Colitis in a patient with familial Mediterranean fever: Is it Crohn's disease or ulcerative colitis?

A 24-year-old woman was referred to our hospital with joint pain, fever, abdominal pain, and diarrhea. A colonoscopy revealed longitudinal ulcers with a cobblestone appearance throughout the entire colon, suggestive of Crohn's disease. However, treatment with 5-aminosalicylic acid, azathioprine, and infliximab failed to achieve clinical remission. A colonoscopy 5 months later revealed a diffusely spreading granular mucosa without visible vasculature, compatible with active ulcerative colitis. Based on these serial changes in colonic lesions, we tested the patient for MEFV gene mutations and found variants E148Q and L110P in exon 2. Administration of colchicine resulted in complete clinical remission. Our experience suggests that drastic changes in the features of colonic inflammation may be a clue to the diagnosis of enterocolitis associated with familial Mediterranean fever.

African swine fever virus modulates the endoplasmic reticulum stress-ATF6-calcium axis to facilitate viral replication.

African swine fever (ASF), caused by African swine fever virus (ASFV), is a devastating infectious disease of domestic pigs and wild boar, which threatens the global pig industry. Endoplasmic reticulum (ER) is a multifunctional signaling organelle in eukaryotic cells that is involved in protein synthesis, processing, posttranslational modification and quality control. As intracellular parasitic organisms, viruses have evolved several strategies to modulate ER functions to favor their life cycles. We have previously demonstrated that the differentially expressed genes associated with unfolded protein response (UPR), which represents a response to ER stress, are significantly enriched upon ASFV infection. However, the correlation between the ER stress or UPR and ASFV replication has not been illuminated yet. Here, we demonstrated that ASFV infection induces ER stress both in target cells and in vivo, and subsequently activates the activating transcription factor 6 (ATF6) branch of the UPR to facilitate viral replication. Mechanistically, ASFV infection disrupts intracellular calcium (Ca2+) homeostasis, while the ATF6 pathway facilitates ASFV replication by increasing the cytoplasmic Ca2+ level. More specifically, we demonstrated that ASFV infection triggers ER-dependent Ca2+ release via the inositol triphosphate receptor (IP3R) channel. Notably, we showed that the ASFV B117L protein plays crucial roles in ER stress and the downstream activation of the ATF6 branch, as well as the disruption of Ca2+ homeostasis. Taken together, our findings reveal for the first time that ASFV modulates the ER stress-ATF6-Ca2+ axis to facilitate viral replication, which provides novel insights into the development of antiviral strategies for ASFV.

The epidemiological and infectious characteristics of novel types of Coxiella burnetii co-infected with Coxiella-like microorganisms from Xuyi County, Jiangsu province, China.

Coxiella burnetii (C. burnetii) is the causative agent of Q fever, a type of zoonoses withwidespread distribution. In 2019, a case of Q fever was diagnosed by metagenomic next-generation sequencing (mNGS) method in Xuyi County (Jiangsu province, China). The seroprevalence of previous fever patients and the molecular epidemiology of Coxiella in wild hedgehogs and harbouring ticks around the confirmed patient were detected to reveal the genetic characteristics and pathogenicity of the Coxiella strains. Four of the 90 serum samples (4.44%) were positive for specific C. burnetii IgM antibody, suggesting that local humans are at risk of Q fever. The positive rates of C. burnetii in hedgehogs and ticks were 21.9% (7/32) and 70.5% (122/173), respectively. At least 3 strains of Coxiella were found prevalent in the investigated area, including one new genotype of pathogenic C. burnetii (XYHT29) and two non-pathogenic Coxiella-like organisms (XYHT19 and XYHT3). XYHT29 carried by ticks and wild hedgehogs successfully infected mice, imposing a potential threat to local humans. XYHT19, a novel Coxiella-like microorganism, was first discovered in the world to co-infect with C. burnetii in Haemaphysalis flava. The study provided significant epidemic information that could be used for prevention and control strategies against Q fever for local public health departments and medical institutions.

Bartonella spp. in Phlebotominae Sand Flies, Brazil.

Bartonella spp. are opportunistic, vectorborne bacteria that can cause disease in both animals and humans. We investigated the molecular occurrence of Bartonella spp. in 634 phlebotomine sand fly specimens, belonging to 44 different sand fly species, sampled during 2017-2021 in north and northeastern Brazil. We detected Bartonella sp. DNA in 8.7% (55/634) of the specimens by using a quantitative real-time PCR targeting the 16S-23S internal transcribed spacer intergenic region. Phylogenetic analysis positioned the Lutzomyia longipalpis sand fly-associated Bartonella gltA gene sequence in the same subclade as Bartonella ancashensis sequences and revealed a Bartonella sp. sequence in a Dampfomyia beltrani sand fly from Mexico. We amplified a bat-associated Bartonella nuoG sequence from a specimen of Nyssomyia antunesi sand fly. Our findings document the presence of Bartonella DNA in sand flies from Brazil, suggesting possible involvement of these insects in the epidemiologic cycle of Bartonella species.

Rift Valley Fever Epizootic, Rwanda, 2022.

A Rift Valley fever epizootic affected livestock in Rwanda during March-October 2022. We confirmed 3,112 infections with the virus, including 1,342 cases, 1,254 abortions, and 516 deaths among cattle, goats, and sheep. We recommend a One Health strategy for investigations and response to protect animal and human health.

Spatial and temporal variation of five different pathogens and symbionts in Ixodes ricinus nymphs in the Netherlands.

The incidence of diseases caused by pathogens transmitted by the tick Ixodes ricinus vary over time and space through incompletely understood mechanisms. An important determinant of the disease risk is the density of infected ticks, which is the infection prevalence times the density of questing ticks. We therefore investigated the spatial and temporal variation of four pathogens and one of the most abundant symbionts in Ixodes ricinus in questing nymphs over four years of monthly collections in 12 locations in the Netherlands. The infection prevalence of all microbes showed markedly different patterns with significant spatial variation for Borrelia burgdorferi (s.l.), Neoehrlichia mikurensis, Rickettsia helvetica, and Midichloria mitochondrii, significant seasonal variation of B. burgdorferi (s.l.), N. mikurensis, and M. mitochondrii and a significant interannual variation of R. helvetica. Despite its ubiquitous presence, no spatio-temporal variation was observed for the infection prevalence of B. miyamotoi. The variation in infection prevalence was generally smaller than the variation in the density of nymphs, which fluctuated substantially both seasonally and between locations. This means that the variation in the densities of infected nymphs for all pathogens was mostly the result of the variation in densities of nymphs. We also investigated whether there were positive or negative associations between the symbionts, and more specifically whether ticks infected with vertically transmitted symbionts like M. mitochondrii and R. helvetica, have a higher prevalence of horizontally transmitted symbionts, such as B. burgdorferi (s.l.) and N. mikurensis. We indeed found a clear positive association between M. mitochondrii and B. burgdorferi (s.l.). The positive association between R. helvetica and B. burgdorferi (s.l.) was less clear and was only shown in two locations. Additionally, we found a clear positive association between B. burgdorferi (s.l.) and N. mikurensis, which are both transmitted by rodents. Our longitudinal study indicated strong between-location variation, some seasonal patterns and hardly any differences between years for most symbionts. Positive associations between symbionts were observed, suggesting that infection with a (vertically transmitted) symbiont may influence the probability of infection with other symbionts, or that there is a common underlying mechanism (e.g. feeding on rodents).

The classification, origin, and evolutionary dynamics of severe fever with thrombocytopenia syndrome virus circulating in East Asia.

The classification of severe fever with thrombocytopenia syndrome virus (SFTSV) lacked consistency due to limited virus sequences used across previous studies, and the origin and transmission dynamics of the SFTSV remains not fully understood. In this study, we analyzed the diversity and phylodynamics of SFTSV using the most comprehensive and largest dataset publicly available for a better understanding of SFTSV classification and transmission. A total of 1267 L segments, 1289 M segments, and 1438 S segments collected from China, South Korea, and Japan were included in this study. Maximum likelihood trees were reconstructed to classify the lineages. Discrete phylogeographic analysis was conducted to infer the phylodynamics of SFTSV. We found that the L, M, and S segments were highly conserved, with mean pairwise nucleotide distances of 2.80, 3.36, and 3.35% and could be separated into 16, 13, and 15 lineages, respectively. The evolutionary rate for L, M, and the S segment was 0.61 × 10-4 (95% HPD: 0.48-0.73 × 10-4), 1.31 × 10-4 (95% HPD: 0.77-1.77 × 10-4) and 1.27 × 10-4 (95% HPD: 0.65-1.85 × 10-4) subs/site/year. The SFTSV most likely originated from South Korea around the year of 1617.6 (95% HPD: 1513.1-1724.3), 1700.4 (95% HPD: 1493.7-1814.0), and 1790.1 (95% HPD: 1605.4-1887.2) for L, M, and S segments, respectively. Hubei Province in China played a critical role in the geographical expansion of the SFTSV. The effective population size of SFTSV peaked around 2010 to 2013. We also identified several codons under positive selection in the RdRp, Gn-Gc, and NS genes. By leveraging the largest dataset of SFTSV, our analysis could provide new insights into the evolution and dispersal of SFTSV, which may be beneficial for the control and prevention of severe fever with thrombocytopenia syndrome.

Effect of Severe Fever With Thrombocytopenia Syndrome Virus Genotype on Disease Severity, Viral Load, and Cytokines in South Korea.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by Bandavirus dabieense (SFTS virus [SFTSV]). Recently, at least 6 different genotypes of SFTSV have been identified, with genotypes A, D, and F dominant in China and B dominant in Japan and Korea. This study investigated the effect of SFTSV genotypes circulating in South Korea on disease severity, viral load, and cytokine profile. Methods: We prospectively enrolled 70 patients with SFTS from July 2015 to June 2022. Serial plasma samples were obtained during hospitalization and analyzed. Viral load was measured by real-time reverse-transcription polymerase chain reaction. Partial sequences of the viral genome were analyzed for genotyping. Plasma concentrations of 17 cytokines were measured by multiplex-bead immunoassay. Results: Of 70 samples, 51 could be genotyped. Genotype B was predominant (80.4%) and other genotypes were uncommon. Intensive care unit admission rates (51.2% vs 50.0%) and mortality rates (26.8% vs 40.0%) did not show any significant differences between genotype B and non-B genotypes. The initial viral load did not show any significant differences (3.59 vs 3.64 log copies/µL), whereas viral load measured at hospital day 3-4 tended to be higher in genotype B than non-B genotypes (3.83 vs 1.83 log copies/µL, P = .07). Additionally, the plasma concentrations of interferon-α, interleukin 10, and interferon-γ-induced protein 10, which are closely related to mortality in cases of SFTS, did not show any significant differences. Conclusions: SFTSV genotype B was the prevalent genotype in South Korea, with no genotype-specific difference in clinical outcomes, initial viral load, or cytokine profiles.

Tropical Co-infection in a Tertiary Care Center in South India: A Case Report.

Tropical co-infections, characterized by overlapping clinical manifestations and the potential for diagnostic confusion, pose significant challenges in the management of febrile illnesses in endemic regions. This case report presents a 33-year-old male with a five-day history of fever, gastrointestinal symptoms, and dry cough, ultimately diagnosed with co-infections of dengue, leptospirosis, and Salmonella paratyphi A. This case underscores the challenges posed by the overlapping clinical features of endemic tropical diseases, emphasizing the necessity for comprehensive diagnostic strategies and tailored treatment protocols in managing febrile illnesses in endemic regions. Clinicians must also consider serological cross-reactivity when interpreting diagnostic tests, as it can complicate the identification of co-infections and impact treatment decisions, necessitating vigilance and an integrated approach in clinical practice.

A Case Report of Hemophagocytic Lymphohistiocytosis Masquerading as Sepsis.

Profound inflammation due to cytokine storm is often the underlying cause of death in patients with hemophagocytic lymphohistiocytosis (HLH). Sepsis, while a precipitant, is also the great masquerader that may hide early signs of HLH. Prompt recognition is important to prevent rapid clinical decline and death. A patient presented with two weeks of unremitting fever of 103°F, dysuria, bilateral flank pain, and confusion. Obstructive uropathy and pyelonephritis were treated with a Foley catheter and antibiotics. There were abnormal developments during his hospitalization including a deep vein thrombus despite prophylactic anticoagulation. Antibiotics and Foley management did not improve fevers or renal injury so he eventually required continuous renal replacement therapy and blood product transfusions. In rapid progression, the patient developed pancytopenia, neutropenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia suspicious for HLH. A bone marrow biopsy was consistent with progressive T-cell lymphoma, the likely cause of secondary HLH. Antineoplastics, corticosteroids, and opportunistic prophylaxis were pursued. Unfortunately, the cytopenias worsened, and the patient developed shock with hypoxemia and hypotension, followed by cardiac arrest and demise.

Diagnostic delays in familial Mediterranean fever: a Juvenile Inflammatory Rheumatism (JIR) cohort study.

Several studies reported that Familial Mediterranean Fever (FMF) diagnosis may be missed or delayed even in countries with a high FMF prevalence. Our aim was to study on a large cohort of European FMF patients the frequency and associated factors of diagnosis delay. Clinical data were extracted from the Juvenile Inflammatory Rheumatism (JIR)-cohort. All FMF patients fulfilled Livneh Criteria and had been sequenced for MEFV exon 10. FMF-diagnostic delay (d-FMF) was defined as the duration between the onset of the symptoms and the diagnosis of more than 10 years. 960 FMF patients were enrolled: delayed diagnosis (d-FMF) was noted in 200 patients (20%). d-FMF patients were significantly older compared to non d-FMF with a median age of 46.4 years old vs. 15.5 (p < 0.0001). Women displayed more d-FMF compared to men (56 vs. 47%, p = 0.03). Clinical presentation during attacks was not statistically significant except for erysipelas-like erythema, which was higher among d-FMF patients (33 vs. 22%, p = 0.0003). The presence of one or two pathogenic MEFV mutation was not different between patients. Compared to other FMF, d-FMF patients displayed significantly more AA amyloidosis (10 vs. 2.6%, p < 0.0001) and received more biotherapy (18 vs. 3.8%, p < 0.0001). Twenty percent of FMF patients had a diagnostic delay >10 years, including more women. The differential diagnosis of abdominal attacks with menstrual pain may be an explanation, and erysipelas-like erythema may not be recognized as FMF by all practitioners.

Serial evaluation of liver enzyme activities in dogs with pulmonary coccidioidomycosis administered per os fluconazole.

Pulmonary coccidioidomycosis is a relatively common fungal disorder in dogs that have lived in or traveled to endemic regions and fluconazole is a common antifungal treatment. Liver enzymopathy can occur with fluconazole administration, but the frequency of occurrence nor potentially associative factors have been explored in dogs with pulmonary coccidioidomycosis. Therefore, our objectives were to describe the occurrence and magnitude of liver enzyme activity (LEA) elevation in dogs with pulmonary coccidioidomycosis during treatment with per os fluconazole and identify variables associated with liver enzymopathy. This was a retrospective observational study that analyzed serum biochemical data obtained from a separate prospective study that included 32 client-owned dogs with newly diagnosed pulmonary coccidioidomycosis from October 2020 to February 2021. Per os fluconazole administration (median dosage: 16.2 mg/kg/day) was initiated after diagnosis and dogs were evaluated once every 3 months thereafter until remission or for a maximum of 12 months. Recorded biochemical parameters at each visit (including baseline) included alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT). Magnitude of increased LEA was based on the fold increase above the upper limit of the reference interval and defined as mild (<5×), moderate (5-10×) or severe (>10×). Forty-seven percent (15/32) of dogs were documented to have elevations in one or more LEAs after initiation of fluconazole administration during the study period. Thirty-four percent and 25% of dogs had elevated ALP and ALT activities, respectively, at some point during treatment. Elevations in AST and GGT activities were rare. The magnitude of LEA elevation was mild in all cases. Logistic regression models did not identify associations between age, weight, sex, neutered status, prednisone administration, fluconazole dose or duration of treatment with the occurrence of liver enzymopathy. Approximately half of dogs with pulmonary coccidioidomycosis are expected to develop mild increases in activities of ALP and/or ALT with rare involvement of AST or GGT at some point during treatment with fluconazole up to 12 months.

Genome sequence of dengue virus serotype 1 isolated from a pediatric patient enrolled in an Ivermectin trial in Thailand.

We sequenced the genome of dengue virus serotype 1 (DENV1) strain 4101301, isolated from a child with dengue fever in Thailand and cultured in C6/36 mosquito cells. These data are crucial for studying DENV1's genetic diversity, evolution, and epidemiology and advancing the knowledge for developing antiviral drugs and vaccines targeting DENV.

Navigating the threat of African swine fever: a comprehensive review.

African swine fever (ASF) is caused by Asfivirus and has become one of the most important diseases of swine in recent years. ASF was an endemic disease of the sub-Saharan Africa but later spread to various parts of the world. The infection in ticks and wild swine, alongside global pork trade, drives its spread and persistence. Once introduced to an area, the disease is difficult to eliminate due to sylvatic, domestic, and tick-swine transmission cycles. Because of the existence of various modes of transmission of the ASF virus, biosecurity measures have not been very successful. The line of treatment is not of much use and the outcome of this disease is usually fatal. The prognosis or the recovery of the animal depends on the virulence of the strain involved. Development of vaccines has been attempted but to date has not been very successful. This review focuses on the basic context of ASF, the challenges associated with it, and the options that might be available to prevent its occurrence which includes the different vaccine development strategies tried and tested till now.

Detection of the first recombinant African swine fever virus (genotypes I and II) in domestic pigs in Russia.

INTRODUCTION: African swine fever (ASF) is a contagious viral disease that affects pigs and wild boars, with a mortality rate of up to 100% in susceptible animals. The virus has been circulating in Europe and Asia since its introduction in 2007. Initially, all studied isolates were identified as genotype II, but in 2021 genotype I was reported in China. Later in 2023, the first recombinant virus of genotype I and II was identified in China, with an isolate dating back to 2021, this was followed by the detection of 6 recombinant isolates in Vietnam. METHODS: In this study, an ASFV isolate from the Primorsky Region of Russia obtained from a domestic pig was analyzed by sequencing several genome markers as well as the full genome. Eight pigs were infected with the isolate to assess its virulence. RESULTS: Virus replication in cell culture showed hemadsorption, while sequencing of genome markers clustered the isolate into both genotype I and genotype II. The whole-genome sequence showed that the Russian isolate shared a 99.99% identity with recombinant isolates described earlier in China. Experimental animals developed ASF disease after the introduction of a low dose of the virus (10 HAU50) and died within 7 days post-infection, presenting an acute form of the disease. CONCLUSION: This is the first report on recombinant ASFV in Russia's territory. The results once again confirm the transboundary nature of the disease, demonstrating the vulnerability of the global pig industry underscoring the need for developing new ASF vaccines effective against recombinant strains and emphasizing the importance of continuous molecular monitoring to detect emerging threats promptly.

The Potential Role of Cell-Death Mechanisms in the Pathogenesis of Familial Mediterranean Fever Attacks: Granzyme A and Beyond.

BACKGROUND: FMF is the most common autoinflammatory disease. The activation of the pyrin inflammasome is the mainstay of the pathogenesis, which might lead to a specific cell-death mechanism, pyroptosis. Pyroptosis is a programmed inflammatory cell death mediated by gasdermin proteins, featuring cell swelling, membrane rupture, and release of inflammatory contents Aim: In this study we aimed to analyze the cell-death mechanisms in the pathogenesis of FMF attacks. METHODS: Twenty-five FMF patients were included, and PFAPA patients (n = 10) and healthy controls (HC, n = 10) served as controls. We collected plasma samples from FMF and PFAPA patients during the attack and the attack-free period. We measured the soluble plasma levels of sFas, sFasL, granzyme A, granzyme B, perforin, granulysin, IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, and IFN-γ by commercial pre-defined cytometric bead array kits. RESULTS: There was no significant difference between groups in terms of sex and age between FMF patients and HCs, but PFAPA patients were younger than other groups due to the nature of the disease. We then analyzed the components of apoptosis and pyroptosis. The levels of sFasL (p = 0.035) and granzyme A (p = 0.038) in FMF patients were significantly increased during the attack period and decreased to levels comparable to HCs during the attack-free period. This increase was not seen in the PFAPA patients, with comparable levels with the HC group both during attack period and attack-free period. During the attack period of FMF patients, granzyme B (p = 0.145) and perforin (p = 0.203) levels were also increased; however, the differences were not statistically significant. The levels of sFasL, granzyme A, granzyme B, and perforin were closely correlated with each other during the attack period of FMF patients. CONCLUSIONS: Our study on death pathways during an FMF attack, suggests an upregulation in both pyroptosis through the granzyme-gasdermin pathway and apoptosis with the increased FasL and perforin levels, which was different from PFAPA patients. These findings might shed light on the reason for the nature of self-limited attacks, but further studies are needed to prove this hypothesis.

Influence of Right Atrial Pressure on the Prognosis of Patients with Rheumatic Mitral Stenosis Undergoing Percutaneous Mitral Balloon Valvuloplasty.

BACKGROUND: Pulmonary hypertension (PH) often complicates mitral stenosis (MS). The prognostic impact of pulmonary vascular resistance (PVR) in MS patients remains unclear. Previous study has demonstrated the prognostic impact of right atrial pressure (RAP) in patients with primary PH. We aim to determine the prognostic impact of PVR and RAP in patients with rheumatic MS undergoing percutaneous mitral balloon valvuloplasty (PMBV). METHODS: A total of 58 patients with symptomatic severe rheumatic MS who underwent PMBV between 2016 and 2020 were included. Patients were divided into two groups: PVR ≤ 2WU (N = 26) and PVR > 2WU (N = 32). The composite endpoint included death, reintervention or persistent NYHA functional class III-IV during follow-up. RESULTS: The median age was 50 (42-60) years, with 82.8% being female. Median pulmonary artery systolic pressure (PASP) was 42 (35-50.5) mmHg. Patients with PVR ≤ 2WU had lower PASP on both echocardiogram and catheterization. The PMBV success rate was 75.9%. Multivariate analysis, adjusted for PVR, showed RAP as the only independent predictor of the composite endpoint (HR:1.507, 95% CI:1.015-2.237, p = 0.042). The optimal RAP cutoff was 9.5 mmHg (HR:3.481, 95% CI:1.041-11.641; p = 0.043). CONCLUSIONS: RAP was an independent predictor of adverse outcomes in patients with rheumatic MS undergoing PMBV, while PVR did not show prognostic significance. These findings suggest that the prognostic value of PVR may be lower than expected.

Targeting Polyprotein to Design Potential Multiepitope Vaccine against Omsk Hemorrhagic Fever Virus (OHFV) by Evaluating Allergenicity, Antigenicity, and Toxicity Using Immunoinformatic Approaches.

Omsk Hemorrhagic Fever Virus (OHFV) is an RNA virus with a single-stranded, positive-sense genome. It is classified under the Flaviviridae family. The genome of this virus is 98% similar to the Alkhurma hemorrhagic fever virus (AHFV), which belongs to the same family. Cases of the virus have been reported in various regions of Saudi Arabia. Both OHFV and AHFV have similarities in pathogenic polyprotein targets. No effective and licensed vaccines are available to manage OHFV infections. Therefore, an effective and safe vaccine is required that can activate protective immunity against OHFV. The current study aimed to design a multiepitope subunit vaccine against the OHFV utilizing several immunoinformatic tools. The polyprotein of OHFV was selected and potent antigenic, non-allergenic, and nontoxic cytotoxic T-lymphocyte (CTL), helper T-lymphocyte (HTL), and linear B-lymphocyte (LBL) epitopes were chosen. After screening, eight (8) CTL, five (5) HTL, and six (6) B cell epitopes were joined with each other using different linkers. Adjuvant human beta defensin-2 was also linked to the epitopes to increase vaccine antigenic and immunogenic efficiency. The designed vaccine was docked with Toll-like receptor 4 (TLR4) as it activates and induces primary and secondary immune responses against OHFV. Codon optimization was carried out, which resulted in a CAI value of 0.99 and 53.4% GC contents. In addition, the construct was blindly docked to the TLR4 immune receptor and subjected to conformational dynamics simulation analysis to interpret the intricate affinity and comprehend the time-dependent behavior. Moreover, it was predicted that immune responses to the developed vaccine construct reported formation of strong humoral and cellular immune cells. Therefore, the proposed vaccine may be considered in experimental assays to combat OHFV infections. Laboratory experiments for the above predictions are essential in order to evaluate the effectiveness, safety, and protective properties of the subject in question.

Next generation yellow fever vaccine induces an equivalent immune and transcriptomic profile to the current vaccine: observations from a phase I randomised clinical trial.

BACKGROUND: Yellow fever (YF), a mosquito-borne acute viral haemorrhagic illness, is endemic to many tropical and subtropical areas of Africa and Central and South America. Vaccination remains the most effective prevention strategy; however, as repeated outbreaks have exhausted vaccine stockpiles, there is a need for improved YF vaccines to meet global demand. A live-attenuated YF vaccine candidate (referred to as vYF) cloned from a YF-17D vaccine (YF-VAX®) sub-strain, adapted for growth in Vero cells cultured in serum-free media, is in clinical development. We report the innate and adaptive immune responses and the transcriptome profile of selected genes induced by vYF. METHODS: Healthy adults aged 18-60 years were randomised at a 1:1:1:1 ratio to receive one dose of vYF at 4, 5 or 6 Log CCID50 or YF-VAX (reference vaccine), administered subcutaneously in the upper arm (ClinicalTrials.gov identifier: NCT04142086). Blood/serum samples were obtained at scheduled time points through 180 days (D180) post-vaccination. The surrogate endpoints assessed were: serum cytokine/chemokine concentrations, measured by bead-based Multiplex assay; peripheral blood vYF-specific IgG and IgM memory B cell frequencies, measured by FluoroSpot assay; and expression of genes involved in the immune response to YF-17D vaccination by RT-qPCR. FINDINGS: There was no increase in any of the cytokine/chemokine concentrations assessed through D14 following vaccination with vYF or YF-VAX, except for a slight increase in IP-10 (CXCL10) levels. The gene expression profiles and kinetics following vaccination with vYF and YF-VAX were similar, inclusive of innate (antiviral responses [type-1 interferon, IFN signal transduction; interferon-stimulated genes], activated dendritic cells, viral sensing pattern recognition receptors) and adaptive (cell division in stimulated CD4+ T cells, B cell and antibody) immune signatures, which peaked at D7 and D14, respectively. Increases in vYF-specific IgG and IgM memory B cell frequencies at D28 and D180 were similar across the study groups. INTERPRETATION: vYF-induced strong innate and adaptive immune responses comparable to those induced by YF-VAX, with similar transcriptomic and kinetic profiles observed. FUNDING: Sanofi.

The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide.

Microbial molecules translocated from the intestinal lumen into the host's internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.