Emergence Of Pathogens Research Articles

Delivery of endolysin across outer membrane of Gram-negative bacteria using translocation domain of botulinum neurotoxin

The emergence of multidrug-resistant pathogens has outpaced the development of new antibiotics, leading to renewed interest in endolysins. Endolysins have been investigated as novel biocontrol agents for Gram-positive bacteria. However, their efficacy against Gram-negative species is limited by the barrier presented by their outer membrane, which prevents endolysin access to the peptidoglycan substrate. Here, we used the translocation domain of botulinum neurotoxin to deliver endolysin across the outer membrane of Gram-negative bacteria. The translocation domain selectively interacts with and penetrates membranes composed of anionic lipids, which have been used in nature to deliver various proteins into animal cells. In addition to the botulinum neurotoxin translocation domain, we have fused bacteriophage-derived receptor binding protein to endolysins. This allows the attached protein to efficiently bind to a broad spectrum of Gram-negative bacteria. By attaching these target-binding and translocation machineries to endolysins, we aimed to develop an engineered endolysin with broad-spectrum targeting and enhanced antibacterial activity against Gram-negative species. To validate our strategy, we designed engineered endolysins using two well-known endolysins, T5 and LysPA26, and tested them against 23 strains from six species of Gram-negative bacteria, confirming that our machinery can act broadly. In particular, we observed a 2.32 log reduction in 30 min with only 0.5 µM against an Acinetobacter baumannii isolate. We also used the SpyTag/SpyCatcher system to easily attach target-binding proteins, thereby improving its target-binding ability. Overall, our newly developed endolysin engineering strategy may be a promising approach to control multidrug-resistant Gram-negative bacterial strains.

The laboratory investigation, management, and infection prevention and control of Candida auris: a narrative review to inform the 2024 national guidance update in England.

The emergent fungal pathogen Candida auris is increasingly recognised as an important cause of healthcare-associated infections globally. It is highly transmissible, adaptable, and persistent, resulting in an organism with significant outbreak potential that risks devastating consequences. Progress in the ability to identify C. auris in clinical specimens is encouraging, but laboratory diagnostic capacity and surveillance systems are lacking in many countries. Intrinsic resistance to commonly used antifungals, combined with the ability to rapidly acquire resistance to therapy, substantially restricts treatment options and novel agents are desperately needed. Despite this, outbreaks can be interrupted, and mortality avoided or minimised, through the application of rigorous infection prevention and control measures with an increasing evidence base. This review provides an update on epidemiology, the impact of the COVID-19 pandemic, risk factors, identification and typing, resistance profiles, treatment, detection of colonisation, and infection prevention and control measures for C. auris. This review has informed a planned 2024 update to the United Kingdom Health Security Agency (UKHSA) guidance on the laboratory investigation, management, and infection prevention and control of Candida auris. A multidisciplinary response is needed to control C. auris transmission in a healthcare setting and should emphasise outbreak preparedness and response, rapid contact tracing and isolation or cohorting of patients and staff, strict hand hygiene and other infection prevention and control measures, dedicated or single-use equipment, appropriate disinfection, and effective communication concerning patient transfers and discharge.

Understanding pathogen emergence through the lens of Candida auris.

Understanding pathogen emergence through the lens of Candida auris.

Le numérique et l'infectiologie — Livre blanc du groupe d'infectiologie digitale de la société de pathologie infectieuse de langue française

IntroductionDigital health is rapidly developing and supporting the transition to personalized medicine. Implementing digital tools in clinical practice requires multidisciplinary work. In this context, the "Société de Pathologie Infectieuse de Langue Française" has launched the "Groupe d'Infectiologie Digitale" (GID) in 2022. Its aim was to present the specifics of digital infectiology and to identify strategic opportunities. MethodsThe GID met quarterly for a year and a half, with closer meetings for each sub-group. A white paper was drafted. ResultsInfectiology is a transversal specialty integrating multimodal and multiscale data, which benefits from the development of digital tools for care, research and education. After a few definitions, the specificities of infectiology are highlighted, such as epidemics and pathogen emergence, the importance of the community-hospital link, illiteracy among some patients, and confidentiality issues in the context of transmissible diseases. Strategic use cases and points for attention are presented to support the development of digital tools in infectiology. The challenges and limits associated with secondary data reuse and the development of artificial intelligence are highlighted. Finally, we explore potential uses of digital tools in education. ConclusionIt is essential to bridge the gap between medical practice, patients, digital experts and institutions in this rapidly expanding field. The development of similar initiatives at national and European levels would combine efforts to develop validated and useful tools for patients.

Universal antibacterial and anti-inflammatory treatment using chitosan-prussian blue nanozyme

Bacterial infections are a growing global public health problem, exacerbated by the widespread and often inappropriate use of antibiotics, leading to the emergence of non-antibiotic pathogens. Herein, we synthesized a chitosan-Prussian blue nanozyme (CS@PB), a non-antibiotic agent, for universal antibacterial and anti-inflammatory treatment of bacterial infections. Confocal microscopy images showed that CS@PB significantly enhanced the physical interaction between chitosan and bacteria, thereby increasing the antibacterial ability. Moreover, these nanozymes exhibited potent antioxidant and anti-inflammatory properties, promoting macrophage polarization toward the M2-like phenotype, reducing oxidative stress, and alleviating inflammation. This dual-action approach effectively accelerates the healing of bacteria-infected inflammatory wounds. The synergistic bactericidal and anti-inflammatory properties of CS@PBs inhibited wound infection and promoted the healing of skin infections in a mouse model. In addition, CS@PB displayed remarkable lung retention and potent bactericidal effects, resulting in significantly improved survival rates in mouse models of acute pulmonary bacterial infections. In conclusion, CS@PBs exhibited exceptional bactericidal capabilities, anti-inflammatory properties, and minimal toxicity, suggesting that they are promising candidates for a new generation of non-antibiotic antimicrobial agents for the treatment of bacterial infections.

Design of Novel Saposin-like Bacteriocins Using a Hybrid Approach.

A multitude of approaches will be required to respond to the threat posed by the emergence and spread of antibiotic resistant pathogens. Bacteriocins have gained increasing attention as a possible alternative to antibiotics, as such peptide antimicrobials have mechanisms of action different from antibiotics and are therefore equally potent against antibiotic resistant bacteria as their susceptible counterparts. A group of bacteriocins known as saposin-like bacteriocins is believed to act directly on the bacterial membrane. Based on seven saposin-like leaderless bacteriocins, we have constructed a library of hybrid peptides containing all combinations of the N- and C-terminal halves of the native bacteriocins. All hybrid peptides were synthesized using in vitro protein expression and assayed for antimicrobial activity towards several pathogens. Of the 42 hybrid peptides, antimicrobial activity was confirmed for 11 novel hybrid peptides. Furthermore, several of the hybrid peptides exhibited altered antimicrobial spectra and apparent increase in potency compared to the peptides from which they were derived. The most promising hybrid, termed ISP26, was then obtained synthetically and shown to inhibit most of the Gram-positive species tested, including opportunistic pathogens and food spoilage bacteria. Additionally, ISP26 was shown to inhibit Acinetobacter, a species of Gram-negative bacteria frequently isolated from nosocomial infections. The activity of the hybrid library provides valuable insights into the design and screening of new active bacteriocins.

Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses

Defending against future pandemics requires vaccine platforms that protect across a range of related pathogens. Nanoscale patterning can be used to address this issue. Here, we produce quartets of linked receptor-binding domains (RBDs) from a panel of SARS-like betacoronaviruses, coupled to a computationally designed nanocage through SpyTag/SpyCatcher links. These Quartet Nanocages, possessing a branched morphology, induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented in the vaccine. Equivalent antibody responses are raised to RBDs close to the nanocage or at the tips of the nanoparticle’s branches. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increase the strength and breadth of an otherwise narrow immune response. A Quartet Nanocage including the Omicron XBB.1.5 ‘Kraken’ RBD induced antibodies with binding to a broad range of sarbecoviruses, as well as neutralizing activity against this variant of concern. Quartet nanocages are a nanomedicine approach with potential to confer heterotypic protection against emergent zoonotic pathogens and facilitate proactive pandemic protection.

306 Awardee Talk: Characterization and surveillance testing of problematic pathogens within the livestock industry using metagenomic and long read sequencing

Abstract With increased intensification of livestock production, the rate of disease susceptibility and emergence of pathogens has increased. Currently in the beef cattle industry, infectious bovine keratoconjunctivitis (IBK), is a problematic disease that is not well understood where vaccines have shown to have low efficacy. This is partly due to the lack of understanding of the ocular microbiome, where IBK disease progression may be a result of a polymicrobial disease due to certain bacterial and/or viral taxa predisposing the animal to infection. To understand the microbial ecology of IBK we used metagenomic shotgun sequencing to characterize the bovine ocular microbiome and virome. Infected and healthy beef calves were sampled before, during, and after IBK infection and shotgun metagenomic sequencing was performed to identify microbial changes during IBK infection. Preliminary data showed that we were able to identify 230 contigs consisting of bacteriophages such as Escherichia virus, Bacillus virus, Corynebacterium virus, and Mycoplasma virus. Out of the 230 bacteriophages, 213 of them are lytic phages. Additionally, preliminary data showed bacteria contigs such as Moraxella bovoculi, and Mycoplasma bovoculi Like IBK, the rate of disease emergence has increased in the last decade. As such, rapid in-field surveillance tools are greatly needed to monitor the emergence of known and unknown pathogens for early intervention. Current tools such as RT-PCR and enzyme linked immunosorbent assay (ELISA) require previous genomic knowledge to detect pathogens and are limited to the pathogen of interest. We have developed a long-read sequencing-based surveillance tool that eliminates the need of prior knowledge to detect both bacterial and viral pathogens simultaneously. The approach we developed can rapidly and accurately identify pathogens within clinical samples in as short as 12 h from sample collection to results. Here we present sequence-based microbiome studies and tools to help understand disease etiology and develop novel surveillance tools to improve food security within the livestock industry.

Animal geographies of industrial animal agriculture in the Pandemic Era: the tragedy and insecurity of multispecies ethnography

ABSTRACT Amidst the capitalist logics governing life and death in the industrial production of pigs and poultry in Denmark, we confront the ethico-methodological challenges of conducting multispecies research in this time of increased pathogen emergence and transmission: the ‘Pandemic Era’. Drawing on our empirical insights, we contend that worldly animal geographies in the Pandemic Era are constituted by biological and existential insecurity, underscoring the importance of this work. Through affectively attuning to the bordering devices of biosecurity, we convey the capaciousness of performative understandings of species that industrial agriculture constrains but which animal geographers can advance. Acts of witnessing in industrial agriculture expose the limitations of multispecies ethnography that simultaneously catalyse advancement in the field. Whilst our work reckons with the tragedy of multispecies ethnography in industrial landscapes, the limits we have encountered, from the methodological to the ethical, are incitements to critique and innovate modes of attunement that extend beyond the field of animal geographies itself.

Emergence and Potential Spread of Rust Disease on Wisteria floribunda and Corydalis incisa Influenced by Climate Change in Korea

Global climate change influences the emergence, spread, and severity of rust diseases that affect crops and forests. In Korea, the rust diseases that affect Wisteria floribunda and its alternate host Corydalis incisa are rapidly spreading northwards. Through morphological, molecular, phylogenetic, and pathogenicity approaches, Neophysopella kraunhiae was identified as the causal agent, alternating between the two host plants to complete its life cycle. Using the maximum entropy model (Maxent) under shared socioeconomic pathways (SSPs), the results of this study suggest that by the 2050s, C. incisa is likely to extend its range into central Korea owing to climate shifts, whereas the distribution of W. floribunda is expected to remain unchanged nationwide. The generalized additive model revealed a significant positive correlation between the presence of C. incisa and the incidence of rust disease, highlighting the role that climate-driven expansion of this alternate host plays in the spread of N. kraunhiae. These findings highlight the profound influence of climate change on both the distribution of a specific plant and the disease a rust fungus causes, raising concerns about the potential emergence and spread of other rust pathogens with similar host dynamics.

Non-invasive surveillance of shared pathogens in the Eurasian brown bear (Ursus arctos) human interface

Multi-host communities are perfect scenarios for the emergence and spread of pathogens, threatening the recovery of endangered, isolated, or inbred populations, such as the brown bear (Ursus arctos) in northwestern Spain. The population recovery in recent years has forced bears to occupy highly anthropized areas, increasing their interaction with human and domestic animals, with potential consequences for global health. During 2022–2023 a survey of parasites, bacteria and viruses shared between wildlife, domestic animals and humans was performed in this population using non-invasive surveillance, i.e., bear fecal samples (n = 73) and sponge-based sampling of trees (n = 42; 14 rubbed trees and 28 control trees). Pathogen detection rates were defined as the percentage of qPCR or culture-positive samples. Generalized linear models were fitted to assess their relationship with environmental variables including dispersion of the human population, and percentage of agricultural and periurban habitats in a 6 km-buffer around each sample. Canine Adenovirus type 1 (45.2%), Giardia spp. (15.1%), Salmonella spp. (12.3%), and extended-spectrum-beta-lactamases (ESBL) Escherichia coli (1.4%) were identified in fecal samples. In contrast, only five sponges from three rubbed and two control trees resulted positive to E. coli (14.3%). The results suggest that several pathogens are common in the Cantabrian brown bear population and that anthropization of the territory modulates their prevalence and richness.The effective design of management programs for bear conservation will require a one-health approach, in which genetic analysis of non-invasive samples can be key tools for the sanitary surveillance at the wildlife-livestock-human interface.

One Health approach to Coxiella burnetii in Brazilian indigenous communities

Indigenous health has posted complex challenges worldwide, particularly due to historical economic, territorial, social and environmental processes, which may lead to emergence and reemergence of pathogens. In addition to few Coxiella burnetii serosurveys in vulnerable populations, especially in developing tropical countries, no comprehensive One Health approach has focused on human-animal infection along with potential environmental determinants. Accordingly, this study aimed to assess the seroprevalence of anti-C. burnetii antibodies in indigenous populations and their dogs from 10 indigenous communities distributed in southern and southeastern Brazil, along with the correspondent healthcare professionals. In overall, 8/893 (0.90%; 95% CI 0.45–1.76) indigenous and 1/406 (0.25%) dog samples were seropositive, with 7/343 (2.04%) individuals the 1/144 (0.69%) dog from the Ocoy community, located in the city of São Miguel do Iguaçu, bordering Argentina at south, and far 10 km at west from Paraguay. All 84 healthcare professionals tested seronegative.

Neoscytalidium dimidiatum: A newly identified postharvest pathogen of pears and its implications for pome fruits

AbstractTürkiye is a prominent contributor to pear and diverse pome fruit production. Pear fruit with unusual brown to black spots and rot symptoms observed in public marketplaces in Mardin province have raised concerns regarding postharvest fruit health. The consistent isolation of a fungus from these fruits revealed morphological features indicative of Neoscytalidium dimidiatum. Phylogenetic confirmation of its identity ensued through BLASTn searches targeting, the internal transcribed spacer (ITS) of ribosomal DNA, the partial translation elongation factor 1‐alpha gene (tef1), and the partial β‐tubulin gene (tub2). Pathogenicity evaluations were conducted on common pome fruits, namely pears, apples, and quinces, unveiling the susceptibility of all examined fruits to postharvest infection by this emergent pathogen. Furthermore, an investigation was carried out to discern the pathogen's response to varying temperature ranges on pear fruits, revealing that the most pronounced lesions occurred at 30°C, followed by 25°C, 35°C, and 20°C. Conversely, no lesion development was observed at 10°C, 15°C, or 40°C. To the best of our knowledge, this study represents the first report of N. dimidiatum as the etiological agent responsible for postharvest rot in pear fruit. The implications of these findings highlight the potential threat posed by this pathogen to pome fruits postharvest, especially in regions where cold storage facilities are not widely utilized, warranting increased vigilance and preventive measures.

Lipid A in outer membrane vesicles shields bacteria from polymyxins.

The continuous emergence of multidrug-resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae being a prominent threat. We conducted a comprehensive study on K. pneumoniae's antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last-resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)-stressed K. pneumoniae exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Klebsiella. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In all models, OMVs protected K. pneumoniae from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed K. pneumoniae could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed K. pneumoniae compared to control OMVs. The lipid A-dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Klebsiella from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross-protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug-resistant bacterial infections.

Trends in imported infections among migrants and travellers to Spain: a decade of analysis through the +Redivi network (2012-2022).

High-speed global travel, increased trade, world population growth, migration, urbanization and climate change have favoured the emergence and spread of pathogens. We aimed to analyse the evolution of imported infections in Spain during 2012-2022 and the potential impact of some of the abovementioned factors on differential morbidity patterns. In this retrospective study (January 2012 to December 2022), we analysed data collected by the +Redivi network across 25 health centres. The network's standardised database records new cases of imported infections, including patient demographics, travel history, pre-travel advice and diagnostic information. To assess outcome rates over time and potential interactions, we constructed penalized weighted models to reduce the bias related to a low event rate and used weighted logistic regression for morbidity outcomes. We recorded 25 632 episodes, comprising 13 913 migrants, 4047 visiting friends and relatives (VFR) immigrants, 392 VFR travellers and 7280 travellers. Most immigrants came from South America (48.3%), Sub-Saharan Africa (28.5%), North Africa (6.6%), South Central Asia (5.4%) and Central America/Caribbean (5.3%). The most common regions visited by travellers were Sub-Saharan Africa (33.5%), South America (24.5%), Central America/Caribbean (13.5%), Southeast Asia (12%) and South Central Asia (10%). The proportion of diagnoses of malaria, strongyloidiasis and unspecified self-limiting febrile syndrome < 3weeks remained unchanged during the study period. An increased frequency of diagnosis was reported for schistosomiasis, blastocystosis, giardiasis, dengue, diarrhoea, new cases of HIV, latent and pulmonary tuberculosis, whereas a decrease was reported for syphilis, chikungunya fever, Chagas disease and eosinophilia. We detected interactions between time and sex or type of participant across the different diagnoses. Our study underscores the importance of epidemiological data in understanding infectious diseases dynamics among travellers and migrants, emphasizing how demographic shifts, migration trends and healthcare policies affect disease profiles. Comprehensive data play an essential role in enhancing public health policies and travel advice.

Efficient antibiotic remediation from wastewater using a lamellar free-standing 2D graphene oxide/Ti3C2Tx hybrid membrane

The existence of elevated levels of antibiotics in wastewater has facilitated the emergence and spread of pathogens with antimicrobial resistance (AMR). When combined with the worldwide water scarcity issue, this situation results in detrimental impacts on both the ecosystem and human well-being. Traditional methods employed by wastewater treatment facilities exhibit limited effectiveness in eliminating antibiotics. This paper describes the synthesis and performance of two-dimensional (2D) lamellar free-standing graphene oxide (GO)/Ti3C2Tx membrane for the removal of antibiotics from wastewater. The 50 %GO/Ti3C2Tx composite membrane demonstrated a remarkable increase in water flux, achieving 61.9 L m−2 h−1, surpassing the performance of the pristine GO membrane, which achieved 22.8 L m−2 h−1. Additionally, the GO/Ti3C2Tx composite membranes exhibited outstanding tetracycline rejection, consistently exceeding 99 %, a significant improvement compared to the pristine Ti3C2Tx membrane. The composite membranes of with a ratio of GO to MXene of 50 %, 40 %, 30 % and 20 % had contact angles of 54.5°, 57.4°, 60.6°, and 61.6°, respectively. Combining GO and Ti3C2Tx at specific mass ratios enhanced properties, evidenced by altered interlayer spacing and hydrophilicity. Furthermore, the superior composite membrane demonstrated superior antifouling properties compared to both pristine GO and Ti3C2Tx membranes.

Ultraviolet light C prototype device against Sporothrix brasiliensis as a potential physical method for surface disinfection.

Sporothrix brasiliensis is recognized as an emergent fungal pathogen and the high amount of fungal propagules in the lesions of infected cats allows the contamination of surfaces by direct contact. Given that the environment can play a role in the transmission of this fungus, effective methods to eliminate this pathogen from contaminated surfaces are necessary. Physical methods, such as ultraviolet light C (UVC), are broad used for surfaces disinfection, however, non-data about its activity against S. brasiliensis is reported. Therefore, we aimed to evaluate an easy handled prototype of a UVC device, in the inhibition of S. brasiliensis. Three doses and times of exposure of irradiance were tested: 3.5mJ/cm2 (1s), 5.25mJ/cm2 (1.5s) and 329mJ/cm2 (94s) against a standardized inoculum of yeast and mold phase of S. brasiliensis. A decrease in CFU was shown in all doses of irradiance in both phases of S. brasiliensis, the average reduction ranged from 78 to 100% among doses, being a complete fungicidal activity achieved against the yeast phase after the 94s exposure (329mJ/cm2). Our data shows that UVC is a potential physical method for disinfection of surfaces contaminated with S. brasiliensis, and the prototype device developed provides an easy handling, and quickly results.

Distribution and survival of pathogens from different waste components and bioaerosol traceability analysis in household garbage room

Household garbage rooms release abundant bioaerosols and are an important source of pathogens; however, information on the distribution and survival patterns of pathogens in different waste components is limited. In this study, a culture method and 16S rRNA high-throughput sequencing were used to determine bacterial communities, culturable pathogens, and human bacterial pathogens (HBPs). The results showed that abundant culturable bacteria were detected in all waste types, and a large number of S. aureus was detected on the surface of recyclable wastes, whereas S. aureus, total coliforms, Salmonella, Enterococcus, and hemolytic bacteria were detected in food waste and other waste. The activities of these detected pathogenic bacteria decreased after 24 h of storage but re-activated within one week. Factors affecting the emergence of pathogens varied with different waste components. Sequencing results showed that Pseudomonas, Acinetobacter, and Burkholderia were abundant in the waste samples, whereas Achromobacter, Exiguobacteriums, Bordetella, and Corynebacterium were the primary pathogens in the bioaerosol and wall attachment. The results of traceability analysis showed that bioaerosol microbes were mainly derived from raw kitchen waste (5.98%) and plastic and paper contaminated with food waste (19.93%) in garbage rooms. In addition, bioaerosols were the main source of microflora in the wall attachment, which possessed high HBP diversity and required more attention. These findings will help in understanding the microbial hazards in different waste components and provide guidance for the control and risk reduction of bioaerosols during waste management and recycling.

Xanthomonas as a Model System for Studying Pathogen Emergence and Evolution.

In this review, we highlight studies in which whole-genome sequencing, comparative genomics, and population genomics have provided unprecedented insights into past and ongoing pathogen evolution. These include new understandings of the adaptive evolution of secretion systems and their effectors. We focus on Xanthomonas pathosystems that have seen intensive study and improved our understanding of pathogen emergence and evolution, particularly in the context of host specialization: citrus canker, bacterial blight of rice, and bacterial spot of tomato and pepper. Across pathosystems, pathogens appear to follow a pattern of bursts of evolution and diversification that impact host adaptation. There remains a need for studies on the mechanisms of host range evolution and genetic exchange among closely related but differentially host-specialized species and to start moving beyond the study of specific strain and host cultivar pairwise interactions to thinking about these pathosystems in a community context.

Inhibition of Pim kinases triggers a broad antiviral activity by affecting innate immunity and via the PI3K-Akt-mTOR axis the endolysosomal system

Zoonoses such as ZIKV and SARS-CoV-2 pose a severe risk to global health. There is urgent need for broad antiviral strategies based on host-targets filling gaps between pathogen emergence and availability of therapeutic or preventive strategies. Significant reduction of pathogen titers decreases spread of infections and thereby ensures health systems not being overloaded and public life to continue. Based on previously observed interference with FGFR1/2-signaling dependent impact on interferon stimulated gene (ISG)-expression, we identified Pim kinases as promising druggable cellular target. We therefore focused on analyzing the potential of pan-Pim kinase inhibition to trigger a broad antiviral response.The pan-Pim kinase inhibitor AZD1208 exerted an extraordinarily high antiviral effect against various ZIKV isolates, SARS-CoV-2 and HBV. This was reflected by strong reduction in viral RNA, proteins and released infectious particles. Especially in case of SARS-CoV-2, AZD1208 led to a complete removal of viral traces in cells. Kinome-analysis revealed vast changes in kinase landscape upon AZD1208 treatment, especially for inflammation and the PI3K/Akt-pathway. For ZIKV, a clear correlation between antiviral effect and increase in ISG-expression was observed. Based on a cell culture model with impaired ISG-induction, activation of the PI3K-Akt-mTOR axis, leading to major changes in the endolysosomal equilibrium, was identified as second pillar of the antiviral effect triggered by AZD1208-dependent Pim kinase inhibition, also against HBV.We identified Pim-kinases as cellular target for a broad antiviral activity. The antiviral effect exerted by inhibition of Pim kinases is based on at least two pillars: innate immunity and modulation of the endolysosomal system.