Brucellosis Research Articles

From a rat otorrhagia to a febrile rash

A 19-year-old patient, without medical history, presented a first episode of continuous fever (about 39°C) for 14 days, with rash and arthromyalgia and functional impotence of the ankles for 7 days. Clinically, the patient had asthenia with ankle biarthritis with a predominantly palm-plant rash (Figure 1). Right ankle joint puncture finding inflammatory fluid (5300 nucleated elements/mm3 including 91% neutrophils), without microcrystals. Immunological test (rheumatoid factor and citrullinated anti-peptide antibodies) was negative. The skin biopsy performed in an area of pathological skin is in favor of an infectious origin, with microabscesses.

Phage single-stranded DNA-binding protein or host DNA damage triggers the activation of the AbpAB phage defense system.

Although numerous phage defense systems have recently been discovered in bacteria, how these systems defend against phage propagation or sense phage infections remains unclear. The Escherichia coli AbpAB defense system targets several lytic and lysogenic phages harboring DNA genomes. A phage-encoded single-stranded DNA-binding protein, Gp32, activates this system similar to other phage defense systems such as Retron-Eco8, Hachiman, ShosTA, Nhi, and Hna. DNA replication inhibitors or defects in DNA repair factors activate the AbpAB system, even without phage infection. This is one of the few examples of activating phage defense systems without phage infection or proteins. The AbpAB defense system may be activated by sensing specific DNA-protein complexes.

Outbreak economic analysis of six imported hemorrhagic fevers following detection at 24 hours

Abstract A ten-language search found no economic analysis of symptomatic hemorrhagic fever importation for Crimean Congo (CCHF), Hantavirus (HV), Lassa (LV), Marburg (MARV), Middle East Respiratory Syndrome (MERS) or Nipah (NV) into the USA/EU/UK. This study used available literature to calculate the cost of importation of the six selected fevers with each outbreak detected at 24 hours. A PRISMA search of Pubmed and grey literature was undertaken to uncover respective R0, case fatality ratios, average hospital stay, time to death, frontline casualty frequency and contact histories. A simulated breakout, t24 intervention, Borel distribution contact model, with R0 determined infection (0-1.59) and death rate (CFR: 0.01-0.5) was formed. Treatment inc. plasma therapy, and PPE best prices were determined. ICU median operational costs were factored with contact tracing. Indirect admin costs, based on national mean values, frontline replacement, GNI per capita productivity losses through isolation (21 days as standard), hospitalisation and death were factored. Mean patient discharge ranged 4.4 - 28 days (CCHF to MERS). Time to death ranged 2 - 15 days (HV, NV). The number infected at t48 ranged 1 - 9.59 (CCHF/HV to MARV). Contacts ranged 27 - 169 (CCHF to MARV/NV/MERS). Direct costs of outbreak care, labour, and tracing ranged €424707 - €2850083.07 (CCHF - MARV). Indirect costs, attributed to administrative burdens ranged €5264 -€32800.02 (CCHF to MARV). Productivity losses, attributed separately to the isolated, treated, and dead totaled €2042613 - €26198606 (CCHF - MARV). The total outbreak cost ranged €2488512.78 - €29081489.72 (EU, CCHF - MARV). Significant direct, indirect and productivity costs were attributed to the importation of a single case of six hemorrhagic fevers when detected at t24. The significant societal cost of MARV in particular highlights the importance of continued hemorrhagic fever research and preparedness to healthcare systems in protecting future budgets. Key messages • The importation of hemorrhagic fevers has significant direct and indirect budgetary, and productivity, impacts. • Besides human cost, financial costs demand public health enhanced surveillance and response plans for hemorrhagic fever importation.

The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection.

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.

Abnormal M1 polarization of placental macrophage induced by IL-15/STAT5 activation in VVC may lead to adverse pregnancy outcomes

Pregnant women with vulvovaginal candidiasis (VVC) may experience adverse pregnancy outcomes such as premature delivery, intrauterine infection, abortion, and neonatal infection. Therefore, finding new treatments for VVC in pregnancy is a public health priority. We aimed to study the adverse consequences of Candida albicans (C. albicans) vaginal infection in pregnant mice and explore the mechanisms by which C. albicans affects macrophages. Our findings contribute to the development of new approaches to treat VVC during pregnancy. We established an animal model of vaginal infection by C. albicans in pregnant mice and observed adverse pregnancy outcomes such as decreased body weight, reduced implantation number, and increased abortion rates. Additionally, we infected mouse macrophage line RAW264.7 cells with C. albicans and established a cell model. We employed RT-qPCR, Western blot, and immunofluorescence staining to verify the changes in the IL-15/STAT5 signaling pathway and the role it played on the M1 polarization of C. albicans-infected macrophages at both the gene and protein levels. Our results indicate that the adverse pregnancy outcomes in VVC may be linked to changes in the IL-15/STAT5 pathway induced by C. albicans, which could impact macrophage M1 polarization.

Temperature Control in the Era of Personalized Medicine: Knowledge Gaps, Research Priorities, and Future Directions.

Hypoxic-ischemic brain injury (HIBI) is the leading cause of death and disability after cardiac arrest. To date, temperature control is the only intervention shown to improve neurologic outcomes in patients with HIBI. Despite robust preclinical evidence supporting hypothermia as neuroprotective therapy after cardiac arrest, there remains clinical equipoise regarding optimal core temperature, therapeutic window, and duration of therapy. Current guidelines recommend continuous temperature monitoring and active fever prevention for at least 72 h and additionally note insufficient evidence regarding temperature control targeting 32 °C-36 °C. However, population-based thresholds may be inadequate to support the metabolic demands of ischemic, reperfused, and dysregulated tissue. Promoting a more personalized approach with individualized targets has the potential to further improve outcomes. This review will analyze current knowledge and evidence, address research priorities, explore the components of high-quality temperature control, and define critical future steps that are needed to advance patient-centered care for cardiac arrest survivors.

Abortive infection antiphage defense systems: separating mechanism and phenotype.

Bacteria have evolved a wide array of mechanisms that allow them to eliminate phage infection. 'Abortive infection' (abi) systems are an expanding category of such mechanisms, defined as those which induce programmed cell death (or dormancy) upon infection, and thus halt phage propagation within a bacterial population. This definition entails two requirements - a phenotypic observation (cell death upon infection), and a mechanistic determination of its sources (system-induced death). The phenotypic and mechanistic aspects of abi are often implicitly assumed to be tightly linked, and studies regularly tend to establish one and deduce the other. However, recent evidence points to a complicated relationship between the mechanism of defense and the phenotype observed upon infection. We argue that rather than viewing the abi phenotype as an inherent quality of a set of defense systems, it should be more appropriately thought of as an attribute of interactions between specific phages and bacteria under given conditions. Consequently, we also point to potential pitfalls in the prevailing methods for ascertaining the abi phenotype. Overall, we propose an alternative framework for parsing interactions between attacking phages and defending bacteria.

Modelling the Unidentified Abortion Burden from Four Infectious Pathogenic Microorganisms (Leptospira interrogans, Brucella abortus, Brucella ovis, and Chlamydia abortus) in Ewes Based on Artificial Neural Networks Approach: The Epidemiological Basis for a Control Policy.

A two-stage cluster survey design was conducted to estimate the seroprevalence of abortifacient microorganisms and to identify putative factors of infectious abortion. The overall seroprevalence of Brucella was 70.7%, while Leptospira spp. was 55.2%, C. abortus was 21.9%, and B. ovis was 7.4%. Serological detection with four abortion-causing microorganisms was determined only in 0.87% of sheep sampled. The best GLM is integrated via serological detection of serovar Hardjo and Brucella ovis in animals of the slopes with elevation between 2600 and 2800 meters above sea level from the municipality of Xalatlaco. Other covariates included in the GLM, such as the sheep pen built with materials of metal grids and untreated wood, dirt and concrete floors, bed of straw, and the well water supply were also remained independently associated with infectious abortion. Approximately 80% of those respondents did not wear gloves or masks to prevent the transmission of the abortifacient zoonotic microorganisms. Sensitizing stakeholders on good agricultural practices could improve public health surveillance. Further studies on the effect of animal-human transmission in such a setting is worthwhile to further support the One Health initiative.

Wernicke-Korsakoff Syndrome associated with hyperemesis gravidarum and fetal death: Case report and literature review

We describe a clinical case of a pregnant patient with hyperemesis gravidarum who progressed to abortion, Wernicke's encephalopathy, and Korsakoff's psychosis, all related to thiamine deficiency. The patient presented symptoms of disorientation, nonspecific limb movements, and fever, initially treated with metronidazole and ceftriaxone for suspected infected abortion. Subsequently, the patient was diagnosed with retained and infected abortion, and thiamine replacement therapy was initiated with an intravenous loading dose of 900 mg/day. During hospitalization, the patient presented with tetraparesis, nystagmus, decreased level of consciousness, anterograde and retrograde amnesia, confabulation, and aphasia. Magnetic resonance imaging showed lesions in the pons, typical of Wernicke's encephalopathy. The patient was empirically treated with acyclovir and ampicillin and showed clinical improvement. The text also provides a brief narrative review of the literature on the topic.

Activation of a Vibrio cholerae CBASS anti-phage system by quorum sensing and folate depletion.

To counteract infection with phage, bacteria have evolved a myriad of molecular defense systems. Some of these systems initiate a process called abortive infection, in which the infected cell kills itself to prevent phage propagation. However, such systems must be inhibited in the absence of phage infection to prevent spurious death of the host. Here, we show that the cyclic oligonucleotide based anti-phage signaling system (CBASS) accomplishes this by sensing intracellular folate molecules and only expressing this system in a group. These results enhance our understanding of the evolution of the seventh Vibrio cholerae pandemic and more broadly how bacteria defend themselves against phage infection.

Phage-Defense Systems Are Unlikely to Cause Cell Suicide.

As new phage-defense systems (PDs) are discovered, the overlap between their mechanisms and those of toxin/antitoxin systems (TAs) is becoming clear in that both use similar means to reduce cellular metabolism; for example, both systems have members that deplete energetic compounds (e.g., NAD+, ATP) and deplete nucleic acids, and both have members that inflict membrane damage. Moreover, both TAs and PDs are similar in that rather than altruistically killing the host to limit phage propagation (commonly known as abortive infection), both reduce host metabolism since phages propagate less in slow-growing cells, and slow growth facilitates the interaction of multiple phage-defense systems.

Comparative performance of microscopy, nested PCR, and real-time PCR for screening avian haemosporidian parasites in Afrotropical starlings (family Sturnidae).

Prevalence studies of avian haemosporidian parasites frequently use microscopy and the nested polymerase chain reaction (PCR) protocols for detecting infections. Newer PCR protocols to detect parasites are being developed, with the distinct advantage of reducing screening cost and time, as well as increasing efficiency and sensitivity. The detection ability of microscopy and nested PCR was compared against a real-time PCR (qPCR) protocol using genomic DNA extracted from 240 bird blood samples collected from three starling species (Cape Starling, the Greater Blue-eared Starling, and the Wattled Starling; family Sturnidae) in the Kruger national park, South Africa. All three protocols successfully detected avian haemosporidian parasites with the qPCR having a considerable edge against the other two methods. Fifteen unique cytochrome b lineages were identified of which seven were new lineages. Microscopy and nested PCR recorded similar prevalence (32.92% and 35.42% respectively). The qPCR protocol used here, although more sensitive (52.92% prevalence), is not able to differentiate between parasite genera but provides the opportunity to screen a large number of samples in large-scale studies within a specific region. This study recommends the development and adoption of new molecular protocols with increased sensitivity and accuracy in prevalence studies. Nevertheless, microscopy remains essential for the morphological description of parasites and for distinguishing between abortive and successful chronic infections. The PCR-based method displays the detection of the parasitic genome but does not reveal whether parasites have or will develop into a successful infection.

Prevalence of Different Courses of Feline Leukaemia Virus Infection in Four European Countries.

Prevalence of progressive feline leukaemia virus (FeLV) infection is known to still be high in cats in Europe, especially in Southern Europe, but the prevalence of other outcomes of FeLV infection has not been determined in most countries. The present study aimed to investigate the prevalence of progressive, regressive, abortive, and focal infection in four European countries, two with a high (Italy, Portugal) and two with a low expected prevalence (Germany, France). Blood samples of 934 cats (Italy: 269; Portugal: 240; France: 107; Germany: 318) were evaluated for the p27 antigen, as well as anti-whole virus, anti-SU, and anti-p15E antibodies by enzyme-linked immunosorbent assay (ELISA) in serum and for proviral DNA by quantitative polymerase chain reaction (qPCR) in whole blood. Positive p27 antigen ELISA results were confirmed by reverse transcriptase-qPCR (RT-qPCR) detecting viral RNA in saliva swabs and/or blood. The outcome of FeLV infection was categorised as progressive (antigen-positive, provirus-positive), regressive (antigen-negative, provirus-positive), abortive (antigen- and provirus-negative, antibody-positive), and focal (antigen-positive, provirus-negative) infection. Overall FeLV prevalence was 21.2% in Italy, 20.4% in Portugal, 9.5% in Germany, and 9.3% in France. Prevalence of progressive, regressive, abortive, and focal infection in Italy was 7.8%, 4.5%, 6.3%, and 2.6%; in Portugal 3.8%, 8.3%, 6.7%, and 1.7%; in Germany 1.9%, 1.3%, 3.5%, and 2.8%; in France 1.9%, 3.7%, 2.8%, and 0.9%, respectively. In conclusion, overall FeLV prevalence is still very high, especially in Southern European countries. Therefore, testing, separation of infected cats, and vaccination are still important measures to reduce the risk of FeLV infection.

Disseminated non-tuberculous mycobacterial infection caused by Mycobacterium obuense in an immunocompromised patient: a case report

BackgroundMycobacterium obuense (M. obuense) is a rapidly growing mycobacterium (RGM) which has been considered nonpathogenic. Here, we report a case of disseminated non-tuberculous mycobacterial (NTM) infection caused by M. obuense in an immunocompromised patient.Case presentationA 16-year-old boy was referred to our hospital due to acute myeloid leukemia. During the treatment of leukemia, the patient exhibited continuous fever, and diffuse miliary nodules with random distribution were found on chest computed tomography. Repeated examinations of bacterial culture tests revealed sputum and urine samples to be smear-positive for acid-fast bacillus, and blood culture from a peripherally inserted central catheter line showed the growth of NTM. The NTM species was identified as M. obuense by mass spectrometry and confirmed by genome sequencing. Combination therapy with amikacin, rifampicin, azithromycin, and moxifloxacin significantly improved the patient’s symptoms and radiological findings.ConclusionWe report a case of disseminated NTM infection caused by M. obuense for which combination anti-microbial therapy was effective. An immunocompromised host indwelling catheter is at risk of RGM bloodstream infections. Although relatively rare, M. obuense may be considered as a potential pathogen causing infectious diseases, especially in high-risk patients.

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review.

On November 7, 2017, the US Food and Drug Administration approved the use of letermovir (LMV) for prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive allogeneic stem cell transplant recipients. After 6 years of use, a large body of real-world experience has been accumulated that validates the Phase III clinical trial results, in which LMV was shown to significantly reduce the risk of clinically significant CMV infection-defined as CMV end-organ disease or CMV DNAemia requiring pre-emptive antiviral therapy (PET)-and increase survival up to Week 24 after treatment inception. Notwithstanding, several issues still need to be settled, thus further investigation is required. First, since viral DNA may accumulate as a result of LMV-driven abortive CMV infection, what is the optimal viral load threshold in the blood that would prompt LMV prophylaxis interruption and PET inception? Should this be adapted to the patient's risk? Second, what is the impact of LMV prophylaxis on the reconstitution of functional CMV-specific T-cell responses? Would it be a wise approach to individually tailor the duration of LMV treatment according to the number of peripheral blood CMV-specific T cells at the end of regular prophylaxis? Third, how frequently do LMV-resistant strains arise while patients are on LMV prophylaxis and how could this be minimized? Here, we discuss the literature addressing these topics.

The pattern of stability of African swine fever virus in leeches

African swine fever virus (ASFV) can accumulate and survive in leeches for a long time. The reasons for the survival of ASFV in leeches are not entirely clear. Here, we elucidate the virus survival pathway in infected leeches. One of the questions reported previously is addressed in this article. How the virus concentration in the body of the leech is equal to or higher than in the water infected with ASFV? Examination of blood swallowed by leeches reveals that the blood cells retain their morphological characteristics for several weeks. It can explain the long-term persistence of the high levels of ASFV in the leeches that ingested ASFV-infected pig blood. qRT-PCR assay showed the transcription of ASFV genes in infected leeches. However, the infectious particles of the virus measured by HADU haven’t increased. Quantitative studies of the ASFV revealed a high content of both viral genes and infectious particles in the skin of leeches compared with other body parts. Electron microscopy analysis revealed the ability of the ASFV to effectively bind to the skin surface of the leeches, which explained the high concentrations of ASFV in the leeches’ skin. A significant difference in the transcriptional activity between early and late viral genes indicates that the virus entered the initial stage of replication, but for some reason failed to complete it, which is typical of abortive infections.

Prokaryotic Gabija complex senses and executes nucleotide depletion and DNA cleavage for antiviral defense

The Gabija complex is a prokaryotic antiviral system consisting of the GajA and GajB proteins. GajA was identified as a DNA nicking endonuclease but the functions of GajB and the complex remain unknown. Here, we show that synergy between GajA-mediated DNA cleavage and nucleotide hydrolysis by GajB initiates efficient abortive infection defense against virulent bacteriophages. The antiviral activity of GajA requires GajB, which senses DNA termini produced by GajA to hydrolyze (d)A/(d)GTP, depleting essential nucleotides. This ATPase activity of Gabija complex is only activated upon DNA binding. GajA binds to GajB to form stable complexes invivo and invitro. However, a functional Gabija complex requires a molecular ratio between GajB and GajA below 1:1, indicating stoichiometric regulation of the DNA/nucleotide processing complex. Thus, the Gabija system exhibits distinct and efficient antiviral defense through sequential sensing and activation of nucleotide depletion and DNA cleavage, causing a cascade suicide effect.

Activation mechanism of a short argonaute-TIR prokaryotic immune system.

Short prokaryotic argonaute (pAgo) and toll/interleukin-1 receptor/resistance protein (TIR)-analog of PAZ (APAZ) form a heterodimeric SPARTA complex that provides immunity to its prokaryotic host through an abortive infection mechanism. Monomeric SPARTA senses foreign RNA/DNA duplexes to assemble an active tetramer resulting in cell death by nicotinamide adenine dinucleotide (oxidized form) (NAD) depletion via an unknown mechanism. We report nine structures of SPARTA in different functional states at a resolution range of 4.2 to 2.9 angstroms, revealing its activation mechanism. Inactive SPARTA monomers bind to RNA/DNA duplexes to form symmetric dimers mediated by the association of Ago subunits. The initiation of tetramer assembly induces flexibility of the TIR domains enabling a symmetry-breaking rotational movement of a TIR domain in the dimer units which facilitates the TIR oligomerization, resulting in the formation of the substrate binding pocket and the activation of the SPARTA complex's NADase activity. Our findings provide detailed structural and mechanistic insights into activating a short argonaute defense system.

Invited Review: Overview of the causes of abortion in horses, their follow-up, and management.

Abortions in horses represent an important health and economic challenge for equine industry. Primary causes of abortion are divided in non-infectious and infectious. Non-infectious causes include abnormalities of foetal appendices (umbilical cord and placenta essentially), abnormalities of gestation, maternal and foetal origins. Infectious abortions are caused in almost cases by bacterial infections, followed by viruses, fungi, and parasites. New abortive pathogens (as Leptospira, Neospora caninum, Coxiella burnetii, Chlamydophila abortus, and) have been confirmed in equines by comparison already known for their abortive properties in human or in other species. Despite an increasing number of autopsies and continuous improvements in diagnostic tools, in management and surveillance, 20 to 40% of the causes of equine abortion remain unknown depending on the country. To increase the likelihood of a definitive diagnosis in cases of abortion and stillbirth in horses, new diagnostic approaches are needed. This article is protected by copyright. All rights reserved.

A Rare Case of Cladophialophora Isolated in a Renal Transplant Patient after Rejection Therapy

Cladophialophora bantiana is the most common cause of cerebral phaeohyphomycosis. A case of live-related renal allograft recipient complained of high-grade continuous fever on the 5th postoperative day (POD). No organism was isolated on cultures and no foci were found on chest X-ray. He was started on broad-spectrum antibiotics. The patient thereafter developed acute antibody-mediated plus acute cellular rejection on the 7th POD. He received a high dose methylprednisolone with plasmapheresis. On the 18th POD, the patient was diagnosed with right frontotemporal and basal ganglionic region abscess on magnetic resonance imaging of the brain. Urgent neurosurgical intervention was done and the sample was sent for investigation. Initially, there was suspicion of Aspergillus on culture. Injection of liposomal amphotericin B was given for 14 days, after which oral voriconazole was started. The patient improved initially but multiple abscesses recurred on the 46th POD. Abscess was drained. On the final culture report, C. bantiana was isolated. 5-flucytosine was added to voriconazole as dual antifungal therapy.