetii, Francisella tularensis, and Rickettsia spp., are significant health concerns in Africa. The epidemiological occurrence of these pathogens is closely linked to the habitats of their vectors, prevalent in rural and semi-urban areas where humans and livestock coexist. The overlapping clinical presentations, non-specific symptoms, and limited access to commercially available in vitro diagnostics in resource-limited settings exacerbate the complexity of accurate diagnoses. This review aimed to systematically extract and analyze existing literature on tick-borne febrile illnesses in Africa, highlighting the diagnostic challenges and presenting an up-to-date overview of the most relevant pathogens affecting human populations. A comprehensive literature search from January 1990 to June 2024 using databases like PubMed, Cochrane Library, Science Direct, EMBASE, and Google Scholar yielded 13,420 articles, of which 70 met the inclusion criteria. Anaplasma spp. were reported in Morocco, Egypt, and South Africa; Francisella spp. in Kenya and Ethiopia; Ehrlichia spp. in Cameroon; Bartonella spp. in Senegal, Namibia, South Africa, and Ethiopia; Borrelia spp. in Senegal, Gabon, Tanzania, and Ethiopia; Coxiella burnetii in 10 countries including Senegal, Mali, and South Africa; and Rickettsia spp. in 14 countries including Senegal, Algeria, and Uganda. Data were analyzed using a fixed-effect model in R version 4.0.1 and visualized on an African map using Tableau version 2022.2. This review highlights the urgent need for improved diagnostics to better manage and control tick-borne febrile illnesses in Africa.

Metagenomic Detection of Bacterial Zoonotic Pathogens among Febrile Patients, Tanzania, 2007-20091.

Bacterial zoonoses are established causes of severe febrile illness in East Africa. Within a fever etiology study, we applied a high-throughput 16S rRNA metagenomic assay validated for detecting bacterial zoonotic pathogens. We enrolled febrile patients admitted to 2 referral hospitals in Moshi, Tanzania, during September 2007-April 2009. Among 788 participants, median age was 20 (interquartile range 2-38) years. We performed PCR amplification of V1-V2 variable region 16S rRNA on cell pellet DNA, then metagenomic deep-sequencing and pathogenic taxonomic identification. We detected bacterial zoonotic pathogens in 10 (1.3%) samples: 3 with Rickettsia typhi, 1 R. conorii, 2 Bartonella quintana, 2 pathogenic Leptospira spp., and 1 Coxiella burnetii. One other sample had reads matching a Neoerhlichia spp. previously identified in a patient from South Africa. Our findings indicate that targeted 16S metagenomics can identify bacterial zoonotic pathogens causing severe febrile illness in humans, including potential novel agents.

Seroprevalence of Q fever (Coxiella burnetii) in sheep in the Kwahu West municipality, Eastern Region, Ghana

Query fever, also known as Q fever, is a zoonotic disease caused by Coxiella burnetii. It is a cause of abortion in livestock and presents as a febrile illness in humans. A correlation between the incidence of the disease in humans and abortion in goats and sheep farms has been reported in countries such as the Netherlands and Australia. In Ghana, the occurrence of Q fever in both livestock and humans has not been fully explored. This study sought to determine the seroprevalence of Q fever in livestock in Nkawkaw, in the Eastern Region of Ghana. Sera obtained from 92 sheep from 12 farms were tested using the indirect multi-species ELISA for the detection of anti-Coxiella burnetii antibodies. Animal demographics, farms’ proximity to human settlement and history of abortion in relation to the Q fever status were assessed.The overall prevalence of Q fever was 13.0 % [95 % CI 6.9–21.6] (12/92). Both sexes were equally affected, with a sex-specific prevalence of 13.0 % each. The farm-specific prevalence was 50 %. Abortions were reported on eight (8) of the 12 farms, and all farms were located less than 200 m from human habitation. Only proximity of farm to human settlement showed statistical significance. Q fever is prevalent in Nkawkaw and requires the attention of both animal and health authorities, using the One- Health approach to nip any future epidemics in its bud.

ICTV Virus Taxonomy Profile: Nairoviridae 2024.

Nairoviridae is a family for negative-sense RNA viruses with genomes of about 17.2-21.1 kb. These viruses are maintained in and/or transmitted by arthropods among birds, reptiles and mammals. Norwaviruses and orthonairoviruses can cause febrile illness in humans. Several orthonairoviruses can infect mammals, causing mild, severe and sometimes, fatal diseases. Nairovirids produce enveloped virions containing two or three single-stranded RNA segments with open reading frames that encode a nucleoprotein (N), sometimes a glycoprotein precursor (GPC), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) report on the family Nairoviridae, which is available at www.ictv.global/report/nairoviridae.

Higher livestock abortion burden in arid and semi-arid lands, Kenya, 2019-2020.

Tracking livestock abortion patterns over time and across factors such as species and agroecological zones (AEZs) could inform policies to mitigate disease emergence, zoonoses risk, and reproductive losses. We conducted a year-long population-based active surveillance of livestock abortion between 2019 and 2020, in administrative areas covering 52% of Kenya's landmass and home to 50% of Kenya's livestock. Surveillance sites were randomly selected to represent all AEZs in the country. Local animal health practitioners electronically transmitted weekly abortion reports from each ward, the smallest administrative unit, to a central server, using a simple short messaging service (SMS). Data were analyzed descriptively by administrative unit, species, and AEZ to reveal spatiotemporal patterns and relationships with rainfall and temperature. Of 23,766 abortions reported in all livestock species, sheep and goats contributed 77%, with goats alone contributing 53%. Seventy-seven per cent (n = 18,280) of these abortions occurred in arid and semi-arid lands (ASALs) that primarily practice pastoralism production systems. While spatiotemporal clustering of cases was observed in May-July 2019 in the ASALs, there was a substantial seasonal fluctuation across AEZs. Kenya experiences high livestock abortion rates, most of which go unreported. We recommend further research to document the national true burden of abortions. In ASALs, studies linking pathogen, climate, and environmental surveillance are needed to assign livestock abortions to infectious or non-infectious aetiologies and conducting human acute febrile illnesses surveillance to detect any links with the abortions.

The presence of Rickettsia felis in communities in the central highlands of Vietnam

Rickettsia felis is an emerging flea-borne spotted fever pathogen that causes febrile illness in humans. In Vietnam, R. felis was detected in hospitalized patients, but there is no information on its presence in the Vietnamese community. This cross-sectional study aimed to determine the presence of R. felis in humans of the Central Highlands of Vietnam. A total of 158 blood and 213 serum samples were subjected to PCR and IFAT, respectively, to detect the presence of R. felis DNA and antibodies against R. felis. PCR assays detected R. felis DNA in four out of 158 blood samples, accounting for a prevalence of 2.53 % (95 % CI: 0.81 %-6.76 %). Phylogenetic analysis indicated the presence of R. felis and R. felis genotype RF2125 in the communities in the Central Highlands of Vietnam. The result of IFAT identified seven out of 213 serum samples (3.29 %, 95 % CI: 1.45 %-6.93 %) positive for antibodies against R. felis. This study was the first to demonstrate the presence of active R. felis infections in the communities in the Central Highlands of Vietnam utilizing both molecular and serological methods.

Rift Valley Fever Virus-Infection, Pathogenesis and Host Immune Responses.

Rift Valley Fever Virus is a mosquito-borne phlebovirus causing febrile or haemorrhagic illness in ruminants and humans. The virus can prevent the induction of the antiviral interferon response through its NSs proteins. Mutations in the NSs gene may allow the induction of innate proinflammatory immune responses and lead to attenuation of the virus. Upon infection, virus-specific antibodies and T cells are induced that may afford protection against subsequent infections. Thus, all arms of the adaptive immune system contribute to prevention of disease progression. These findings will aid the design of vaccines using the currently available platforms. Vaccine candidates have shown promise in safety and efficacy trials in susceptible animal species and these may contribute to the control of RVFV infections and prevention of disease progression in humans and ruminants.

In Silico Physicochemical Characterization of Fusion Proteins from Emerging Amazonian Arboviruses.

Mayaro (MAYV), Saint Louis encephalitis (SLEV), and Oropouche (OROV) viruses are neglected members of the three main families of arboviruses with medical relevance that circulate in the Amazon region as etiological agents of outbreaks of febrile illnesses in humans. As enveloped viruses, MAYV, SLEV, and OROV largely depend on their class II fusion proteins (E1, E, and Gc, respectively) for entry into the host cell. Since many aspects of the structural biology of such proteins remain unclear, the present study aimed at physicochemically characterizing them by an in silico approach. The complete amino acid sequences of MAYV E1, SLEV E, and OROV Gc proteins derived by conceptual translation from annotated coding regions in the reference sequence genome of the respective viruses were obtained from the NCBI Protein database in the FASTA format and then submitted to the ClustalO, Protcalc, Pepstats, Predator, Proscan, PCprof, Phyre2, and 3Drefine web servers for the determination of sequence identities, the estimation of residual properties, the prediction of secondary structures, the identification of potential post-translational modifications, the recognition of antigenic propensities, and the modeling/refinement of three-dimensional structures. Sequence identities were 20.44%, 18.82%, and 13.70% between MAYV/SLEV, SLEV/OROV, and MAYV/OROV fusion proteins, respectively. As for the residual properties, MAYV E1 and SLEV E proteins showed a predominance of the non-polar profile (56% and 55% of the residues, respectively), whereas the OROV Gc protein showed a predominance of the polar profile (52% of the residues). Regarding predicted secondary structures, MAYV E1 and SLEV E proteins showed fewer alpha-helices (16.51% and 15.17%, respectively) than beta-sheets (21.79% and 25.15%, respectively), while the opposite was observed in the OROV Gc protein (20.39% alpha-helices and 12.14% beta-sheets). Regarding post-translational modifications, MAYV E1, SLEV E, and OROV Gc proteins showed greater relative potential for protein kinase C phosphorylation, N-myristoylation, and casein kinase II phosphorylation, respectively. Finally, antigenic propensities were higher in the N-terminus half than in the C-terminus half of these three proteins, whose three-dimensional structures revealed three distinctive domains. In conclusion, MAYV E1 and SLEV E proteins were found to share more physicochemical characteristics with each other than the OROV Gc protein, although they are all grouped under the same class of viral fusion proteins.

Novel Orthonairovirus Isolated from Ticks near China-North Korea Border.

We isolated a new orthonairovirus from Dermacentor silvarum ticks near the China-North Korea border. Phylogenetic analysis showed 71.9%-73.0% nucleic acid identity to the recently discovered Songling orthonairovirus, which causes febrile illness in humans. We recommend enhanced surveillance for infection by this new virus among humans and livestock.

Adenoviral vectored vaccination protects against Crimean-Congo Haemorrhagic Fever disease in a lethal challenge model.

The tick-borne bunyavirus, Crimean-Congo Haemorrhagic Fever virus (CCHFV), can cause severe febrile illness in humans and has a wide geographic range that continues to expand due to tick migration. Currently, there are no licensed vaccines against CCHFV for widespread usage. In this study, we describe the preclinical assessment of a chimpanzee adenoviral vectored vaccine (ChAdOx2 CCHF) which encodes the glycoprotein precursor (GPC) from CCHFV. We demonstrate here that vaccination with ChAdOx2 CCHF induces both a humoral and cellular immune response in mice and 100% protection in a lethal CCHF challenge model. Delivery of the adenoviral vaccine in a heterologous vaccine regimen with a Modified Vaccinia Ankara vaccine (MVA CCHF) induces the highest levels of CCHFV-specific cell-mediated and antibody responses in mice. Histopathological examination and viral load analysis of the tissues of ChAdOx2 CCHF immunised mice reveals an absence of both microscopic changes and viral antigen associated with CCHF infection, further demonstrating protection against disease. There is the continued need for an effective vaccine against CCHFV to protect humans from lethal haemorrhagic disease. Our findings support further development of the ChAd platform expressing the CCHFV GPC to seek an effective vaccine against CCHFV. This research was supported by funding from the Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) [BB/R019991/1 and BB/T008784/1].

Clinical usefulness of metagenomic next-generation sequencing for Rickettsia and Coxiella burnetii diagnosis

Rickettsia and Coxiella burnetii are zoonotic tick-borne pathogens that cause febrile illnesses in humans. Metagenomic next-generation sequencing (mNGS) is a new technology used to diagnose infectious diseases. However, clinical experience with applying the test to rickettsioses and Q fever is relatively limited. Therefore, this study aimed to explore the diagnostic performance of mNGS in detecting Rickettsia and C. burnetii. We retrospectively studied patients with rickettsioses or Q fever between August 2021 and July 2022. Peripheral blood mNGS and polymerase chain reaction (PCR) were performed for all patients. Clinical data were retrieved for analysis. Thirteen patients were included in this study (eleven confirmed cases and two suspected cases). Signs and symptoms included fever (13, 100%), rash (7, 53.8%), muscle soreness (5, 38.5%), headache (4, 30.8%), skin eschar (3, 23.1%), and disturbance of consciousness (2, 15.4%). In addition, eight patients (61.6%) had thrombocytopenia, ten (76.9%) had liver function impairment, and two (15.4%) had renal function impairment. The results of mNGS revealed seven patients with R. japonica (53.8%), five with C. burneti (38.5%), two with R. heilongjiangensis (15.4%), and one with R. honei (7.7%). PCR results were positive in 11 patients (84.6%). After receiving doxycycline-based treatment, 12 (92.3%) patients returned to a normal temperature within 72 h. All patients were discharged in better health. Therefore, mNGS can help diagnose Rickettsia and C. burnetii and shorten the diagnosis time, especially for patients with atypical clinical manifestations and unclear epidemiologic evidence of a tick bite or exposure.

Substantial viral and bacterial diversity at the bat-tick interface.

Ticks harbour a high diversity of viruses, bacteria and protozoa. The soft tick Carios vespertilionis (Argasidae) is a common ectoparasite of bats in the Palearctic region and is suspected to be vector and reservoir of viruses and other microbial species in bat populations, some of which may act as zoonotic agents for human disease. The Soprano pipistrelle (Pipistrellus pygmaeus, Vespertilionidae) is widely distributed in Europe, where it can be found inside or close to human habitation. We used meta-transcriptomic sequencing to determine the RNA virome and common microbiota in blood-fed C. vespertilionis ticks collected from a Soprano pipistrelle bat roosting site in south-central Sweden. Our analyses identified 16 viruses from 11 virus families, of which 15 viruses were novel. For the first time in Sweden we identified Issuk-Kul virus, a zoonotic arthropod-borne virus previously associated with outbreaks of acute febrile illness in humans. Probable bat-associated and tick-borne viruses were classified within the families Nairoviridae, Caliciviridae and Hepeviridae, while other invertebrate-associated viruses included members of the Dicistroviridae, Iflaviridae, Nodaviridae, Partitiviridae, Permutotetraviridae, Polycipiviridae and Solemoviridae. Similarly, we found abundant bacteria in C. vespertilionis, including genera with known tick-borne bacteria, such as Coxiella spp. and Rickettsia spp. These findings demonstrate the remarkable diversity of RNA viruses and bacteria present in C. vespertilionis and highlight the importance of bat-associated ectoparasite surveillance as an effective and non-invasive means to track viruses and bacteria circulating in bats and ticks.

Detection and Characterization of Alongshan Virus in Ticks and Tick Saliva from Lower Saxony, Germany with Serological Evidence for Viral Transmission to Game and Domestic Animals.

The newly discovered group of Jingmenviruses has been shown to infect a wide range of hosts and has been associated with febrile illness in humans. During a survey for Jingmenviruses in ticks from Lower Saxony, Germany, Alongshan virus (ALSV) was identified in Ixodes spp. ticks. Additional virus screenings revealed the presence of ALSV in the bodies and saliva of ticks collected at several locations in Lower Saxony. Vector competence studies that included Ixodes ricinus and Dermacentor reticulatus validated the replication of ALSV within those tick species. In vitro feeding experiments with ALSV-injected Ixodes ricinus demonstrated effective viral transmission during blood feeding. To evaluate the potential viral transmission during a natural blood meal, sera from wild game and domestic animals were investigated. One serum sample from a red deer was found to be positive for ALSV RNA, while serological screenings in game and domestic animals revealed the presence of ALSV-specific antibodies at different locations in Lower Saxony. Overall, those results demonstrate the broad distribution of ALSV in ticks in Lower Saxony and hypothesize frequent exposure to animals based on serological investigations. Hence, its potential risk to human and animal health requires further investigation.

Doxycycline-resistant Scrub Typhus in a Syndromic Child

Scrub Typhus, a human febrile illness caused by Orientia tsutsugamushi, is common in Asia and infects persons those visiting the endemic areas. Scrub typhus is a zoonotic infection. It is transmitted by a trombiculid mite which introduces the bacteria by its bite. Scrub typhus is associated with maculopapular rashes and local and/or generalised lymphadenopathy.It is characterised by eschar at the site of the bite. A child with doxycycline-resistant scrub typhus is being presented here. A 10-year-old female child was bought to the hospital with complaints of fever for six days, cough for three days, loose stools for two days, and vomiting for one day duration. S1 and S2 sounds were heard while bilateral vesicular breath sounds were normal. There was no hepatosplenomegaly and Central Nervous System (CNS) examination showed no focal neurologic deficits. Investigations showed a normal leukocyte count and Differential Leucocyte Count (DLC), microcytic hypochromic anaemia, thrombocytopenia, hyponatremia, and elevated liver enzymes. Scrub Immunoglobulin M (IgM) was positive. Chest radiograph showed a bell-shaped chest with vertical straightening of ribs. The child was started on intravenous (i.v.) fluids, Doxycycline 4 mg/kg, and paracetamol. The child continued to spike fever at day 6 of Doxycycline and hence was started on Azithromycin 10 mg/kg, following which the fever subsided and the child was discharged.

Anti-Arbovirus Antibodies Cross-React With Severe Acute Respiratory Syndrome Coronavirus 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in regions where dengue (DENV) and chikungunya (CHIKV) viruses are endemic. Any serological cross-reactivity between DENV, CHIKV, and SARS-CoV-2 is significant as it could lead to misdiagnosis, increased severity, or cross-protection. This study examined the potential cross-reactivity of anti-DENV and CHIKV antibodies with SARS-CoV-2 using acute and convalescent-phase samples collected before the SARS-CoV-2 pandemic. These included healthy, normal human (NHS, n = 6), CHIKV-positive (n = 14 pairs acute and convalescent), primary DENV-positive (n = 20 pairs), secondary DENV-positive (n = 20 pairs), and other febrile illnesses sera (n = 23 pairs). Samples were tested using an in-house SARS-CoV-2 and a EUROIMMUN IgA and IgG ELISAs. All NHS samples were negative, whereas 3.6% CHIKV, 21.7% primary DENV, 15.7% secondary DENV, and 10.8% febrile diseases sera resulted as anti-SARS-CoV-2 antibody positive. The EUROIMMUN ELISA using spike 1 as the antigen detected more positives among the primary DENV infections than the in-house ELISA using spike 1-receptor binding domain (RBD) protein. Among ELISA-positive samples, four had detectable neutralizing antibodies against SARS-CoV-2 reporter virus particles yet none had detectable neutralizing antibodies against the live Wuhan strain of SARS-CoV-2. These data demonstrated the SARS-CoV-2 diagnostic cross-reactivity, but not neutralizing antibody cross-reactivity, among dengue seropositive cases. IMPORTANCE SARS-CoV-2 continues to cause significant morbidity globally, including in areas where DENV and CHIKV are endemic. Reports using rapid diagnostic and ELISAs have demonstrated that serological cross-reactivity between DENV and SARS-CoV-2 can occur. Furthermore, it has been observed that convalescent DENV patients are at a lower risk of developing COVID-19. This phenomenon can interfere with the accuracy of serological testing and clinical management of both DENV and COVID-19 patients. In this study, the cross-reactivity of primary/secondary anti-DENV, CHIKV, and other febrile illness antibodies with SARS-CoV-2 using two ELISAs has been shown. Among ELISA-positive samples, four had detectable levels of neutralizing antibodies against SARS-CoV-2 reporter virus particles. However, none had detectable neutralizing antibodies against the live Wuhan strain of SARS-CoV-2. These data demonstrated SARS-CoV-2 diagnostic cross-reactivity, but not neutralizing antibody cross-reactivity, among dengue seropositive cases. The data discussed here provide information regarding diagnosis and may help guide appropriate public health interventions.

Discovery of a small-molecule inhibitor targeting the ovarian tumor domain of a novel Tamdy orthonairoviruse associated with human febrile illness.

Tick-borne orthonairoviruses have been characterized as a global health threat to humans and animals. Tacheng Tick virus 1 (TcTV-1) from this family was provided as evidence that is associated with the febrile illness syndrome. Here, we first identify and demonstrate that the ovarian tumor(OTU) domain of TcTV-1 has remarkable deubiquitinating activity both in vitro and in vivo. By solving the crystal structure of TcTV-1 OTU (tcOTU) domain and comparing it to that of human deubiquitinating enzymes, we found that overall structures of tcOTU and human OTU family are similar, but the residues involved in the catalytic pocket vary widely. Based on the tcOTU domain we screened 5090 bioactive compounds and found mecobalamin had a good effect on suppressing the deubiquitinating activity. The structural model of tcOTU and mecobalamin suggests that mecobalamin occupies the site of the substrate Ub, by blocking the substrate binding to the enzyme. Thus, our results showed OTU domain of TcTV-1 has a robust deubiquitinating activity and mecobalamin or its derivatives might be promising candidates for the treatment or prevention of disease caused by theTcTV-1 virus.

Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

Oropouche orthobunyavirus (OROV; Peribunyaviridae) is a mosquito-transmitted virus that causes widespread human febrile illness in South America, with occasional progression to neurologic effects. Host factors mediating the cellular entry of OROV are undefined. Here, we show that OROV uses the host protein low-density lipoprotein-related protein 1 (Lrp1) for efficient cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. In addition, chimeric vesicular stomatitis virus (VSV) expressing OROV glycoproteins (VSV-OROV) bound to the Lrp1 ectodomain invitro. Furthermore, we demonstrate the biological relevance of the OROV-Lrp1 interaction in a proof-of-concept mouse study in which treatment of mice with RAP at the time of infection reduced tissue viral load and promoted survival from an otherwise lethal infection. These results with OROV, along with the recent finding of Lrp1 as an entry factor for Rift Valley fever virus, highlight the broader significance of Lrp1 in cellular infection by diverse bunyaviruses. Shared strategies for entry, such as the critical function of Lrp1 defined here, provide a foundation for the development of pan-bunyaviral therapeutics.

Jingmen Tick Virus in Ticks from Kenya.

Jingmen tick virus (JMTV) is an arbovirus with a multisegmented genome related to those of unsegmented flaviviruses. The virus first described in Rhipicephalus microplus ticks collected in Jingmen city (Hubei Province, China) in 2010 is associated with febrile illness in humans. Since then, the geographic range has expanded to include Trinidad and Tobago, Brazil, and Uganda. However, the ecology of JMTV remains poorly described in Africa. We screened adult ticks (n = 4550, 718 pools) for JMTV infection by reverse transcription polymerase chain reaction (RT-PCR). Ticks were collected from cattle (n = 859, 18.88%), goats (n = 2070, 45.49%), sheep (n = 1574, 34.59%), and free-ranging tortoises (Leopard tortoise, Stigmochelys pardalis) (n = 47, 1.03%) in two Kenyan pastoralist-dominated areas (Baringo and Kajiado counties) with a history of undiagnosed febrile human illness. Surprisingly, ticks collected from goats (0.3%, 95% confidence interval (CI) 0.1–0.5), sheep (1.8%, 95% CI 1.2–2.5), and tortoise (74.5%, 95% CI 60.9–85.4, were found infected with JMTV, but ticks collected from cattle were all negative. JMTV ribonucleic acid (RNA) was also detected in blood from tortoises (66.7%, 95% CI 16.1–97.7). Intragenetic distance of JMTV sequences originating from tortoise-associated ticks was greater than that of sheep-associated ticks. Phylogenetic analyses of seven complete-coding genome sequences generated from tortoise-associated ticks formed a monophyletic clade within JMTV strains from other countries. In summary, our findings confirm the circulation of JMTV in ticks in Kenya. Further epidemiological surveys are needed to assess the potential public health impact of JMTV in Kenya.