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Frontiers in Cellular and Infection... 2020Orthohantaviruses are zoonotic viruses that are naturally maintained by persistent infection in specific reservoir species. Although these viruses mainly circulate among... (Review)
Review
Orthohantaviruses are zoonotic viruses that are naturally maintained by persistent infection in specific reservoir species. Although these viruses mainly circulate among rodents worldwide, spill-over infection to humans occurs. Orthohantavirus infection in humans can result in two distinct clinical outcomes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). While both syndromes develop following respiratory transmission and are associated with multi-organ failure and high mortality rates, little is known about the mechanisms that result in these distinct clinical outcomes. Therefore, it is important to identify which cell types and tissues play a role in the differential development of pathogenesis in humans. Here, we review current knowledge on cell tropism and its role in pathogenesis during orthohantavirus infection in humans and reservoir rodents. Orthohantaviruses predominantly infect microvascular endothelial cells (ECs) of a variety of organs (lungs, heart, kidney, liver, and spleen) in humans. However, in this review we demonstrate that other cell types (e.g., macrophages, dendritic cells, and tubular epithelium) are infected as well and may play a role in the early steps in pathogenesis. A key driver for pathogenesis is increased vascular permeability, which can be direct effect of viral infection in ECs or result of an imbalanced immune response in an attempt to clear the virus. Future studies should focus on the role of identifying how infection of organ-specific endothelial cells as well as other cell types contribute to pathogenesis.
Topics: Endothelial Cells; Orthohantavirus; Hantavirus Infections; Hemorrhagic Fever with Renal Syndrome; Humans; Tropism
PubMed: 32903721
DOI: 10.3389/fcimb.2020.00399 -
Nature Communications Jun 2023Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We...
Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits.
Topics: Mice; Rats; Animals; Endothelial Cells; Rodentia; Macaca mulatta; Brain; Tropism; Mice, Knockout; Dependovirus; Genetic Vectors; Transduction, Genetic; Calcium-Binding Proteins; Extracellular Matrix Proteins
PubMed: 37291094
DOI: 10.1038/s41467-023-38582-7 -
Viruses May 2022The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in... (Review)
Review
The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.
Topics: COVID-19; Cardiovascular System; Disease Progression; Humans; Pandemics; SARS-CoV-2; Tropism
PubMed: 35746609
DOI: 10.3390/v14061137 -
JACC. Heart Failure Aug 2021The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF).
BACKGROUND
Several randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined.
METHODS
This study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences.
RESULTS
Empagliflozin is associated with significant reductions in EAT volume (-5.14 mL; 95% CI: -8.36 to -1.92) compared with placebo (-0.75 mL; 95% CI: -3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (-5.33 cm [95% CI: -12.61 to 1.95] vs 9.13 cm [95% CI: -2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (-1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (-7.24 mL [95% CI: -11.59 to -2.91] vs 0.70 mL [95% CI: -0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (-11.08 mL [95% CI: -19.62 to -2.55] vs 0.80 mL [95% CI: -1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (-0.58 cm/s [95% CI: -0.92 to -0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers.
CONCLUSIONS
Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222).
Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Glucosides; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Tropism
PubMed: 34325888
DOI: 10.1016/j.jchf.2021.04.014 -
Annual Review of Immunology Apr 2022Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by... (Review)
Review
Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by arthritogenic and encephalitic alphaviruses results in distinct clinical manifestations, both virus groups induce robust innate and adaptive immune responses. However, differences in cellular tropism, type I interferon induction, immune cell recruitment, and B and T cell responses result in differential disease progression and outcome. In this review, we discuss aspects of immune responses that contribute to protective or pathogenic outcomes after alphavirus infection.
Topics: Alphavirus; Alphavirus Infections; Animals; Humans; Immunity; Interferon Type I; Tropism
PubMed: 35134315
DOI: 10.1146/annurev-immunol-101220-014952 -
Cold Spring Harbor Perspectives in... Oct 2020Bone is a frequent site of metastases in many cancers. Both bone properties and the tumor-intrinsic traits are associated with the metastatic propensity to bone (i.e.,... (Review)
Review
Bone is a frequent site of metastases in many cancers. Both bone properties and the tumor-intrinsic traits are associated with the metastatic propensity to bone (i.e., the bone tropism). Whereas an increasing body of mechanistic studies expanded our understanding on bone tropism, they also revealed complexity across the bone lesions originated from different cancer types. In this review, we will discuss the physical, chemical, and biological properties of bone microenvironment, identify potential players in every stage of bone metastases, and introduce some of the known mechanisms regulating the bone colonization. Our objectives are to integrate the knowledge established in different biological contexts and highlight the determinants of bone tropism.
Topics: Animals; Bone Neoplasms; Humans; Osteoclasts; Tropism; Tumor Microenvironment
PubMed: 31615871
DOI: 10.1101/cshperspect.a036848 -
Frontiers in Cellular and Infection... 2021Understanding why certain people get sick and die while others recover or never become ill is a fundamental question in biomedical research. A key determinant of this... (Review)
Review
Understanding why certain people get sick and die while others recover or never become ill is a fundamental question in biomedical research. A key determinant of this process is pathogen and disease tropism: the locations that become infected (pathogen tropism), and the locations that become damaged (disease tropism). Identifying the factors that regulate tropism is essential to understand disease processes, but also to drive the development of new interventions. This review intersects research from across infectious diseases to define the central mediators of disease and pathogen tropism. This review also highlights methods of study, and translational implications. Overall, tropism is a central but under-appreciated aspect of infection pathogenesis which should be at the forefront when considering the development of new methods of intervention.
Topics: Humans; Tropism; Viral Tropism
PubMed: 33718287
DOI: 10.3389/fcimb.2021.640987 -
Journal of Biomedical Science Mar 2014Enterovirus 71 (EV71) is a member of Picornaviridae that causes mild and self-limiting hand, foot, and mouth disease (HFMD). However, EV71 infections can progress to... (Review)
Review
Enterovirus 71 (EV71) is a member of Picornaviridae that causes mild and self-limiting hand, foot, and mouth disease (HFMD). However, EV71 infections can progress to polio-like paralysis, neurogenic pulmonary edema, and fatal encephalitis in infants and young children. Large EV71 outbreaks have been reported in Taiwan, China, Japan, Malaysia, Singapore, and Australia. This virus is considered a critical emerging public health threat. EV71 is an important crucial neurotropic enterovirus for which there is currently no effective antiviral drug or vaccine. The mechanism by which EV71 causes severe central nervous system complications remains unclear. The interaction between the virus and the host is vital for viral replication, virulence, and pathogenicity. SCARB2 or PSGL-1 receptor binding is the first step in the development of viral infections, and viral factors (e.g., 5' UTR, VP1, 3C, 3D, 3' UTR), host factors and environments (e.g., ITAFs, type I IFN) are also involved in viral infections. The tissue tropism and pathogenesis of viruses are determined by a combination of several factors. This review article provides a summary of host and virus factors affecting cell and tissue tropism and the pathogenesis of enteroviruses.
Topics: Disease Outbreaks; Enterovirus A, Human; Enterovirus Infections; Hand, Foot and Mouth Disease; Humans; Tropism; Virus Replication
PubMed: 24602216
DOI: 10.1186/1423-0127-21-18 -
PLoS Pathogens Jul 2022Enteroviruses (EVs) are among the most prevalent viruses worldwide. They are characterized by a high genetic and phenotypic diversity, being able to cause a plethora of...
Enteroviruses (EVs) are among the most prevalent viruses worldwide. They are characterized by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. They belong to the same species, but display distinct phenotypic characteristics and in vivo tropism. Here, we used these two viruses as well as relevant 3D respiratory, intestinal and neural tissue culture models, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting EV-D68 tissue tropism. Using transcriptomic analysis, we underscore fundamental differences between intestinal and respiratory tissues, both in the steady-state and in response to infection. Intestinal tissues present higher cell proliferation rate and are more immunotolerant than respiratory tissues. Importantly, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response of intestinal and respiratory tissues. EV-D68 strongly activates antiviral pathways while EV-D94, on the contrary, barely induces any host defense mechanisms. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues.
Topics: Antigens, Viral; Antiviral Agents; Enterovirus; Enterovirus D, Human; Enterovirus Infections; Humans; Respiratory Tract Infections; Tropism
PubMed: 35789345
DOI: 10.1371/journal.ppat.1010632 -
Viruses Dec 2021Cell surface receptors play a key role in a virus' ability to recognize and invade cells and tissues, which basically defines viral pathogenicity [...].
Cell surface receptors play a key role in a virus' ability to recognize and invade cells and tissues, which basically defines viral pathogenicity [...].
Topics: Antiviral Agents; COVID-19; Epithelial Cells; Humans; Receptors, Virus; SARS-CoV-2; Tropism; Vaccines; Viral Tropism
PubMed: 35062272
DOI: 10.3390/v14010068