Recent Advances in Tick Antigen Discovery and Anti-Tick Vaccine Development.

Ticks can seriously affect human and animal health around the globe, causing significant economic losses each year. Chemical acaricides are widely used to control ticks, which negatively impact the environment and result in the emergence of acaricide-resistant tick populations. A vaccine is considered as one of the best alternative approaches to control ticks and tick-borne diseases, as it is less expensive and more effective than chemical controls. Many antigen-based vaccines have been developed as a result of current advances in transcriptomics, genomics, and proteomic techniques. A few of these (e.g., Gavac® and TickGARD®) are commercially available and are commonly used in different countries. Furthermore, a significant number of novel antigens are being investigated with the perspective of developing new anti-tick vaccines. However, more research is required to develop new and more efficient antigen-based vaccines, including on assessing the efficiency of various epitopes against different tick species to confirm their cross-reactivity and their high immunogenicity. In this review, we discuss the recent advancements in the development of antigen-based vaccines (traditional and RNA-based) and provide a brief overview of recent discoveries of novel antigens, along with their sources, characteristics, and the methods used to test their efficiency.

Quantitative proteomics analysis reveals core and variable tick salivary proteins at the tick-vertebrate host interface.

Few studies have examined tick proteomes, how they adapt to their environment, and their roles in the parasite-host interactions that drive tick infestation and pathogen transmission. Here we used a proteomics approach to screen for biologically and immunologically relevant proteins acting at the tick-host interface during tick feeding and, as proof of principle, measured host antibody responses to some of the discovered candidates. We used a label-free quantitative proteomic workflow to study salivary proteomes of (i) wild Ixodes ricinus ticks fed on different hosts, (ii) wild or laboratory ticks fed on the same host, and (iii) adult ticks cofed with nymphs. Our results reveal high and stable expression of several protease inhibitors and other tick-specific proteins under different feeding conditions. Most pathways functionally enriched in sialoproteomes were related to proteolysis, endopeptidase, and amine-binding activities. The generated catalogue of tick salivary proteins enabled the selection of six candidate secreted immunogenic peptides for rabbit immunizations, three of which induced strong and durable antigen-specific antibody responses in rabbits. Furthermore, rabbits exposed to ticks mounted immune responses against the candidate peptides/proteins, confirming their expression at the tick-vertebrate interface. Our approach provides insights into tick adaptation strategies to different feeding conditions and promising candidates for developing antitick vaccines or markers of exposure of vertebrate hosts to tick bites.

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite-Host Crosstalk.

Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. The functions of many PIs have now been characterized and are showing clinical relevance for the treatment of human diseases such as arthritis, hepatitis, cancer, AIDS, and cardiovascular diseases, amongst others. Other PIs have potential use in agriculture as insecticides, anti-fungal, and antibacterial agents. PIs from tick salivary glands are special due to their pharmacological properties and their high specificity, selectivity, and affinity to their target proteases at the tick-host interface. In this review, we discuss the structure and function of PIs in general and those PI superfamilies abundant in tick salivary glands to illustrate their possible practical applications. In doing so, we describe tick salivary PIs that are showing promise as drug candidates, highlighting the most promising ones tested in vivo and which are now progressing to preclinical and clinical trials.

Prognostic value of scoring tools in severe trauma patients admitted to the emergency department.

BACKGROUND: Severe Trauma is a misleading cause of death in young people. Early assessment of prognosis is the cornerstone in the management of such patients. Several prognostic scores have been proposed during the last decade. AIM: To evaluate the prognostic performance of trauma scores in terms of mortality in severe trauma patients admitted to the emergency department. METHODS: This was a prospective, observational and prognostic study with inclusion of severe trauma patients admitted to the emergency department over a 20 months period. We focused on the predictive value of 4 trauma scores in terms of mortality in severe trauma admitted to the resuscitation room. Four scores were included: ISS, NISS, EMTRAS and GAP score. Univariate and multivariate analysis of mortality at the 30th post-traumatic day were conducted with comparison of ROC curves of the scores. Moreover, Correlation between the several scores was studied. RESULTS: We included 298 patients. The median age was 40 (15-90) years. The sex ratio was 4,5. Clinical characteristics were n (%): GCS ≤ 8: 62 (21); PAS <90 mm Hg: 32 (11) and pulse oximetry <90%: 44 (15). The median ISS was 17 (1-75) and 176 (59%) trauma patients had a score ISS ≥ 16. The median NISS was 22 (1-75). The median EMTRAS was 3 (0-9). The median GAP was 21 (3-26). The global mortality was 21.5%. Independent predictors of mortality were: EMTRAS score ≥ 3 (adjusted OR 1.80, 95% CI [1.05-3.08], p = 0.0033), ISS ≥ 16 (adjusted OR 2.05; 95% CI [1.26-3.46], p = 0.002), GAP <20 (adjusted OR 1.92, 95% CI [1.268-2.92], p = 0.002) 1.74, 95% CI [1.17-2.592], p = 0.005). The GAP score had the best AUC= 0.811 followed by the EMTRAS with an AUC of 0.789. Finally, all the scores were strongly correlated. CONCLUSION: Severe trauma is a dynamic process with a heavy morbidity and mortality. In our study, physiological scores and combined score were correlated with prognosis as well as anatomical scores and could be proposed for early gravity assessment in severe trauma enhancing triage, management and prognosis of polytrauma patients.

Post-traumatic fracture-dislocation of the humeral head with intrathoracic migration: A case report.

INTRODUCTION: Severe trauma is a frequent condition encountered in Emergency department (ED) in which vital prognosis can easily be engaged. This condition could be responsible for unusual injuries occurrence. Emergency physician must be aware of these situations where adequate management is urgently required. We report a case of e 45-year-old patient who was admitted to the ED after a high velocity road traffic accident resulting in multiple injuries and fracture dislocation and migrating humeral head into intra thoracic position. OBSERVATION: We report the clinical case of a patient aged 45 years without medical history admitted to the ED after being involved in a high-velocity road traffic accident. On clinical presentation, the patient was dyspneic and desaturated on ambient air room, he presented moreover clinical signs of blunt right shoulder trauma and deformation of the 2 thighs. Final screening of injuries by radiological and a tomographic exams retained a polytrauma status with fracture dislocation and migration of humeral head, homolateral hemothorax and double femur fracture. Patient was managed by multidisciplinary surgical approaches. Discusssion et conclusion: We illustrated by this case a very rare post trauma condition represented by a fracture dislocation of the humeral head resulting in an intrathoracic migration and a homolateral hemothorax. This diagnosis was reported only a few times by the literature within last decades and management suffers from lack of treatment guidelines, which remain team-dependent. At the very early stage of management and before surgical step, emergency physician must be aware of the possibility of this clinical condition with evolution into some threatening clinical presentations with specific management.

Transcriptomic analysis of the tick midgut and salivary gland responses upon repeated blood-feeding on a vertebrate host.

Ticks are blood-feeding arthropods that use the components of their salivary glands to counter the host's hemostatic, inflammatory, and immune responses. The tick midgut also plays a crucial role in hematophagy. It is responsible for managing blood meals (storage and digestion) and protecting against host immunity and pathogen infections. Previous transcriptomic studies revealed the complexity of tick sialomes (salivary gland transcriptomes) and mialomes (midgut transcriptomes) which encode for protease inhibitors, lipocalins (histamine-binding proteins), disintegrins, enzymes, and several other tick-specific proteins. Several studies have demonstrated that mammalian hosts acquire tick resistance against repeated tick bites. Consequently, there is an urgent need to uncover how tick sialomes and mialomes respond to resistant hosts, as they may serve to develop novel tick control strategies and applications. Here, we mimicked natural repeated tick bites in a laboratory setting and analyzed gene expression dynamics in the salivary glands and midguts of adult female ticks. Rabbits were subjected to a primary (feeding on a naive host) and a secondary infestation of the same host (we re-exposed the hosts but to other ticks). We used single salivary glands and midguts dissected from individual siblings adult pathogen-free female Ixodes ricinus to reduce genetic variability between individual ticks. The comprehensive analysis of 88 obtained RNA-seq data sets allows us to provide high-quality annotated sialomes and mialomes from individual ticks. Comparisons between fed/unfed, timepoints, and exposures yielded as many as 3000 putative differentially expressed genes (DEG). Interestingly, when classifying the exposure DEGs by means of a clustering approach we observed that the majority of these genes show increased expression at early feeding time-points in the mid-gut of re-exposed ticks. The existence of clearly defined groups of genes with highly similar responses to re-exposure suggests the existence of molecular swiches. In silico functional analysis shows that these early feeding reexposure response genes form a dense interaction network at protein level being related to virtually all aspects of gene expression regulation and glycosylation. The processed data is available through an easy-to-use database-associated webpage (https://arn.ugr.es/IxoriDB/) that can serve as a valuable resource for tick research.

Long Non-Coding RNAs and Their Potential Roles in the Vector-Host-Pathogen Triad.

Long non-coding (lnc)RNAs have emerged as critical regulators of gene expression and are involved in almost every cellular process. They can bind to other molecules including DNA, proteins, or even other RNA types such messenger RNA or small RNAs. LncRNAs are typically expressed at much lower levels than mRNA, and their expression is often restricted to tissue- or time-specific developmental stages. They are also involved in several inter-species interactions, including vector-host-pathogen interactions, where they can be either vector/host-derived or encoded by pathogens. In these interactions, they function via multiple mechanisms including regulating pathogen growth and replication or via cell-autonomous antimicrobial defense mechanisms. Recent advances suggest that characterizing lncRNAs and their targets in different species may hold the key to understanding the role of this class of non-coding RNA in interspecies crosstalk. In this review, we present a general overview of recent studies related to lncRNA-related regulation of gene expression as well as their possible involvement in regulating vector-host-pathogen interactions.

Base Excess usefulness for prediction of immediate mortality in severe trauma patients admitted to the Emergency department.

BACKGROUND: Trauma is a leading cause of death in young people and hemorrhagic shock is a leading mechanism of this mortality. Hypoperfusion can be difficult to diagnose clinically, especially in younger patients. Arterial Base Excess (BE) has been used as an early indicator of hypoperfusion. AIM: To evaluate the prognostic value of admission BE in severe trauma patients admitted to the emergency department (ED). METHODS: In this prospective study, severe trauma patients meeting high velocity criteria admitted to the ED during the study period were included. BE was calculated from arterial blood gas samples. Multivariate analysis was performed for Day-1 and Day-7 post trauma mortality. ROC characteristics and survival curves were used. RESULTS: We included 479 patients. Median age was 37 (18-90). Eighty-one per cent were male. Clinical characteristics n(%): GCS<13: 170(35); SBP<90 mmHg: 64(13) and SpO2 <90%: 82(17). Mean ISS was 22 ± 13. Mortality was at days 1 and 7: 2.2% and 27.3%, respectively. Median BE was -3.2 mmol/l (-25; 28). Forty-five per cent had a BE ≤ -3.5 mmol/l. In multivariate analysis, initial BE ≤ -6.5 mmol/l was predictive of first day mortality with an Odds Ratio; [CI95%] = 3.17; [1.4-7.1]; p=0.005. Similar results were found at Day 7: Odds Ratio; [CI95%] = 1.5; [1.14-1.96]; p=0.003. BE showed high prognostic value for both mortality rates. Survival curve was significant for BE> -6.5mmol/l. CONCLUSION: in this study, a high BE above 6.5mmol/L showed a significant prognostic value in immediate and early mortality and is proposed as a marker of injury severity in trauma patients admitted to the ED. Prediction was better for the immediate mortality and thus could be proposed as a triage tool in the ED.

Drug related adverse events due to cardiotropic agents : Epidemiology and prognosis in the emergency department.

INTRODUCTION: The severity of cardiotropic agents overuse is related to the risk of cardiac and hemodynamic life-threatening situations. Toxicity is attributed to their narrow therapeutic spectrum and pharmacodynamic properties. The clinical presentation, however, remains polymorphic and represents a challenge for the emergency physician to relate accountability to the exact agent. AIM: To evaluate epidemiological, clinical and prognostic profile of patients visiting emergency department in whom iatrogeny secondary to cardiotropic use was diagnosed. METHODS: This was a single-center prospective study over 12 months. We included successively all patients aged over 18 years in whom diagnosis of cardiotropic iatrogeny was made. Cardiotropic related drug-induced events were selected after collegial decision making processing. Prognosis was evaluated in terms of severity and mortality at day 30. Univariate analysis was conducted. P<0.05 was significant. RESULTS: We enrolled 51 patients. Median age was 72 years with IQR (25,75) of (62,78). Sex ratio was 0.64. Twenty cases of misuse were identified (39%) with 51% of cases being related to the physician. Accountability of the adverse drug event (ADE) was 51%. The ADE was considered severe in 45% of cases and the death rate on day 30 was 12%. Drug classes were dominated by beta-blockers in 20 patients (39%) and anti-arrhythmic agents (Amiodarone ®) in 18 patients (35%). Beta-blockers were significantly the most incriminated in the occurrence of severe ADE. A double iatrogeny was found in 13 patients (25%). Misuse and physician-related ADE were found to be predictive of the severity of ADE in univariate analysis with respectively: For misuse:(OR brut=22, CI95%=[5.2;93.5] ; p<0.001) and for related physician ADE (OR brut = 3,7 ; CI95%=[1.1;12] ; P= 0.015). Predictive factors of mortality at day 30 in the univariate analysis were: Past renal failure : OR brut 5,8; CI95%[1,3-26,5]; p=0,015 ; misuse with OR brut=16.7, 95% CI=[1.9-143.5], p=0.002 and severe ADE with OR brut=15, 95% CI=[1.75-129], p=0.032. CONCLUSION: This study showed that ADE related to Cardiotropic agents are frequent and remain a serious condition especially in elderly. Betablockers agents were the mostly incriminated therapeutic class in the severity of the clinical condition by its hemodynamic repercussions responsible of a high rate of hospitalizations and mortality. Misuse and physician-related ADE were found to be predictive of the severity. Whereas, occurrence of severe ADE, misuse and past renal failure were predictive of mortality. Moreover, in 51% patients, ADE was preventable and related to the prescription of physician showing the main role of the preventability and the role of the prescriber in the genesis of this severe condition.

Insights into the role of tick salivary protease inhibitors during ectoparasite–host crosstalk

Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. The functions of many PIs have now been characterized and are showing clinical relevance for the treatment of human diseases such as arthritis, hepatitis, cancer, AIDS, and cardiovascular diseases, amongst others. Other PIs have potential use in agriculture as insecticides, anti-fungal, and antibacterial agents. PIs from tick salivary glands are special due to their pharmacological properties and their high specificity, selectivity, and affinity to their target proteases at the tick–host interface. In this review, we discuss the structure and function of PIs in general and those PI superfamilies abundant in tick salivary glands to illustrate their possible practical applications. In doing so, we describe tick salivary PIs that are showing promise as drug candidates, highlighting the most promising ones tested in vivo and which are now progressing to preclinical and clinical trials.