Search Results (283)

Background/Objectives: Moschus (musk) has long been used in traditional Tibetan medicine to prevent and treat epidemic febrile illnesses. However, its antiviral mechanisms remain poorly understood. Given the urgent need for effective treatments against viral respiratory tract infections (VRTIs), this study aimed to systematically investigate the molecular targets and pharmacological pathways through which Moschus may exert therapeutic effects. Methods: Based on the identification of bioactive compounds with favorable pharmacokinetics, we applied integrated network pharmacology and multi-omics analyses to systematically identify key therapeutic targets involved in VRTIs. Gene Set Enrichment Analysis (GSEA) and immune infiltration further revealed strong associations with multiple immune cell subsets, reflecting their pivotal roles in immunomodulatory mechanisms during viral infections. Molecular docking confirmed the strong binding affinities between Moschus compounds and these key targets. Results: Notably, testosterone exhibited the strongest and most consistent binding across key targets, suggesting its potential as a pivotal bioactive compound. Importantly, the antiviral effects of Moschus may be mediated in part by the downregulation of the key genes MCL1, MAPK3, and CDK2, which are involved in the regulation of viral replication, apoptosis, and host immune responses. Conclusions: This study provides a comprehensive mechanistic framework supporting the multi-target antiviral potential of Moschus, offering a scientific basis for its further development as a therapeutic agent against VRTIs. Full article

Background: Rickettsioses are diseases caused by obligate intracellular non-motile coccobacilli transmitted via arthropods. The most common rickettsioses are scrub typhus (ST), typhus group rickettsioses (TGR), and spotted fever group rickettsioses (SFGR). This study aims to provide information and insight into rickettsioses seropositivity among suspected patients in East and Peninsular Malaysia over a six-year period from 2016 to 2021. Methodology/Principal Findings: Data obtained from four state hospitals and one national research institute providing rickettsial serological testing were analyzed using the IBM SPSS (Statistical Package for the Social Sciences) software program. The six-year analysis revealed that ST had the highest number of seropositivity cases, followed by TGR, and SFGR, for both immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. Of the 3228 samples, 21.6%, 16.1%, and 13.9% of suspected patients were IgM seropositive for ST, TGR, and SFGR, respectively. IgG seropositivity for ST was 21.9%, followed by TGR at 21.4%, and SFGR at 17.2% among suspected rickettsioses cases. All regions in Malaysia were significantly associated with IgM seropositivity for ST, TGR, and SFGR. IgM seropositivity for SFGR was significantly higher in females. Age group 41–65 years was highly associated with IgG seropositivity for ST, TGR, and SFGR. Conclusions/Significance: Analysis of six-year data on ST, TGR, and SFGR seropositivity in Malaysia revealed variations across regions, age groups, and genders. This seropositivity study underscores ST, TGR, and SFGR as possible causes of acute febrile illness among patients suspected of rickettsial disease in Malaysia. The findings contributed to the awareness of reemerging rickettsioses and warrant public health interventions that may reduce the incidence of rickettsioses in Malaysia. Abstract summary: Scrub typhus (ST), typhus group rickettsioses (TGR), and spotted fever group rickettsioses (SFGR) are significant global public health concerns. Our results showed that the highest number of IgM and IgG seropositivity cases was observed for ST, followed by TGR and SFGR. All regions in Malaysia were significantly associated with IgM seropositivity for ST, TGR, and SFGR. East Malaysia exhibited significantly higher seropositivity for ST, TGR, and SFGR than other regions in Malaysia. IgM seropositivity for SFGR was significantly higher in females. The age group 41–65 years was highly associated with IgG seropositivity for ST, TGR, and SFGR. This study highlights the value of serological data in uncovering the hidden burden of disease in Malaysia. In addition, the findings contributed to bridging knowledge gaps on the limited data from Malaysia spanning extended periods, despite being one of the countries in the endemic Tsutsugamushi Triangle. The findings from this study may direct future research on rickettsioses and warrant public health interventions in Malaysia. Full article

(1) Background: Murine typhus, caused by Rickettsia typhi, is a neglected rickettsial disease and an underdiagnosed cause of acute febrile illness (AFI), particularly in endemic regions such as Indonesia. (2) Case description: We report a case series of four patients presenting with AFI of less than seven days in duration. Three patients were admitted with moderate disease, while one presented with septic shock with the macrophage activation-like syndrome (MALS) phenotype. Common clinical features included myalgia and headache; additional symptoms included cough, sore throat, and abdominal pain. Laboratory findings revealed bicytopenia, elevated transaminases, and raised inflammatory and bacterial infection markers. Common tropical infections—dengue, typhoid fever, and leptospirosis—and other potential sources of infection were excluded early during hospitalization. Diagnosis was confirmed by nucleic acid amplification testing (NAAT), which detected R. typhi in all patients. Doxycycline was initiated following confirmation, leading to defervescence within 36–48 h. (3) Conclusions: Murine typhus remains an underrecognized cause of febrile illness in Indonesia. In the near future, the inclusion of rickettsial testing in the diagnostic protocol of AFI will be crucial, as it enables timely administration of effective, low-cost treatment. Full article

Background: The evaluation of antiviral or vaccination strategies for the prevention of dengue infections in a traveler population would require extensive and complex studies. This prospective study aimed to identify a cohort of dengue naïve participants living in Medellín, a dengue endemic area, as a proxy for travelers and to determine the incidence of primary dengue virus (DENV) infection (symptomatic and asymptomatic) in this cohort. In Colombia, epidemic dengue waves occur every 3–4 years, with infected Aedes mosquitoes present in ~80% of the territory, including Medellín. Methods: Participants > 16 years of age, living in Medellín, were screened for anti-DENV immunoglobulin G (IgG). DENV seronegative participants were enrolled in this study. A serological anti-DENV survey was performed, with semiannual sample collections for up to 2 years. Acute DENV infections were evaluated by monitoring fever and testing for DENV nonstructural protein 1 and/or RNA. Results: Of the 4885 screened participants, 3008 participants (62%) were DENV seronegative and enrolled. Among them, 2263 (75%) completed this study, and 2644 (88%) had at least one serosurvey visit after baseline. Of those, 52 (2%) had laboratory-confirmed DENV seroconversion, and 19 (<1%) had febrile illness, but none had laboratory-confirmed DENV infection. Conclusions: This study identified a cohort of predominantly students, seronegative at study start, living in Medellín and serving as a proxy for a prospective DENV infection traveler population. Laboratory-confirmed primary DENV infection was found in 2% of participants, with <1% reporting febrile illnesses, meeting the WHO criteria for probable clinical dengue cases. Full article

Orthoflaviviruses (formerly flaviviruses) are known for their role in numerous diseases affecting both humans and animals. Despite the worldwide distribution of orthoflaviviruses, individual species are only found in endemic or epidemic regions. However, in recent decades, certain orthoflaviviruses have spread beyond their traditional geographic boundaries, even crossing continents. Given the long-distance movements of birds, the knowledge of zoonotic orthoflaviviruses associated with birds is essential because of their possible introduction into new regions, as was the case with West Nile virus and Usutu virus. A thorough literature review was conducted on zoonotic orthoflaviviruses related to birds, including lesser-known (re-)emerging and neglected orthoflaviviruses that are limited to specific regions and/or avian hosts but have the potential to spread to a wider geographical area and pose a higher risk of transmission to humans. Several of these viruses possess significant zoonotic potential and can cause a wide spectrum of diseases in humans, ranging from mild febrile illnesses (Zika virus) to severe neuroinvasive diseases (tick-borne encephalitis, West Nile, Japanese encephalitis virus) and hemorrhagic fevers (yellow fever, dengue virus). Geographic distribution, hosts, vectors, incidence of human infections, and impact on human and animal health of zoonotic flaviviruses related to birds are critically reviewed. The viruses have been categorized based on the role of birds as an orthoflavivirus host and the clinical presentation in human infections. Full article

For centuries, traditional medical systems have utilized Cistus leaf infusions, extracts, and essential oils in the treatment of inflammatory conditions, respiratory infections, febrile illnesses, and gastrointestinal disorders. Contemporary research has increasingly focused on the identification and characterization of biologically active constituents—particularly polyphenols and other antioxidants—that may modulate key physiological and cellular processes in the human body. These include mechanisms related to oxidative stress, inflammation, aging, and carcinogenesis. The therapeutic relevance of Cistus-derived compounds is further supported by their generally favorable safety profile and high tolerability, which distinguishes them from many synthetic pharmaceuticals. Moreover, the accessibility of Cistus preparations as dietary supplements or herbal infusions allows for their regular consumption without the need for complex therapeutic regimens. This positions Cistus as a promising candidate for integrative health strategies aimed at disease prevention and health maintenance. This review provides a comprehensive overview of the pharmacological potential and therapeutic applications of Cistus extracts, with particular emphasis on their antioxidant and bioactive properties. Full article

HIKESHI-related hypomyelinating leukodystrophy (HHL) is a life-threatening disorder caused by homozygous pathogenic variants in HIKESHI. Symptoms include infantile onset progressive spastic dystonic quadriplegia, nystagmus, failure to thrive, diffused hypomyelination, and severe morbidity or death following febrile illness. V54L variants in HIKESHI are particularly prevalent within the Ashkenazi Jewish population. Here, we identified a novel P78S disease-causing variant in HIKESHI in a patient of Christian Arab origin, presenting with clinical and radiologic features characteristic of HHL. In silico analysis suggests that the mutated residue may affect the HIKESHI protein’s dimerization domain. We generated a comprehensive set of induced pluripotent stem cells (iPSCs) from the index case and two additional HHL patients. To investigate mechanisms potentially linked to febrile illness in HHL, we used these cells to study the heat shock (HS) response. HHL-iPSCs showed dramatically decreased levels of HIKESHI compared with healthy controls following HS. In addition, they exhibited increased HSP70 mRNA levels in response to HS, suggesting an increased sensitivity. HHL-iPSCs had impaired HSP70 translocation to the nucleus. Our results provide a human-relevant model for HHL. Full article

Outbreaks of infectious diseases contribute significantly to morbidity and mortality in resource-limited settings, yet the capacity to identify their etiology remains limited. We aimed to characterize microbes and antimicrobial resistance (AMR) genes in Tanzanian children affected by an acute febrile illness (AFI) outbreak using metagenomic next-generation sequencing (mNGS). A cross-sectional study was conducted on archived blood samples from children who presented with AFI between 2018 and 2019. Total nucleic acids were extracted from 200 µL of blood, and complementary DNA (cDNA), along with enriched pathogenic DNA, was sequenced using the Illumina MiSeq platform. mNGS data were analyzed using CZ-ID Illumina mNGS bioinformatics pipeline v7.0. Results were obtained from 25 participants (mean age: 11.6 years; SD ± 5), of whom 36% had a moderate to high-grade fever. The following five potential microbial causes of AFI were identified: Escherichia coli (n = 19), Paraclostridium bifermentans (n = 2), Pegivirus C (n = 2), Shigella flexneri (n = 1) and Pseudomonas fluorescens (n = 1), with E. coli being the most prevalent. Twelve AMR genes were detected, including mdtC, acrF, mdtF, and emrB. E. coli harbored most of the AMR genes previously associated with resistance to commonly used antibiotics. mNGS offers a promising complementary approach to conventional diagnostics for identifying pathogens and AMR profiles in vulnerable populations. Full article

Zika and malaria are important vector-borne febrile illnesses in humans. In this study, we determined the circulation of Zika virus and malaria infections, their hotspots, and their predominant clinical features. A cross-sectional study was carried out in six Local Government Areas (LGAs) in Kaduna State, Nigeria, from September 2018 to May 2019. Four hundred and twenty sera were screened for Zika virus (ZV) IgM and IgG, and Plasmodium falciparum antigen using ELISA and immunochromatographic test, respectively. Overall, a seroprevalence of 14.5% was found for Zika, and 9.3% for malaria. Nineteen (4.5%) and thirty-five (8.3%) patients were seropositive for ZV IgM and IgG, respectively. Co-infection rates for Zika (ZV IgM) and malaria (0.5%: 2/420), and for ZV IgG and malaria (0.7%: 3/420) were observed. Lere (10%: 7/70 for ZV IgM), Kachia (14.3%: 10/70 for ZV IgG) and Zaria (18.6%: 13/70 for malaria) LGAs were identified as hotspots for Zika and malaria. Age was significantly associated with malaria (p = 0.008) and ZV IgG (p = 0.004). Patients aged 1–10 years had the highest malaria seroprevalence (18.4%), while those aged 21–30 years had the highest ZV IgM prevalence (6.1%: 7/114). Out of the pregnant patients (56/420) tested, 5.37% (3/56) had antibodies to both recent and past ZV infection. A significant association was found between maculopapular rash (p = 0.021) and Zika, as well as between duration of the fever and recent Zika infection (p = 0.041). We highlight that malaria is endemic in Kaduna and that ZV is silently circulating, providing baseline data for further molecular epidemiological studies. Full article

Background: adenoviruses (AdVs) are DNA viruses that typically cause mild infections in immunocompetent children, and typically involve the respiratory and gastrointestinal tract. Adenoviral pharyngitis is a common paediatric illness, particularly in children under 4 years old. The aim of our 7-year retrospective study, conducted at a tertiary care paediatric emergency department (ED), was to describe the clinical and laboratory characteristics and management of patients with pharyngeal AdV infections. Specifically, we examined how the management of patients with adenoviral pharyngitis has evolved following the introduction of a rapid antigen nasopharyngeal swab test for AdVs, which has been performed directly in the ED since 2023. Methods: in this single-centre retrospective observational study, the demographic and clinical information for children discharged from the ED who had been diagnosed with a pharyngeal AdV infection between 1 January 2017 and 31 December 2023 were retrospectively reviewed. Moreover, we compared data before and after the introduction of rapid AdV antigenic swabs, which have been directly performed in the ED since the beginning of 2023. Statistical analysis was undertaken using the Student’s t-test and Pearson and Fisher’s exact test, as appropriate. Significance was set at p-value < 0.05. Results: during the study period, 172 children were diagnosed with adenoviral pharyngitis based on a positive swab. All patients were febrile, with a median duration of fever of 4 days. Blood tests were requested for 84.9% of patients at admission, resulting in a mean WBC count of 13,250/mmc and a mean CRP of 70.6 mg/L. The highest CRP median values were found on the third day of fever. Out of 383 swabs performed during 2017–2022, 13.6% were positive vs a 32% positive rate for the 372 swabs performed in 2023. The mean duration of observation in the ED before 2023 was 31.4 h vs. 10.4 h in 2023. Similarly, 9% of patients with adenoviral pharyngitis were admitted to a paediatric ward before 2023 and only 0.8% in 2023. Conclusions: the primary reason for ED admission in cases of adenoviral pharyngitis is fever lasting several days due to hyperinflammation. Differential diagnosis with bacterial infection is essential to limit the number of hospitalisations and inappropriate antibiotic therapy. The introduction of the rapid antigen nasopharyngeal swab has simplified the diagnosis of adenoviral pharyngitis, enabling timely and accurate differentiation from bacterial causes. Full article

Rickettsiae are Gram-negative and obligate intracellular bacteria that cause rickettsioses. These pathogens are typically transmitted by arthropod vectors, such as ticks, mesostigmatid mites, and fleas. Rickettsiae are responsible for many emerging infectious diseases worldwide and are the second most frequently reported cause of non-malarial febrile illnesses in Southeast Asia. However, in Malaysia, studies on the prevalence and distribution of rickettsiae have primarily focused on humans, with limited data on these bacteria in vectors and small mammal hosts. Thus, this study aims to investigate the presence of Rickettsia spp. in small mammals and their associated mesostigmatid mites collected from potential rickettsioses areas in Selangor. Animal trapping was conducted across three different ecological study sites comprising a recreational area, agricultural land, and coastal area. A total of 41 small mammals and 363 mesostigmatid mites were collected and identified. Ten percent of the total individual mites were processed for morphological examination, and the remaining mites were then pooled by hosts, with five individual mites per tube, for DNA extraction. The collected samples, comprising blood, animal tissue, and pooled mites, were subjected to DNA extraction and were screened for Rickettsia spp. via nested polymerase chain reaction (PCR), targeting the citrate synthase-encoding gene (gltA) and outer membrane protein B gene (ompB). Interestingly, two pools (3.33%) of Laelaps spp. recovered from Maxomys whiteheadi and Bandicota indica, collected from a recreational area, tested positive for Rickettsia spp. Sequence analysis and phylogenetic tree of the ompB gene revealed the presence of Rickettsia felis in both laelapid mite pools. To our knowledge, this study provides the first molecular detection of R. felis in Laelaps spp. in Malaysia. Full article

Introduction: Spotted fever group (SFG) rickettsioses are tick-transmitted infections caused by Gram-negative, obligately intracellular bacteria in the genus Rickettsia. They present as an acute undifferentiated febrile illness, and they are often accompanied by rash and/or eschar. Although the rash of SFG rickettsioses usually consists of macules and papules, some, like in Rickettsia parkeri rickettsiosis, can also manifest with papulovesicular or pustular lesions. Case: We herein present a case of SFG rickettsiosis, due to R. parkeri, that masqueraded as Sweet syndrome (the prototype neutrophilic dermatosis) after the initial results of a shave biopsy. Further investigation of the biopsy specimen by immunohistochemical and PCR analysis would eventually confirm SFG rickettsiosis, with R. parkeri being detected by real-time PCR. Discussion:Rickettsia parkeri is transmitted by the Gulf Coast tick (Amblyomma maculatum) and is an increasingly recognized cause of SFG rickettsiosis in the United States. Rickettsia parkeri should be considered in those with an acute undifferentiated febrile illness with lesions that are pustular or papulovesicular, as prompt recognition and empirical administration of doxycycline results in the rapid resolution of symptoms. Full article

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski’s rule for drug likeness. A protein–protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets—IL10, FASLG, PTPRC, and FCGR3A—were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors—Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine—against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation—IL10, FASLG, PTPRC, and FCGR3A—the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery. Full article

The Chikungunya virus (CHIKV) is a priority endemic pathogen identified by the World Health Organization and its infection induces an acute febrile illness in humans that is often associated with arthritis and musculoskeletal pain. Therefore, specific vaccines and treatments are urgently needed to prevent or treat Chikungunya disease. Here, we identify a series of CHIKV-specific neutralizing nanobodies (Nbs) from an alpaca which exhibit distinct binding modes compared to those previously reported. Two representative anti-CHIKV Nbs, N033-Fc and N053-Fc, demonstrated significant antiviral activity in Ifnar^−/− mice against lethal challenge. Further studies elucidated the functional mechanisms of N033-Fc and N053-Fc in blocking CHIKV infection at multiple stages of the viral life cycle. This study identifies multiple candidate Nbs that may be suitable for next-generation antibody therapies to combat CHIKV infection. Full article

Background: FIRES is a rare and catastrophic presentation of a de novo refractory status epilepticus (RSE) in healthy individuals following mild febrile illness. It carries a high burden of morbidity and an estimated mortality of 12% in children. In over half of patients, an underlying cause is not discovered (cryptogenic FIRES). The theory that post-infectious inflammation promotes aberrant neuronal excitation has led to the use of immunomodulatory therapies as treatment for FIRES. High-dose glucocorticoids and intravenous immunoglobulin (IVIG) are used as first-line therapies but are ineffective in most cases. A comprehensive initial evaluation is critical in directing second-line therapies; however, an autoimmune and inflammatory workup is seldom completed prior to treatment. Despite recent trends toward using cytokine-directed therapies, outcomes remain poor. Methods: This single-institution retrospective case series describes three cases of FIRES in similarly aged children. Each patient experienced super-refractory status epilepticus (SRSE) resistant to first-line systemic immunotherapy (SIT). The novel use of baricitinib, a non-selective JAK inhibitor, proved effective for one patient, while IL-1 and IL-6 inhibition were effective in the other two. All patients suffered moderate-to-severe neurologic and cognitive impairment at the time of discharge. Conclusions: FIRES is a poorly understood catastrophic presentation of refractory status epilepticus (RSE) requiring a multimodal approach to treatment. Cytokine profiling can be helpful in identifying cryptogenic cases from those with an underlying cause if conducted early in the clinical course. The early use of second-line immunomodulatory therapies may aid in decreasing neuroinflammation and improve outcomes. Full article