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1.
Cell Host Microbe ; 32(4): 606-622.e8, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38479396

ABSTRACT

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders and dysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections.


Subject(s)
Chikungunya Fever , Chikungunya virus , Animals , Humans , Chikungunya Fever/complications , Proteomics , Chikungunya virus/genetics , Cytokines/metabolism
2.
Brain Behav Immun ; 97: 260-274, 2021 10.
Article in English | MEDLINE | ID: mdl-34390806

ABSTRACT

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.


Subject(s)
Nervous System Diseases , Zika Virus Infection , Zika Virus , Animals , Female , Humans , Mice , Placenta , Pregnancy , Virus Replication , Zika Virus Infection/complications
3.
PLoS Negl Trop Dis ; 14(7): e0007656, 2020 07.
Article in English | MEDLINE | ID: mdl-32687542

ABSTRACT

Platelets drive endothelial cell activation in many diseases. However, if this occurs in Plasmodium vivax malaria is unclear. As platelets have been reported to be activated and to play a role in inflammatory response during malaria, we hypothesized that this would correlate with endothelial alterations during acute illness. We performed platelet flow cytometry of PAC-1 and P-selectin. We measured platelet markers (CXCL4, CD40L, P-selectin, Thrombopoietin, IL-11) and endothelial activation markers (ICAM-1, von Willebrand Factor and E-selectin) in plasma with a multiplex-based assay. The values of each mediator were used to generate heatmaps, K-means clustering and Principal Component analysis. In addition, we determined pair-wise Pearson's correlation coefficients to generate correlation networks. Platelet counts were reduced, and mean platelet volume increased in malaria patients. The activation of circulating platelets in flow cytometry did not differ between patients and controls. CD40L levels (Median [IQ]: 517 [406-651] vs. 1029 [732-1267] pg/mL, P = 0.0001) were significantly higher in patients, while P-selectin and CXCL4 showed a nonsignificant trend towards higher levels in patients. The network correlation approach demonstrated the correlation between markers of platelet and endothelial activation, and the heatmaps revealed a distinct pattern of activation in two subsets of P. vivax patients when compared to controls. Although absolute platelet activation was not strong in uncomplicated vivax malaria, markers of platelet activity and production were correlated with higher endothelial cell activation, especially in a specific subset of patients.


Subject(s)
Blood Platelets/cytology , Malaria, Vivax/blood , Adult , Blood Platelets/metabolism , CD40 Ligand/genetics , CD40 Ligand/metabolism , E-Selectin/genetics , E-Selectin/metabolism , Endothelial Cells/metabolism , Female , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-11/genetics , Interleukin-11/metabolism , Malaria, Vivax/genetics , Malaria, Vivax/metabolism , Male , P-Selectin/genetics , P-Selectin/metabolism , Platelet Activation , Platelet Count , Young Adult
5.
Drug Discov Today ; 23(11): 1833-1847, 2018 11.
Article in English | MEDLINE | ID: mdl-29935345

ABSTRACT

Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.


Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Molecular Targeted Therapy/methods , Zika Virus Infection/drug therapy , Zika Virus/drug effects , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Humans , Models, Biological , Molecular Structure
6.
Microbes Infect ; 20(11-12): 661-669, 2018 12.
Article in English | MEDLINE | ID: mdl-29501560

ABSTRACT

Zika virus (ZIKV) greatly impacted the international scientific and public health communities in the last two years due to its association with microcephaly and other neonatal alterations. This review will discuss lessons learned from viral pathogenesis, epidemiology and clinical findings observed during the ZIKV outbreak occurred between 2014 and 2016 in Brazil.


Subject(s)
Disease Outbreaks , Zika Virus Infection/epidemiology , Zika Virus Infection/virology , Zika Virus/pathogenicity , Brazil/epidemiology , Female , Humans , Microcephaly/epidemiology , Microcephaly/etiology , Microcephaly/virology , Placenta/virology , Pregnancy , Viral Tropism , Zika Virus/physiology , Zika Virus Infection/complications , Zika Virus Infection/transmission
7.
J Infect Dis ; 216(2): 172-181, 2017 07 15.
Article in English | MEDLINE | ID: mdl-28838147

ABSTRACT

Background: Zika virus (ZIKV) infections have been linked to different levels of clinical outcomes, ranging from mild rash and fever to severe neurological complications and congenital malformations. Methods: We investigated the clinical and immunological response, focusing on the immune mediators profile in 95 acute ZIKV-infected adult patients from Campinas, Brazil. These patients included 6 pregnant women who later delivered during the course of this study. Clinical observations were recorded during hospitalization. Levels of 45 immune mediators were quantified using multiplex microbead-based immunoassays. Results: Whereas 11.6% of patients had neurological complications, 88.4% displayed mild disease of rash and fever. Several immune mediators were specifically higher in ZIKV-infected patients, and levels of interleukin 10, interferon gamma-induced protein 10 (IP-10), and hepatocyte growth factor differentiated between patients with or without neurological complications. Interestingly, higher levels of interleukin 22, monocyte chemoattractant protein 1, TNF-α, and IP-10 were observed in ZIKV-infected pregnant women carrying fetuses with fetal growth-associated malformations. Notably, infants with congenital central nervous system deformities had significantly higher levels of interleukin 18 and IP-10 but lower levels of hepatocyte growth factor than those without such abnormalities born to ZIKV-infected mothers. Conclusions: This study identified several key markers for the control of ZIKV pathogenesis. This will allow a better understanding of the molecular mechanisms of ZIKV infection in patients.


Subject(s)
Cytokines/blood , Nervous System Malformations/epidemiology , Pregnancy Complications, Infectious/epidemiology , Zika Virus Infection/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Brazil/epidemiology , Child , Female , Fetal Growth Retardation/virology , Humans , Infant, Newborn , Male , Middle Aged , Nervous System Malformations/virology , Pregnancy , Pregnancy Complications, Infectious/virology , Pregnancy Outcome , Viral Load , Young Adult , Zika Virus , Zika Virus Infection/complications
8.
Article in English | MEDLINE | ID: mdl-26870701

ABSTRACT

MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, have been detected in a variety of organisms ranging from ancient unicellular eukaryotes to mammals. They have been associated with numerous molecular mechanisms involving developmental, physiological and pathological changes of cells and tissues. Despite the fact that miRNA-silencing mechanisms appear to be absent in some Apicomplexan species, an increasing number of studies have reported a role for miRNAs in host-parasite interactions. Host miRNA expression can change following parasite infection and the consequences can lead, for instance, to parasite clearance. In this context, the immune system signaling appears to have a crucial role.


Subject(s)
Cryptosporidium/immunology , Gene Expression Regulation/immunology , Host-Parasite Interactions/genetics , MicroRNAs/genetics , Plasmodium/immunology , Toxoplasma/immunology , Cryptosporidiosis/immunology , Cryptosporidiosis/microbiology , Gene Expression Regulation/genetics , Host-Parasite Interactions/immunology , Humans , Malaria/immunology , Malaria/microbiology , Signal Transduction/immunology , Toxoplasmosis/immunology , Toxoplasmosis/microbiology
9.
PLoS One ; 4(12): e8472, 2009 Dec 29.
Article in English | MEDLINE | ID: mdl-20041152

ABSTRACT

BACKGROUND: The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice. CONCLUSION/SIGNIFICANCE: These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.


Subject(s)
Gene Silencing , Hypertrophy, Left Ventricular/enzymology , Intracellular Signaling Peptides and Proteins/metabolism , Myogenic Regulatory Factors/genetics , Protein Serine-Threonine Kinases/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Signal Transduction , Animals , Cells, Cultured , DNA, Mitochondrial/genetics , Hemodynamics , Hypertrophy, Left Ventricular/physiopathology , MEF2 Transcription Factors , Mice , Myocardium/enzymology , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myogenic Regulatory Factors/metabolism , RNA, Small Interfering/metabolism , Rats , TOR Serine-Threonine Kinases , Ventricular Pressure/physiology
10.
FEBS Lett ; 583(18): 2975-81, 2009 Sep 17.
Article in English | MEDLINE | ID: mdl-19698715

ABSTRACT

Transient dephosphorylation of FAK at Tyr-397 is required for cell cycle withdrawal early on during myogenesis. Here, we show that upon serum starvation of C2C12 myoblasts, FAK is transiently dephosphorylated in parallel with SHP-2 activation and association with FAK. SHP-2 knockdown by RNA interference suppressed the transient upregulation of SHP-2 and dephosphorylation of FAK during myogenesis. Furthermore, depletion of SHP-2 retarded the cell cycle withdrawal and the differentiation of serum-starved myoblasts into myotubes. These data provide a mechanistic basis for the reduction in FAK activity in differentiating myoblasts, indicating that myogenesis is critically triggered by FAK/SHP-2 complex.


Subject(s)
Focal Adhesion Kinase 1/metabolism , Muscle Development , Protein Tyrosine Phosphatase, Non-Receptor Type 11/physiology , Signal Transduction , Animals , Cell Cycle , Cell Differentiation , Cells, Cultured , Mice , Muscle, Skeletal/cytology , Myoblasts/cytology , Phosphorylation , Up-Regulation
11.
Front Biosci (Elite Ed) ; 1(1): 189-99, 2009 06 01.
Article in English | MEDLINE | ID: mdl-19482636

ABSTRACT

Mechanical stress is a major triggering stimulus for the installation of cardiac hypertrophy as well as for the structural and functional deterioration occurring in the hypertrophy decompensation. The sensing of mechanical forces and their conversion into biochemical signals depend on the integrity of subcellular structures such as the costameres and Z-disks. Signaling molecules concentrated into these structures are thought to be activated by the stress-induced deformation of structural proteins. Evidence also indicates that Ca2+ may be involved in mediating the mechanical forces conversion into biochemical signals and biological responses. Ca2+ channels, transporters and activated proteins are concentrated at the junctions between the T-tubules and the sarcoplasmic reticulum which are in close proximity to the costameres and Z-disks. This provides a structural basis for the influence of mechanical forces on Ca2+ transport and on the events related to signaling molecules clustered in the costameres and the Z-disks. Emerging data reviewed here are providing insight into how Ca2+ and mechanical mediated signaling are coordinated to modulate the functional and trophic responses of cardiac myocytes to mechanical stress.


Subject(s)
Calcium/metabolism , Cardiomegaly/etiology , Mechanotransduction, Cellular/physiology , Myocytes, Cardiac/physiology , Stress, Mechanical , Costameres/metabolism , Humans , Myocytes, Cardiac/metabolism
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