scholarly journals Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins

2019 ◽  
Author(s):  
Murilo Sena Amaral ◽  
Ernesto Goulart ◽  
Luiz Carlos Caires-Júnior ◽  
David Abraham Morales-Vicente ◽  
Alessandra Soares-Schanoski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Genetic Background ◽  
Zikv Infection ◽  
Dizygotic Twins ◽  
Susceptibility Factors ◽  
Congenital Zika Syndrome ◽  
Host Genetic ◽  
Discordant Twins

AbstractZika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ∼1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers’ infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses’ tissues.Author summaryThe Zika virus (ZIKV) infection in adults is usually characterized by mild flu-like symptoms, with most cases remaining asymptomatic. However, in the last years, widespread ZIKV infection was shown for the first time to be associated with congenital Zika syndrome (CZS) and death of neonates. CZS is a very debilitating condition that includes microcephaly and mental retardation, leading to a strong social and health impact. This dramatic condition calls for a careful evaluation of the molecular mechanisms involved in ZIKV infection in the maternal-fetal interface. It is estimated that CZS occurs in ∼1-40% of cases of pregnant women infected by ZIKV, which suggests that different susceptibility factors might be involved, including the host genetic background. By analyzing trophoblast cells that recapitulate the placenta from three pairs of dizygotic twins discordant for CZS, we were able to show that trophoblasts from CZS-affected twins were significantly more susceptible to ZIKV infection when compared with trophoblasts from the non-affected twins. We also provide a detailed picture of genes differentially expressed by trophoblasts from the discordant twins after infection with ZIKV. These genes can be further investigated as possible therapeutic targets to avoid viral dissemination into developing fetus’ tissues.

scholarly journals Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins

2020 ◽  
Vol 14 (8) ◽  
pp. e0008424
Author(s):  
Murilo Sena Amaral ◽  
Ernesto Goulart ◽  
Luiz Carlos Caires-Júnior ◽  
David Abraham Morales-Vicente ◽  
Alessandra Soares-Schanoski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Gene Expression ◽  
Zikv Infection ◽  
Congenital Zika Syndrome ◽  
Differential Gene ◽  
Discordant Twins

scholarly journals Differential immune response modulation in early Leishmania amazonensis infection of BALB/c and C57BL/6 macrophages based on transcriptome profiles

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Juliana Ide Aoki ◽  
Sandra Marcia Muxel ◽  
Ricardo Andrade Zampieri ◽  
Karl Erik Müller ◽  
Audun Helge Nerland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Genetic Background ◽  
Expression Patterns ◽  
Peritoneal Macrophages ◽  
Leishmania Amazonensis ◽  
Response Modulation ◽  
Host Genetic ◽  
Resistance To Infection ◽  
Susceptibility And Resistance

AbstractThe fate of Leishmania infection can be strongly influenced by the host genetic background. In this work, we describe gene expression modulation of the immune system based on dual global transcriptome profiles of bone marrow-derived macrophages (BMDMs) from BALB/c and C57BL/6 mice infected with Leishmania amazonensis. A total of 12,641 host transcripts were identified according to the alignment to the Mus musculus genome. Differentially expressed genes (DEGs) profiling revealed a differential modulation of the basal genetic background between the two hosts independent of L. amazonensis infection. In addition, in response to early L. amazonensis infection, 10 genes were modulated in infected BALB/c vs. non-infected BALB/c macrophages; and 127 genes were modulated in infected C57BL/6 vs. non-infected C57BL/6 macrophages. These modulated genes appeared to be related to the main immune response processes, such as recognition, antigen presentation, costimulation and proliferation. The distinct gene expression was correlated with the susceptibility and resistance to infection of each host. Furthermore, upon comparing the DEGs in BMDMs vs. peritoneal macrophages, we observed no differences in the gene expression patterns of Jun, Fcgr1 and Il1b, suggesting a similar activation trends of transcription factor binding, recognition and phagocytosis, as well as the proinflammatory cytokine production in response to early L. amazonensis infection. Analysis of the DEG profile of the parasite revealed only one DEG among the 8,282 transcripts, indicating that parasite gene expression in early infection does not depend on the host genetic background.

scholarly journals Therapeutic Effect of Camel Milk and Its Exosomes on MCF7 Cells In Vitro and In Vivo

2018 ◽  
Vol 17 (4) ◽  
pp. 1235-1246 ◽  
Author(s):  
Abdelnaser A. Badawy ◽  
Mohammed A. El-Magd ◽  
Sana A. AlSadrah
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Immune Response ◽  
Local Injection ◽  
Camel Milk ◽  
Anticancer Effect ◽  
Mcf7 Cells ◽  
Beneficial Effects

Background/Objectives: In the Middle East, people consume camel milk regularly as it is believed to improve immunity against diseases and decrease the risk for cancer. Recently, it was noted that most of the beneficial effects of milk come from their nanoparticles, especially exosomes. Herein, we evaluated the anticancer potential of camel milk and its exosomes on MCF7 breast cancer cells (in vitro and in vivo) and investigated the possible underlying molecular mechanism of action. Methods/Results: Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFκB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD+4, CD+8, NK1.1 T cells in spleen). Conclusions: Overall, administration of camel milk–derived exosomes showed better anticancer effect, but less immune response, than treatment by camel milk. Moreover, local injection of exosomes led to better improvement than oral administration. These findings suggest that camel milk and its exosomes have anticancer effect possibly through induction of apoptosis and inhibition of oxidative stress, inflammation, angiogenesis and metastasis in the tumor microenvironment. Thus, camel milk and its exosomes could be used as an anticancer agent for cancer treatment.

scholarly journals Congenital Zika syndrome is associated with maternal protein malnutrition

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw6284 ◽  
Author(s):  
J. Barbeito-Andrés ◽  
P. Pezzuto ◽  
L. M. Higa ◽  
A. A. Dias ◽  
J. M. Vasconcelos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Size ◽  
Epidemiological Data ◽  
Protein Malnutrition ◽  
Rna Seq ◽  
Zikv Infection ◽  
Postnatal Brain ◽  
Low Protein ◽  
Congenital Zika Syndrome ◽  
Pregnant Mice

Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS.

scholarly journals Early Life Disruption of the Microbiota Affects Organ Development and Cytokine Gene Expression in Threespine Stickleback

2020 ◽  
Author(s):  
Lucas J Kirschman ◽  
Anastasia Khadjinova ◽  
Kelly Ireland ◽  
Kathryn C Milligan-Myhre
Keyword(s):  
Gene Expression ◽  
Early Life ◽  
Genetic Background ◽  
Gasterosteus Aculeatus ◽  
Threespine Stickleback ◽  
Microbial Colonization ◽  
Cytokine Gene Expression ◽  
Immune Gene ◽  
Cytokine Gene

Synopsis The microbiota that inhabits vertebrates exerts strong effects on host physiology and can be crucial to the development of a normal phenotype. This includes development of the immune system, somatic growth and maintenance, and morphogenesis. However, the genetic background of the host can also affect these life history traits. To this end, we investigated the effects of the microbiota on growth, development, and immune gene expression on two populations of threespine stickleback (Gasterosteus aculeatus), one anadromous and one freshwater. We tested the hypotheses that microbial colonization and the genetic background of the host would affect survival, cytokine gene expression, growth, and development. We raised in vitro crosses of stickleback larvae with and without conventional microbiota. We then exposed all these treatments to Vibrio anguillarum, a potential fish pathogen, in a full factorial design. We found stickleback raised without conventional microbiota had smaller swim bladders relative to those raised with conventional microbiota. Stickleback raised with conventional microbiota exhibited small increases in cytokine gene expression. We found no differences in growth or survival regardless of treatment. These results are consistent with other investigations that show microbiota disruption, in early life, can alter host organ and tissue development and immune responses

Effect of IFN-γ on the immune response in vivo and on gene expression in vitro

Nature ◽  
1984 ◽  
Vol 307 (5949) ◽  
pp. 381-382 ◽  
Author(s):  
Masataka Nakamura ◽  
Tim Manser ◽  
Gregory D. N. Pearson ◽  
Michael J. Daley ◽  
Malcolm L. Gefter
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Ifn Γ

scholarly journals Prodigiosin Modulates the Immune Response and Could Promote a Stable Atherosclerotic Lession in C57bl/6 Ldlr-/- Mice

2020 ◽  
Vol 21 (17) ◽  
pp. 6417 ◽  
Author(s):  
Alejandro Cuevas ◽  
Nicolás Saavedra ◽  
Luis A. Salazar ◽  
Marcela F. Cavalcante ◽  
Jacqueline C. Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Atherosclerotic Plaque ◽  
Therapeutic Potential ◽  
Inflammatory Marker ◽  
Interleukin 2 ◽  
Atheromatous Plaque ◽  
In Vitro Tests ◽  
Significant Difference

Atherosclerosis is a chronic inflammatory disease, whose progression and stability are modulated, among other factors, by an innate and adaptive immune response. Prodiginines are bacterial secondary metabolites with antiproliferative and immunomodulatory activities; however, their effect on the progression or vulnerability of atheromatous plaque has not been evaluated. This study assessed the therapeutic potential of prodigiosin and undecylprodigiosin on inflammatory marker expression and atherosclerosis. An in vitro and in vivo study was carried out. Migration, low-density lipoprotein (LDL) uptake and angiogenesis assays were performed on cell types involved in the pathophysiology of atherosclerosis. In addition, male LDL receptor null (Ldlr-/-) C57BL/6J mice were treated with prodigiosin or undecylprodigiosin for 28 days. Morphometric analysis of atherosclerotic plaques, gene expression of atherogenic factors in the aortic sinus and serum cytokine quantification were performed. The treatments applied had slight effects on the in vitro tests performed, highlighting the inhibitory effect on the migration of SMCs (smooth muscle cells). On the other hand, although no significant difference in atherosclerotic plaque progression was observed, gene expression of IL-4 and chemokine (C-C motif) ligand 2 (Ccl2) was downregulated. In addition, 50 µg/Kg/day of both treatments was sufficient to inhibit circulating tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in serum. These results suggested that prodigiosin and undecylprodigiosin modulated inflammatory markers and could have an impact in reducing atherosclerotic plaque vulnerability.

scholarly journals Dual transcriptome analysis reveals differential gene expression modulation influenced by Leishmania arginase and host genetic background

2020 ◽  
Vol 6 (9) ◽  
Author(s):  
Juliana Ide Aoki ◽  
Sandra Marcia Muxel ◽  
Maria Fernanda Laranjeira-Silva ◽  
Ricardo Andrade Zampieri ◽  
Karl Erik Müller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Immune Response ◽  
Amino Acid ◽  
Amino Acid Transport ◽  
Genetic Background ◽  
Arginase Activity ◽  
Acid Transport ◽  
Arginine Metabolism ◽  
Expression Modulation

The outcome of Leishmania infection is strongly influenced by the host’s genetic background. BALB/c mice are susceptible to Leishmania infection, while C57BL/6 mice show discrete resistance. Central to the fate of the infection is the availability of l-arginine and the related metabolic processes in the host and parasite. Depending on l-arginine availability, nitric oxide synthase 2 (NOS2) of the host cell produces nitric oxide (NO) controlling the parasite growth. On the other hand, Leishmania can also use host l-arginine for the production of polyamines through its own arginase activity, thus favouring parasite replication. Considering RNA-seq data, we analysed the dual modulation of host and parasite gene expression of BALB/c or C57BL/6 mouse bone marrow-derived macrophages (BMDMs) after 4 h of infection with Leishmania amazonensis wild-type (La-WT) or L. amazonensis arginase knockout (La-arg-). We identified 12 641 host transcripts and 8282 parasite transcripts by alignment analysis with the respective Mus musculus and L. mexicana genomes. The comparison of BALB/c_La-arg- versus BALB/c_La-WT revealed 233 modulated transcripts, with most related to the immune response and some related to the amino acid transporters and l-arginine metabolism. In contrast, the comparison of C57BL/6_La-arg- vs. C57BL/6_La-WT revealed only 30 modulated transcripts, including some related to the immune response but none related to amino acid transport or l-arginine metabolism. The transcriptome profiles of the intracellular amastigote revealed 94 modulated transcripts in the comparison of La-arg-_BALB/c vs. La-WT_BALB/c and 45 modulated transcripts in the comparison of La-arg-_C57BL/6 vs. La-WT_C57BL/6. Taken together, our data present new insights into the impact of parasite arginase activity on the orchestration of the host gene expression modulation, including in the immune response and amino acid transport and metabolism, mainly in susceptible BALB/c-infected macrophages. Moreover, we show how parasite arginase activity affects parasite gene expression modulation, including amino acid uptake and amastin expression.

P3113Functional deficiency in activating fcgamma receptor protects against aortic abdominal aneurysm in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Lopez-Sanz ◽  
S Bernal ◽  
L Jimenez-Castilla ◽  
A Melgar ◽  
J Egido ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Therapeutic Option ◽  
Gamma Chain ◽  
Abdominal Aneurysm ◽  
Fcgamma Receptor ◽  
Cytokines And Chemokines ◽  
Inflammatory Processes ◽  
Degenerative Disorder

Abstract Background and aim Abdominal aortic aneurysm (AAA) is a degenerative disorder characterized by a localized and permanent dilation of the aorta. Pathological features of AAA include proteolysis, vascular smooth muscle cells (VSMC) apoptosis, oxidative stress and inflammation. Previous studies have demonstrated the role of innate and adaptive immunity in the initiation and progression of AAA. However, the specific mechanisms of humoral, antibody-mediated, immune response elicited by self and non-self-antigens are not completely known. IgG Fc receptors (FcgammaR) play an important role in the initiation and regulation of many immunological and inflammatory processes, thus providing a link between humoral and cellular immune responses. In this work, we focus on IgG immune response against antigens exposed in the damaged vessel, analysing the specific role played by FcgammaR in the pathogenesis of AAA. Methods and results AAA was induced by aortic elastase perfusion in wild-type (WT) C57BL/6 mice (n=24 males, 12 weeks old). Compared with healthy aortas, AAA tissue showed IgG and IgM deposition and increased expression levels of activating (IA, IIIA and IVA) and inhibitory (IIB) FcgammaR (5-, 3-, 10, and 2-fold increases; p<0.005) at day 14 post-elastase perfusion. To explore the functional contribution of activating FcgammaR to AAA formation, parallel experiments were performed in mice deficient in gamma-chain (gamma-KO), the common signalling subunit of FcgammaRI, III and IV. Compared with WT mice, gamma-KO mice (n=21) exhibited lower IgG and IgM deposits (21±4% and 28±12% vs WT, respectively; p<0.02) and decreased AAA lesions with reduced aortic expansion (% vs WT: aortic wall thickness, 67±3%; aortic diameter, 55±3%; p<0.0001). AAA lesions from gamma-KO mice showed less disruption of elastin layers (Verhoeff-van Gieson staining) and reduced loss of medial VSMC (α-actin immunofluorescence). Inflammatory markers such as leukocyte content (CD68+ macrophages, Ly6G+ neutrophils, CD45R+ B cells, and CD3+ T lymphocytes) and the gene expression of chemokines (MCP-1, RANTES), adhesion molecules (ICAM-1), cytokines (TNFα, IFNg, IL-10) and metalloproteinases (MMP9) were all significantly lower in AAA lesions from gamma-KO mice than those from WT mice. In vitro, cross-linking of FcgammaR with fibrinogen-containing immune complexes triggers the gene expression of proinflammatory cytokines and chemokines in both VSMC and bone marrow-derived macrophages. Conclusion Activating FcgammaR participate in AAA formation by promoting inflammatory cell recruitment, and cytokine and matrix-degrading protease expression. Therefore, modulation of FcgammaR-dependent responses could be a promising therapeutic option for the treatment of AAA. Acknowledgement/Funding MINECO/FEDER (SAF2015-63696-R), ISCIII (FIS/FEDER PI17/01495), Spanish Society of Arteriosclerosis, La Caixa (HR17-00247), Conchita Rabago Foundation

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