ABSTRACT
Extracellular vesicles (EVs) are membrane-enclosed bio-nanoparticles secreted by cells and naturally evolved to transport various bioactive molecules between cells and even organisms. These cellular objects are considered one of the most promising bio-nanovehicles for the delivery of native and exogenous molecular cargo. However, many challenges with state-of-the-art EV-based candidates as drug carriers still exist, including issues with scalability, batch-to-batch reproducibility, and cost-sustainability of the final therapeutic formulation. Microalgal extracellular vesicles, which we named nanoalgosomes, are naturally released by various microalgal species. Here, we evaluate the innate biological properties of nanoalgosomes derived from cultures of the marine microalgae Tetraselmis chuii, using an optimized manufacturing protocol. Our investigation of nanoalgosome biocompatibility in preclinical models includes toxicological analyses, using the invertebrate model organism Caenorhabditis elegans, hematological and immunological evaluations ex vivo and in mice. We evaluate nanoalgosome cellular uptake mechanisms in C. elegans at cellular and subcellular levels, and study their biodistribution in mice with accurate space-time resolution. Further examination highlights the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization demonstrates that they are biocompatible and innate bioactive effectors with unique bone tropism. These findings suggest that nanoalgosomes have significant potential for future therapeutic applications.
Subject(s)
Anti-Inflammatory Agents , Antioxidants , Extracellular Vesicles , Microalgae , Extracellular Vesicles/metabolism , Animals , Microalgae/metabolism , Mice , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Caenorhabditis elegans/metabolism , Biocompatible Materials/chemistry , Chlorophyta/metabolism , Bone and Bones/metabolism , TropismABSTRACT
Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.
Subject(s)
Blood-Brain Barrier , Brain Neoplasms , Breast Neoplasms , Humans , Brain Neoplasms/secondary , Brain Neoplasms/metabolism , Female , Blood-Brain Barrier/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Animals , Cell Line, Tumor , Microglia/metabolism , Microglia/pathology , Tropism , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , MiceABSTRACT
Rationale: Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods: We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results: The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion: Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.
Subject(s)
Dendritic Cells , Nanoparticles , Nucleic Acids , Dendritic Cells/immunology , Dendritic Cells/drug effects , Animals , Nucleic Acids/administration & dosage , Mice , Nanoparticles/chemistry , Cyclodextrins/chemistry , Mice, Inbred C57BL , Humans , Cell Line, Tumor , Tropism , Tumor Microenvironment/drug effects , Lymph Nodes/immunology , Female , Neoplasms/therapy , Neoplasms/immunologyABSTRACT
OBJECTIVE: To understand lumbosacral transitional vertebra (LSTV)-associated degenerative pathologies and their correlation to low back pain and radicular pain. METHODS: Whole-spine magnetic resonance imaging was evaluated for disc degeneration using Pfirrmann grading, end plate changes using total end plate score (TEPS), and facet tropism in patients with low back pain and radicular pain, and their association with LSTV was analyzed. RESULTS: In group 1, LSTV was seen in 15% of patients with 83% of these patients having sacralization. Disc degeneration was seen in 58%, 51%, and 63% of patients at levels C, B, and A, respectively; patients with sacralization had significant degeneration at all 3 levels. Similarly, the total end plate score and facet tropism were significantly higher in patients with sacralization. Facet tropism was observed in 31%, 40%, and 35% of patients with no -LSTV, patients with sacralization, and patients with lumbarization, respectively. In group 2, LSTV was seen in 17% of patients with sacralization accounting for 82%. Disc degeneration was seen in 44%, 36%, and 54% patients at levels C, B, and A, respectively. No significant difference was observed in the mean total end plate score between groups. Facet tropism was identified in 89% and 81% of patients with sacralization and patients with lumbarization, respectively, compared with only 19% of patients with no LSTV. CONCLUSIONS: Patients with low back pain had a higher incidence of sacralization with corresponding disc degeneration, facet tropism ,and end plate changes. In patients with radicular pain, lumbarization was associated only with facet tropism. These findings may aid clinicians in prognostication and patient counseling.
Subject(s)
Intervertebral Disc Degeneration , Low Back Pain , Lumbar Vertebrae , Magnetic Resonance Imaging , Zygapophyseal Joint , Humans , Intervertebral Disc Degeneration/diagnostic imaging , Intervertebral Disc Degeneration/complications , Male , Female , Magnetic Resonance Imaging/methods , Middle Aged , Low Back Pain/etiology , Low Back Pain/diagnostic imaging , Cross-Sectional Studies , Adult , Lumbar Vertebrae/diagnostic imaging , Zygapophyseal Joint/diagnostic imaging , Aged , Tropism , Sacrum/diagnostic imagingABSTRACT
Root tips can sense moisture gradients and grow into environments with higher water potential. This process is called root hydrotropism. Here, we report three closely related receptor-like kinases (RLKs) that play critical roles in root hydrotropism: ALTERED ROOT HYDROTROPIC RESPONSE 1 (ARH1), FEI1, and FEI2. Overexpression of these RLKs strongly reduce root hydrotropism, but corresponding loss-of-function mutants exhibit an increased hydrotropic response in their roots. All these RLKs show polar localization at the plasma membrane regions in root tips. The biosynthesis of the cell wall, cutin, and wax (CCW) is significantly impaired in root tips of arh1-2 fei1-C fei2-C. A series of known CCW mutants also exhibit increased root hydrotropism and reduced osmotic tolerance, similar to the characteristics of the triple mutant. Our results demonstrat that the integrity of the cell wall, cutin, and root cap wax mediate a trade-off between root hydrotropism and osmotic tolerance.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Gravitropism/physiology , Plant Roots/metabolism , Tropism/physiology , Arabidopsis Proteins/metabolism , Water/metabolism , Cell Wall/metabolismABSTRACT
Roots exhibit hydrotropism in response to moisture gradients, with the hydrotropism-related gene Mizu-kussei1 (MIZ1) playing a role in regulating root hydrotropism in an oblique orientation. However, the mechanisms underlying MIZ1-regulated root hydrotropism are not well understood. In this study, we employed obliquely oriented experimental systems to investigate root hydrotropism in Arabidopsis. We found that the miz1 mutant displays reduced root hydrotropism but increased root gravitropism following hydrostimulation, as compared to wild-type plants. Conversely, overexpression of AtMIZ1 leads to enhanced root hydrotropism but decreased root gravitropism following hydrostimulation, as compared to wild-type plants. Using co-immunoprecipitation followed by mass spectrometry (IP-MS), we explored proteins that interact with AtMIZ1, and we identified PGMC1 co-immunoprecipitated with MIZ1 in vivo. Furthermore, the miz1 mutant exhibited higher expression of the PGMC1 gene and increased phosphoglucomutase (PGM) activity, while AtMIZ1 overexpressors resulted in lower expression of the PGMC1 gene, reduced amyloplast amount, and reduced PGM activity in comparison to wild-type roots. In addition, different Arabidopsis natural accessions having difference in their hydrotropic response demonstrated expression level of PGMC1 was negatively correlated with hydrotropic root curvature and AtMIZ1 expression. Our results provide valuable insights into the role of amyloplast in MIZ1-regulated root hydrotropism.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Water/metabolism , Tropism/genetics , Gravitropism/genetics , Plant Roots/metabolismABSTRACT
A significant association has been established between a newly emerging human parvovirus, cutavirus (CuV), and cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) and its precursor parapsoriasis en plaques (PP). CTCL is a heterogeneous group of skin malignancies of T cells, the cause of which remains unknown. This study aimed to determine the activity, spread, and cell tropism of the skin-persistent CuV. CuV DNA was detected in both skin biopsies (6/20, 30%) and peripheral blood mononuclear cells (PBMCs) (4/29, 13.8%) from 49 CTCL/MF or PP patients, while none from 33 patients with any other type of skin disease or healthy subjects harbored CuV DNA. CuV DNA persisted in the skin or PBMCs for up to 15 years, despite circulating CuV-specific IgG. Spliced CuV mRNA was expressed in skin, indicating viral activity. Also, both of two available stool samples contained encapsidated CuV genomes, suggesting that the patients excrete infectious virus into the environment. Finally, CuV was observed to target circulating and skin-resident CD4 + T cells and some skin keratinocytes and macrophages. This is especially intriguing as malignant T cells in CTCL develop from CD4 + T cells. Hence, CuV should be further investigated for the overall role it plays in the complex tumor microenvironment of CTCL/MF.
Subject(s)
Lymphoma, T-Cell, Cutaneous , Parapsoriasis , Skin Neoplasms , Humans , Leukocytes, Mononuclear , Prevalence , Lymphoma, T-Cell, Cutaneous/pathology , Skin/pathology , Parapsoriasis/genetics , Parapsoriasis/pathology , DNA , Biopsy , Lymphocytes/pathology , Tropism , Tumor MicroenvironmentABSTRACT
Today, adeno-associated virus (AAV)-based vectors are arguably the most promising in vivo gene delivery vehicles for durable therapeutic gene expression. Advances in molecular engineering, high-throughput screening platforms, and computational techniques have resulted in a toolbox of capsid variants with enhanced performance over parental serotypes. Despite their considerable promise and emerging clinical success, there are still obstacles hindering their broader use, including limited transduction capabilities, tissue/cell type-specific tropism and penetration into tissues through anatomical barriers, off-target tissue biodistribution, intracellular degradation, immune recognition, and a lack of translatability from preclinical models to clinical settings. Here, we first describe the transduction mechanisms of natural AAV serotypes and explore the current understanding of the systemic and cellular hurdles to efficient transduction. We then outline progress in developing designer AAV capsid variants, highlighting the seminal discoveries of variants which can transduce the central nervous system upon systemic administration, and, to a lesser extent, discuss the targeting of the peripheral nervous system, eye, ear, lung, liver, heart, and skeletal muscle, emphasizing their tissue and cell specificity and translational promise. In particular, we dive deeper into the molecular mechanisms behind their enhanced properties, with a focus on their engagement with host cell receptors previously inaccessible to natural AAV serotypes. Finally, we summarize the main findings of our review and discuss future directions.
Subject(s)
Capsid , Dependovirus , Capsid/metabolism , Dependovirus/metabolism , Serogroup , Tissue Distribution , Capsid Proteins/genetics , Capsid Proteins/metabolism , Tropism , Genetic Vectors/geneticsABSTRACT
Stem cell-based cancer treatment has garnered significant attention, yet its safety and efficacy remain incompletely understood. The nuclear factor-kappa B (NF-κB) pathway, a critical signaling mechanism involved in tumor growth, angiogenesis, and invasion, serves as an essential metric for evaluating the behavior of stem cells in tumor models. Herein, we report the development of a triple-channel imaging system capable of simultaneously monitoring the tropism of stem cells towards tumors, assessing tumor proliferation, and quantifying tumor NF-κB activity. In this system, we generated a CRISPR-Cas9 gene-edited human glioblastoma cell line, GE-U87-MG, which provided a reliable readout of the proliferation and NF-κB activity of tumors by EF1α-RFLuc- and NF-κB-GLuc-based bioluminescent imaging, respectively. Additionally, near infrared-II emitting Tat-PEG-AgAuSe quantum dots were developed for tracking of stem cell tropism towards tumor. In a representative case involving human mesenchymal stem cells (hMSCs), multichannel imaging revealed no discernible effect of hMSCs on the proliferation and NF-κB activity of GE-U87-MG tumors. Moreover, hMSCs engineered to overexpress the necrosis factor-related apoptosis-inducing ligand were able to inhibit NF-κB activity and growth of GE-U87-MG in vivo. Taken together, our imaging system represents a powerful and feasible approach to evaluating the safety and therapeutic efficacy of stem cells in tumor models.
Subject(s)
Glioblastoma , NF-kappa B , Humans , NF-kappa B/metabolism , Cell Line, Tumor , Stem Cells/metabolism , Apoptosis , Glioblastoma/diagnostic imaging , Glioblastoma/therapy , Glioblastoma/metabolism , Cell Proliferation , Optical Imaging , TropismABSTRACT
People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.
Subject(s)
HIV Infections , HIV-1 , Humans , Proviruses/genetics , HIV-1/genetics , Anti-Retroviral Agents/pharmacology , Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , CD4-Positive T-Lymphocytes , DNA, Viral/genetics , DNA, Viral/metabolism , Viral Load , TropismABSTRACT
Plants partly optimize their water recruitment from the growth medium by directing root growth toward a moisture source, a phenomenon termed hydrotropism. The default mechanism of downward growth, termed gravitropism, often functions to counteract hydrotropism when the water-potential gradient deviates from the gravity vector. This review addresses the identity of the root sites in which hydrotropism-regulating factors function to attenuate gravitropism and the interplay between these various factors. In this context, the function of hormones, including auxin, abscisic acid, and cytokinins, as well as secondary messengers, calcium ions, and reactive oxygen species in the conflict between these two opposing tropisms is discussed. We have assembled the available data on the effects of various chemicals and genetic backgrounds on both gravitropism and hydrotropism, to provide an up-to-date perspective on the interactions that dictate the orientation of root tip growth. We specify the relevant open questions for future research. Broadening our understanding of root mechanisms of water recruitment holds great potential for providing advanced approaches and technologies that can improve crop plant performance under less-than-optimal conditions, in light of predicted frequent and prolonged drought periods due to global climate change.
Subject(s)
Gravitropism , Plant Growth Regulators , Plant Roots , Water , Gravitropism/physiology , Plant Roots/physiology , Plant Roots/growth & development , Plant Growth Regulators/metabolism , Water/metabolism , Tropism/physiology , Indoleacetic Acids/metabolism , Abscisic Acid/metabolismABSTRACT
Until now, the World Health Organization registered over 771 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection worldwide, of which 6.97 million resulted in death. Virus-related cardiovascular events and pre-existing heart problems have been identified as major contributing factors to global infection-related morbidity and mortality, emphasizing the necessity for risk assessment and future prevention. In this review, we highlight cardiac manifestations that might arise from an infection with SARS-CoV-2 and provide an overview of known comorbidities that worsen the outcome. Additionally, we aim to summarize the therapeutic strategies proposed to reverse virus-associated myocardial damage, which will be further highlighted in this review, with an outlook to successful recovery and prevention.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , TropismABSTRACT
Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both host- and virus-induced mechanisms, and some of them are not completely understood. Alphavirus genomes contain cis-acting elements (RNA structures and dinucleotide composition) and encode protein activities that promote the translational and transcriptional resistance to type I IFN-induced antiviral effectors. Among them, IFIT1, ZAP and PKR have played a relevant role in alphavirus evolution, since they have promoted the emergence of multiple viral evasion mechanisms at the translational level. In this review, we will discuss how the adaptations of alphaviruses to vertebrate hosts likely involved the acquisition of new features in viral mRNAs and proteins to overcome the effect of type I IFN.
Subject(s)
Alphavirus , Interferon Type I , Animals , Alphavirus/physiology , Cell Line , Interferon Type I/genetics , Vertebrates , Tropism , Antiviral Agents/pharmacology , Virus ReplicationABSTRACT
Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.
Subject(s)
Herpes Simplex , Pregnancy Complications, Infectious , Pregnancy , Female , Infant, Newborn , Humans , Herpesvirus 2, Human/genetics , Mothers , Proteomics , Protein Kinases/genetics , Protein Kinases/metabolism , Viral Proteins/genetics , Mutation , Tropism , Infectious Disease Transmission, VerticalABSTRACT
Human metapneumovirus (HMPV), a member of the Pneumoviridae family, causes upper and lower respiratory tract infections in humans. In vitro studies with HMPV have mostly been performed in monolayers of undifferentiated epithelial cells. In vivo studies in cynomolgus macaques and cotton rats have shown that ciliated epithelial cells are the main target of HMPV infection, but these observations cannot be studied in monolayer systems. Here, we established an organoid-derived bronchial culture model that allows physiologically relevant studies on HMPV. Inoculation with multiple prototype HMPV viruses and recent clinical virus isolates led to differences in replication among HMPV isolates. Prolific HMPV replication in this model caused damage to the ciliary layer, including cilia loss at advanced stages post-infection. These cytopathic effects correlated with those observed in previous in vivo studies with cynomolgus macaques. The assessment of the innate immune responses in three donors upon HMPV and RSV inoculation highlighted the importance of incorporating multiple donors to account for donor-dependent variation. In conclusion, these data indicate that the organoid-derived bronchial cell culture model resembles in vivo findings and is therefore a suitable and robust model for future HMPV studies. IMPORTANCE: Human metapneumovirus (HMPV) is one of the leading causative agents of respiratory disease in humans, with no treatment or vaccine available yet. The use of primary epithelial cultures that recapitulate the tissue morphology and biochemistry of the human airways could aid in defining more relevant targets to prevent HMPV infection. For this purpose, this study established the first primary organoid-derived bronchial culture model suitable for a broad range of HMPV isolates. These bronchial cultures were assessed for HMPV replication, cellular tropism, cytopathology, and innate immune responses, where the observations were linked to previous in vivo studies with HMPV. This study exposed an important gap in the HMPV field since extensively cell-passaged prototype HMPV B viruses did not replicate in the bronchial cultures, underpinning the need to use recently isolated viruses with a controlled passage history. These results were reproducible in three different donors, supporting this model to be suitable to study HMPV infection.
Subject(s)
Metapneumovirus , Paramyxoviridae Infections , Humans , Animals , Metapneumovirus/physiology , Cytology , Virus Replication , Paramyxoviridae Infections/pathology , Epithelium , Macaca , TropismABSTRACT
A wide range of animal species show variable susceptibility to SARS-CoV-2; however, host factors associated with varied susceptibility remain to be defined. Here, we examined whether susceptibility to SARS-CoV-2 and virus tropism in different animal species are dependent on the expression and distribution of the virus receptor angiotensin-converting enzyme 2 (ACE2) and the host cell factor transmembrane serine protease 2 (TMPRSS2). We cataloged the upper and lower respiratory tract of multiple animal species and humans in a tissue-specific manner and quantitatively evaluated the distribution and abundance of ACE2 and TMPRSS2 mRNA in situ. Our results show that: (i) ACE2 and TMPRSS2 mRNA are abundant in the conduction portion of the respiratory tract, (ii) ACE2 mRNA occurs at a lower abundance compared to TMPRSS2 mRNA, (iii) co-expression of ACE2-TMPRSS2 mRNAs is highest in those species with the highest susceptibility to SARS-CoV-2 infection (i.e., cats, Syrian hamsters, and white-tailed deer), and (iv) expression of ACE2 and TMPRSS2 mRNA was not altered following SARS-CoV-2 infection. Our results demonstrate that while specific regions of the respiratory tract are enriched in ACE2 and TMPRSS2 mRNAs in different animal species, this is only a partial determinant of susceptibility to SARS-CoV-2 infection.IMPORTANCESARS-CoV-2 infects a wide array of domestic and wild animals, raising concerns regarding its evolutionary dynamics in animals and potential for spillback transmission of emerging variants to humans. Hence, SARS-CoV-2 infection in animals has significant public health relevance. Host factors determining animal susceptibility to SARS-CoV-2 are vastly unknown, and their characterization is critical to further understand susceptibility and viral dynamics in animal populations and anticipate potential spillback transmission. Here, we quantitatively assessed the distribution and abundance of the two most important host factors, angiotensin-converting enzyme 2 and transmembrane serine protease 2, in the respiratory tract of various animal species and humans. Our results demonstrate that while specific regions of the respiratory tract are enriched in these two host factors, they are only partial determinants of susceptibility. Detailed analysis of additional host factors is critical for our understanding of the underlying mechanisms governing viral susceptibility and reservoir hosts.
Subject(s)
COVID-19 , Deer , Humans , Animals , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Respiratory System , RNA, Messenger , Tropism , Serine EndopeptidasesABSTRACT
Background: As the overwhelming majority of advanced mRNA delivery systems are preferentially accumulated in the liver, there is an accelerating growth in the demand for the development of non-liver mRNA delivery platforms. Methods: In this study, we prepared cationic lipid-like nanoassemblies through a N-quaternizing strategy. Their physicochemical properties, in vitro mRNA delivery efficiency, and organ tropism in mice were investigated. Results: Introduction of quaternary ammonium groups onto lipid-like nanoassemblies not only enhances their mRNA delivery performance in vitro, but also completely alters their tropism from the spleen to the lung after intravenous administration in mice. Quaternized lipid-like nanoassemblies exhibit ultra-high specificity to the lung and are predominantly taken up by pulmonary immune cells, leading to over 95% of exogenous mRNA translation in the lungs. Such mRNA delivery carriers are stable even after more than one-year storage at ambient temperature. Conclusions: Quaternization provides an alternative method for design of new lung-targeted mRNA delivery systems without incorporation of targeting ligands, which should extend the therapeutic applicability of mRNA to lung diseases.
Subject(s)
Nanoparticles , Spleen , Animals , Mice , RNA, Messenger/genetics , Lung , Tropism , Lipids , Nanoparticles/chemistryABSTRACT
The effects of SARS-CoV-2 in COVID-19 on the nervous system are incompletely understood. SARS-CoV-2 can infect endothelial cells, neurons, astrocytes, and oligodendrocytes with consequences for the host. There are indications that infection of these CNS-resident cells may result in long-term effects, including emergence of neurodegenerative diseases. Indirect effects of infection with SARS-CoV-2 relate to the induction of autoimmune disease involving molecular mimicry or/and bystander activation of T- and B cells and emergence of autoantibodies against various self-antigens. Data obtained in preclinical models of coronavirus-induced disease gives important clues for the understanding of nervous system-related assault of SARS-CoV-2. The pathophysiology of long-COVID syndrome and post-COVID syndrome in which autoimmunity and immune dysregulation might be the driving forces are still incompletely understood. A better understanding of nervous-system-related immunity in COVID-19 might support the development of therapeutic approaches. In this review, the current understanding of SARS-CoV-2 tropism for the nervous system, the associated immune responses, and diseases are summarized. The data indicates that there is viral tropism of SARS-CoV-2 in the nervous system resulting in various disease conditions. Prevention of SARS-CoV-2 infection by means of vaccination is currently the best strategy for the prevention of subsequent tissue damage involving the nervous system.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Autoimmunity , Post-Acute COVID-19 Syndrome , Endothelial Cells , Nervous System , TropismABSTRACT
Plant organs adapt their morphology according to environmental signals through growth-driven processes called tropisms. While much effort has been directed towards the development of mathematical models describing the tropic dynamics of aerial organs, these cannot provide a good description of roots due to intrinsic physiological differences. Here we present a mathematical model informed by gravitropic experiments on Arabidopsis thaliana roots, assuming a subapical growth profile and apical sensing. The model quantitatively recovers the full spatio-temporal dynamics observed in experiments. An analytical solution of the model enables us to evaluate the gravitropic and proprioceptive sensitivities of roots, while also allowing us to corroborate the requirement for proprioception in describing root dynamics. Lastly, we find that the dynamics are analogous to a damped harmonic oscillator, providing intuition regarding the source of the observed oscillatory behavior and the importance of proprioception for efficient gravitropic control. In all, the model provides not only a quantitative description of root tropic dynamics, but also a mathematical framework for the future investigation of roots in complex media.
Subject(s)
Arabidopsis , Gravitropism , Gravitropism/physiology , Plant Roots , Arabidopsis/physiology , TropismABSTRACT
BACKGROUND CONTEXT: Facet joint osteoarthritis (FJOA) is associated with lumbar disc degeneration and has a significant role in the development of lumbar spinal stenosis (LSS). The relationship between various radiographic parameters and the grade of FJOA is not well understood. PURPOSE: To explore radiographical parameters associated with FJOA in LSS without lumbar dynamic instability. STUDY DESIGN: Retrospective study analysis. PATIENT SAMPLE: A total of 122 patients diagnosed with LSS who visited our hospital between January 2015 and July 2022. OUTCOME MEASURES: We evaluated radiographic parameters of patients at L4-5 including lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), grades of FJOA, facet joint orientation (FO), facet joint tropism (FT), intervertebral height index (IHI) and the relative cross-sectional area (RCSA) of paraspinal muscles. METHODS: Patients diagnosed with LSS between January 2015 and July 2022 were enrolled. Demographic characteristics and radiographic parameters were collected. Spinopelvic parameters were measured through the preoperative lateral image of the whole spine, including LL, PI, pelvic tilt, and sacral slope. Lumbar computed tomography scan and magnetic resonance imaging were collected to measure the FO, FT, IHI, and the RCSA of paraspinal muscles respectively. Patients were divided into three groups according to the severity of FJOA graded by the Weishaupt classification: grade 0 and grade 1 were group A, grade 2 were group B, and grade 3 were group C. All variables were compared among the three groups, while the relationship between parameters and grades of FJOA were also analyzed. RESULTS: A total of 122 patients were included. PI was significantly greater in group C compared to group A (p = 0.025) and group B (p=0.022). FT was significantly greater in group C compared to group A (p<.001) and group B (p<.001). The RCSA of multifidus in group A were significantly greater than that in group B (p=0.02) and C (p=0.002). Additionally, FO in group C were significantly lower than group A (p<.001) and group B (p=0.028). The IHI in group C was significantly lower than group A (p=0.017). The correlation analysis indicated that grades of FJOA was positively related to Age, BMI (body mass index), PI, LL and FT, while negatively related to IHI, FO, RCSA of multifidus and RCSA of psoas major. Furthermore, the logistics regression showed that FT, PI, and IHI were important influence factors for FJOA. CONCLUSIONS: The current study confirmed that FT, PI and IHI were significantly associated with grades of FJOA at L4-5. Additionally, longitudinal studies are needed to understand the causal relationship between these parameters and FJOA.