Zika virus hijacks extracellular vesicle tetraspanin pathways for cell-to-cell transmission

ABSTRACTExtracellular vesicles (EVs) are membrane-encapsulated structures released by cells which carry signaling factors, proteins and microRNAs that mediate intercellular communication. Accumulating evidence supports an important role of EVs in the progression of neurological conditions and both the spread and pathogenesis of infectious diseases. It has recently been demonstrated that EVs from Hepatitis C virus (HCV) infected individuals and cells contained replicative-competent viral RNA that was capable of infecting hepatocytes. Being a member of the same viral family, it is likely the Zika virus also hijacks EV pathways to package viral components and secrete vesicles that are infectious and potentially less immunogenic. As EVs have been shown to cross blood-brain and placental barriers, it is possible that Zika virus could usurp normal EV biology to gain access to the brain or developing fetus. Here, we demonstrate that Zika virus infected cells secrete distinct EV sub-populations with specific viral protein profiles and infectious genomes. Zika virus infection resulted in the enhanced production of EVs with varying sizes and density compared to those released from non-infected cells. We also show that the EV enriched tetraspanin CD63 regulates the release of EVs, and Zika viral genomes and capsids following infection. Overall, these findings provide evidence for an alternative means of Zika virus transmission and demonstrate the role of EV biogenesis and trafficking proteins in the modulation of Zika infection.ImportanceZika virus is a re-emerging infectious disease that spread rapidly across the Caribbean and South America. Infection of pregnant women during the first trimester has been linked to microcephaly, a neurological condition where babies are born with smaller heads due to abnormal brain development. Babies born with microcephaly can develop convulsions and suffer disabilities as they age. Despite the significance of Zika virus, little is known about how the virus infects the fetus or causes disease. Extracellular vesicles (EVs) are membrane-encapsulated structures released by cells that are present in all biological fluids. EVs carry signaling factors, proteins and microRNAs that mediate intercellular communication. EVs have been shown to be a means by which some viruses can alter cellular environments and cross previously unpassable cellular barriers. Thus gaining a greater understanding of how Zika affects EV cargo may aid in the development of better diagnostics, targeted therapeutics and prophylactic treatments.

Download Full-text

Extracellular Vesicles in Pulmonary Fibrosis Models and Biological Fluids of Interstitial Lung Disease Patients: A Scoping Review

Life ◽

10.3390/life11121401 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1401

Author(s):

Miriana d’Alessandro ◽

Laura Bergantini ◽

Elena Bargagli ◽

Silvia Vidal

Keyword(s):

Pulmonary Fibrosis ◽

Extracellular Vesicles ◽

Scoping Review ◽

Intercellular Communication ◽

Lung Diseases ◽

Biological Fluids ◽

Interstitial Lung Diseases ◽

Chronic Obstructive ◽

Matrix Deposition

Introduction: Interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders characterized by the pathogenetic involvement of interstitium. Therefore, an elucidation of the etiology and pathogenesis as well as the identification of diagnostic and prognostic biomarkers of such diseases is more compelling than ever. It is of note that there is increasing evidence of the involvement of extracellular vesicles (EVs) in the pathogenesis of lung diseases including lung cancer, chronic obstructive pulmonary disease and pulmonary fibrosis. It has been speculated that EVs play a pivotal role as mediators of intercellular communication, as well as the highlighting of the role of EVs as co-operators in the development of lung diseases such as IPF. Methods: The present study aimed to carry out a systematic exploratory search of the literature (through the scoping review approach) to identify and systematize the main results of the pathogenetic role of EVs in pulmonary fibrosis models and biological fluids from ILD patients, including plasma, bronchoalveolar lavage (BAL) and sputum. Conclusion: Fibroblast-to-mesenchymal differentiation, collagen and extracellular matrix deposition are key mechanisms in the development and progression of IPF. EV-coupled miRNA are important modulators of biological processes in terms of intercellular communication as shown in pulmonary fibrosis models as well as biofluids. The helpfulness of EVs as diagnostic and theranostic markers is worth further investigation. The evolving potential of EVs to translate effective EV-based therapies into clinical practice is of growing interest, due to the urgent need for novel therapeutic strategies for IPF patients.

Download Full-text

Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy — Brazil, 2015

MMWR Morbidity and Mortality Weekly Report ◽

10.15585/mmwr.mm6509e2er ◽

2016 ◽

Vol 65 (9) ◽

Cited By ~ 4

Author(s):

Wanderson Kleber de Oliveira ◽

Juan Cortez-Escalante ◽

Wanessa Tenório Gonçalves Holanda De Oliveira ◽

Greice Madeleine Ikeda do Carmo ◽

Cláudio Maierovitch Pessanha Henriques ◽

...

Keyword(s):

Zika Virus ◽

Virus Transmission ◽

First Trimester ◽

First Trimester Of Pregnancy

Download Full-text

Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy — Brazil, 2015

MMWR Morbidity and Mortality Weekly Report ◽

10.15585/mmwr.mm6509e2 ◽

2016 ◽

Vol 65 (9) ◽

pp. 242-247 ◽

Cited By ~ 218

Author(s):

Wanderson Kleber de Oliveira ◽

Juan Cortez-Escalante ◽

Wanessa Tenório Gonçalves Holanda De Oliveira ◽

Greice Madeleine Ikeda do Carmo ◽

Cláudio Maierovitch Pessanha Henriques ◽

...

Keyword(s):

Zika Virus ◽

Virus Transmission ◽

First Trimester ◽

First Trimester Of Pregnancy

Download Full-text

Exosomic microRNAs as emerging key regulators of intercellular communication in the tumor microenvironment and beyond

microRNA Diagnostics and Therapeutics ◽

10.1515/micrnat-2016-0001 ◽

2016 ◽

Vol 2 (1) ◽

Author(s):

Mariam Murtadha ◽

Muller Fabbri

Keyword(s):

Tumor Microenvironment ◽

Cancer Patients ◽

Intercellular Communication ◽

Potential Role ◽

Biological Fluids ◽

Healthy Controls ◽

Gene Regulatory ◽

Non Coding Rnas ◽

Regulatory Functions

AbstractMicroRNAs (miRs) are small non-coding RNAs with key gene regulatory functions. Recent evidence has shown that miRs have a central role in shaping the biology of the Tumor Microenvironment (TME). The discovery that some exosomes contain high levels of miR cargo that shuttle between cells and mediate intercellular cross-talk has shifted the focus of miR research towards understanding the biological role of exosomic miRs. In this review, we highlight the emerging role of exosomic miRs in molding the tumor microenvironment towards pro-tumor conditions by altering intercellular communication. We briefly discuss some mechanisms of selective loading of miRs into exosomes, as well as emerging evidence that exosomic miRs are present in all biological fluids. Furthermore, we describe the differences in the exosomic miR signatures between cancer patients and healthy controls, and the potential role of exosomic miRs as diagnostic, prognostic, and therapeutic biomarkers.

Download Full-text

Extracellular vesicles, stem cells and the role of miRNAs in neurodegeneration

Current Neuropharmacology ◽

10.2174/1570159x19666210817150141 ◽

2021 ◽

Vol 19 ◽

Author(s):

Ayaz M. Belkozhayev ◽

Minnatallah Al-Yozbaki ◽

Alex George ◽

Raigul Ye Niyazova ◽

Kamalidin O. Sharipov ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Direct Consequence ◽

Therapeutic Benefit ◽

The Body ◽

A Cell ◽

Crucial Information

There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington’s disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.

Download Full-text

Emerging role of extracellular vesicles in the regulation of skeletal muscle adaptation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00914.2018 ◽

2019 ◽

Vol 127 (2) ◽

pp. 645-653 ◽

Cited By ~ 1

Author(s):

Ivan J. Vechetti

Keyword(s):

Skeletal Muscle ◽

Extracellular Vesicles ◽

Human Body ◽

Intercellular Communication ◽

Skeletal Muscle Mass ◽

Genetic Material ◽

Muscle Adaptation ◽

Pathological Conditions ◽

Isolation Methods

Extracellular vesicles (EVs) were initially characterized as “garbage bags” with the purpose of removing unwanted material from cells. It is now becoming clear that EVs mediate intercellular communication between distant cells through a transfer of genetic material, a process important to the systemic adaptation in physiological and pathological conditions. Although speculative, it has been suggested that the majority of EVs that make it into the bloodstream would be coming from skeletal muscle, since it is one of the largest organs in the human body. Although it is well established that skeletal muscle secretes peptides (currently known as myokines) into the bloodstream, the notion that skeletal muscle releases EVs is in its infancy. Besides intercellular communication and systemic adaptation, EV release could represent the mechanism by which muscle adapts to certain stimuli. This review summarizes the current understanding of EV biology and biogenesis and current isolation methods and briefly discusses the possible role EVs have in regulating skeletal muscle mass.

Download Full-text

Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition

International Journal of Molecular Sciences ◽

10.3390/ijms20194813 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4813 ◽

Cited By ~ 5

Author(s):

Sevindzh Kletukhina ◽

Olga Neustroeva ◽

Victoria James ◽

Albert Rizvanov ◽

Marina Gomzikova

Keyword(s):

Epithelial Cells ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Epithelial Mesenchymal Transition ◽

Genetic Material ◽

Biologically Active ◽

Target Cells ◽

Mesenchymal Transition ◽

New Evidence

Epithelial–mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.

Download Full-text

Extracellular Vesicles: A Possible Link between HIV and Alzheimer’s Disease-Like Pathology in HIV Subjects?

Cells ◽

10.3390/cells8090968 ◽

2019 ◽

Vol 8 (9) ◽

pp. 968 ◽

Cited By ~ 6

Author(s):

Sunitha Kodidela ◽

Kelli Gerth ◽

Sanjana Haque ◽

Yuqing Gong ◽

Saifudeen Ismael ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Extracellular Vesicles ◽

Treatment Strategies ◽

Progressive Dementia ◽

Hiv Patients ◽

Age Related ◽

Infected Cells ◽

New Treatment

The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer’s disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.

Download Full-text

Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks

Cancers ◽

10.3390/cancers12123696 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3696

Author(s):

Kevin Ho Wai Yim ◽

Ala’a Al Hrout ◽

Simone Borgoni ◽

Richard Chahwan

Keyword(s):

Communication Networks ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Potential Role ◽

Viral Infections ◽

Biological Effects ◽

Surface Markers ◽

Physiological Conditions ◽

Intercellular Communications

Extracellular vesicles (EVs) are emerging as potent and intricate intercellular communication networks. From their first discovery almost forty years ago, several studies have bolstered our understanding of these nano-vesicular structures. EV subpopulations are now characterized by differences in size, surface markers, cargo, and biological effects. Studies have highlighted the importance of EVs in biology and intercellular communication, particularly during immune and tumor interactions. These responses can be equally mediated at the proteomic and epigenomic levels through surface markers or nucleic acid cargo signaling, respectively. Following the exponential growth of EV studies in recent years, we herein synthesize new aspects of the emerging immune–tumor EV-based intercellular communications. We also discuss the potential role of EVs in fundamental immunological processes under physiological conditions, viral infections, and tumorigenic conditions. Finally, we provide insights on the future prospects of immune–tumor EVs and suggest potential avenues for the use of EVs in diagnostics and therapeutics.

Download Full-text

The biology, function, and biomedical applications of exosomes

Science ◽

10.1126/science.aau6977 ◽

2020 ◽

Vol 367 (6478) ◽

pp. eaau6977 ◽

Cited By ~ 297

Author(s):

Raghu Kalluri ◽

Valerie S. LeBleu

Keyword(s):

Amino Acids ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Biomedical Applications ◽

Molecular Mechanisms ◽

Biological Fluids ◽

Average Diameter ◽

Cell Of Origin ◽

Intracellular Vesicles ◽

Cellular Components

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

Download Full-text