scholarly journals Formal modeling of the key determinants of Hepatitis C Virus (HCV) induced adaptive immune response network: An integrative approach to map the cellular and cytokine-mediated host immune regulations

2018 ◽  
Author(s):  
Ayesha Obaid ◽  
Anam Naz ◽  
Shifa Tariq Ashraf ◽  
Faryal Mehwish Awan ◽  
Aqsa Ikram ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Immune System ◽  
Hepatitis C ◽  
Biological Data ◽  
Signaling Networks ◽  
Host Immune System ◽  
Adaptive Immune ◽  
Ifn Γ

Background. Hepatitis C Virus (HCV) is a major causative agent of liver infection leading to critical liver damage. In response to HCV, the improper regulation of host immune system leads to chronic infection. The host immune system employs multiple cell types, diverse variety of cytokine mediators and interacting signaling networks to neutralize the HCV infection. To understand the complexity of the interactions within the immune signaling networks, systems biology provides an efficient alternative approach. Integrating such approaches with immunology and virology helps to study highly complex immune regulatory networks within the host and presents a concise view of the whole system. Methods. Initially, a logic-based diagram is generated based on multiple reported interactions between immune cells and cytokines during host immune response to HCV. Furthermore, an abstracted sub-network is modeled qualitatively which consists of both the key cellular and cytokine components of the HCV induced immune system. Rene’ Thomas formalism is applied in the study to generate a qualitative model which requires only the qualitative thresholds and associated logical parameters generated via SMBioNet software in accordance with biological observations. Furthermore, the continuous dynamics of the model have been studied via Petri nets based analysis. Results. In the presence of NS5A protein of HCV, the behaviors of the Natural Killer (NK) and T regulatory (Tregs) cells along with cytokines such as IFN-γ, IL-10, IL-12 are predicted. The model also attempts to consider the viral strategies to circumvent immune response mediated by viral proteins. The state graph analysis enabled the prediction of paths leading to disease state. The most probable cycle is predicted based on maximum betweenness centrality. Furthermore, to study the continuous dynamics of the modeled network, a Petri net (PN) model was generated. The predictive ability of the model implicates the critical role of IL-12 over-expression in pathogenesis. This observation speculates that IL-12 has a dual role under varying circumstances and leads to varying disease outcomes. Conclusion. This model attempts to reduce the noisy biological data and captures a holistic view of the regulations amongst the key determinants of HCV induced adaptive immune responses. The observations warrant for further studies to elucidate the role of IL-12 under varying external and internal stimuli. Also, introducing diversion by therapeutic perturbation may divert the system from diseased paths to recovery by stabilizing the activation of IFN-γ producing NK cells. The modeling approach employed in this study can be extended to include real-time experimental data to propose new therapeutic interventions.

scholarly journals Formal modeling of the key determinants of Hepatitis C Virus (HCV) induced adaptive immune response network: An integrative approach to map the cellular and cytokine-mediated host immune regulations

2018 ◽  
Author(s):  
Ayesha Obaid ◽  
Anam Naz ◽  
Shifa Tariq Ashraf ◽  
Faryal Mehwish Awan ◽  
Aqsa Ikram ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Immune System ◽  
Hepatitis C ◽  
Biological Data ◽  
Signaling Networks ◽  
Host Immune System ◽  
Adaptive Immune ◽  
Ifn Γ

Background. Hepatitis C Virus (HCV) is a major causative agent of liver infection leading to critical liver damage. In response to HCV, the improper regulation of host immune system leads to chronic infection. The host immune system employs multiple cell types, diverse variety of cytokine mediators and interacting signaling networks to neutralize the HCV infection. To understand the complexity of the interactions within the immune signaling networks, systems biology provides an efficient alternative approach. Integrating such approaches with immunology and virology helps to study highly complex immune regulatory networks within the host and presents a concise view of the whole system. Methods. Initially, a logic-based diagram is generated based on multiple reported interactions between immune cells and cytokines during host immune response to HCV. Furthermore, an abstracted sub-network is modeled qualitatively which consists of both the key cellular and cytokine components of the HCV induced immune system. Rene’ Thomas formalism is applied in the study to generate a qualitative model which requires only the qualitative thresholds and associated logical parameters generated via SMBioNet software in accordance with biological observations. Furthermore, the continuous dynamics of the model have been studied via Petri nets based analysis. Results. In the presence of NS5A protein of HCV, the behaviors of the Natural Killer (NK) and T regulatory (Tregs) cells along with cytokines such as IFN-γ, IL-10, IL-12 are predicted. The model also attempts to consider the viral strategies to circumvent immune response mediated by viral proteins. The state graph analysis enabled the prediction of paths leading to disease state. The most probable cycle is predicted based on maximum betweenness centrality. Furthermore, to study the continuous dynamics of the modeled network, a Petri net (PN) model was generated. The predictive ability of the model implicates the critical role of IL-12 over-expression in pathogenesis. This observation speculates that IL-12 has a dual role under varying circumstances and leads to varying disease outcomes. Conclusion. This model attempts to reduce the noisy biological data and captures a holistic view of the regulations amongst the key determinants of HCV induced adaptive immune responses. The observations warrant for further studies to elucidate the role of IL-12 under varying external and internal stimuli. Also, introducing diversion by therapeutic perturbation may divert the system from diseased paths to recovery by stabilizing the activation of IFN-γ producing NK cells. The modeling approach employed in this study can be extended to include real-time experimental data to propose new therapeutic interventions.

scholarly journals Hepatitis C Virus E1 Protein Enhances Macrophage iNOS Expression In Vitro

2021 ◽  
Author(s):  
Batkhishig Munkhjargal ◽  
Bilguun Enkhtuvshin ◽  
Uranbileg Ulziisaikhan ◽  
Baljinnyam Tuvdenjamts ◽  
Khulan Unurbuyan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Response ◽  
Inos Expression ◽  
No Production ◽  
E1 Protein ◽  
Ifn Γ

AbstractObjectiveHepatitis C virus (HCV) is a single-stranded RNA virus that causes chronic hepatitis, cirrhosis, and liver cancer. Approximately 170 million individuals are infected with HCV worldwide. The pathogenesis of HCV-associated liver injury is thought to be due to the host antiviral immune response, including the T cell response, and excessive production of proinflammatory cytokines, reactive oxygen species, and nitric oxide (NO).Interferon-γ (IFN-γ) is a key cytokine in the adaptive immune response that is primarily secreted from CD4+ T helper cells to induce cytotoxic T lymphocyte (CTL) cell response against HCV infection. Another important role of IFN-γ is the activation of macrophages in the liver resulting in inhibition of viral replication and increased NO production.Enhanced inducible nitric oxide synthase (iNOS) expression and NO production observed in the liver of HCV-infected patients is positively correlated with viral load and hepatic inflammation. HCV-infected macrophages are major producers of NO in the liver. It is not completely understood how HCV proteins affect iNOS expression and what the role of IFN-γ is in HCV protein expression in HCV-infected macrophages. In this study, we examined the effect of INF-γ and HCV proteins on iNOS expression in the Raw264.7 cell line.ResultsConsistent with other studies, HCV core and NS5A proteins induced iNOS expression in macrophages. Moreover, HCV E1 protein-enhanced iNOS expression is highest in the presence and absence of IFN-γ activation.ConclusionThese results indicate that hepatitis C virus core, NS5A, E1 protein regulates iNOS protein expression in IFN-γ-activated and resting macrophage cell lines. These findings points to a future research direction for understanding the pathogenesis of HCV-related liver inflammation.

scholarly journals Adaptive Immune Response against Hepatitis C Virus

2020 ◽  
Vol 21 (16) ◽  
pp. 5644
Author(s):  
Janine Kemming ◽  
Robert Thimme ◽  
Christoph Neumann-Haefelin
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Persistent Infection ◽  
Adaptive Immune Response ◽  
Hcv Infection ◽  
Viral Escape ◽  
Continuous Exposure ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.

scholarly journals Control of Heterologous Hepatitis C Virus Infection in Chimpanzees Is Associated with the Quality of Vaccine-Induced Peripheral T-Helper Immune Response

2004 ◽  
Vol 78 (1) ◽  
pp. 187-196 ◽  
Author(s):  
C. Rollier ◽  
E. Depla ◽  
J. A. R. Drexhage ◽  
E. J. Verschoor ◽  
B. E. Verstrepen ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Interleukin 2 ◽  
Hcv Infection ◽  
T Helper ◽  
Vaccine Strategy ◽  
Ns3 Protein ◽  
Ifn Γ

ABSTRACT Prophylactic hepatitis C virus (HCV) vaccine trials with human volunteers are pending. There is an important need for immunological end points which correlate with vaccine efficacy and which do not involve invasive procedures, such as liver biopsies. By using a multicomponent DNA priming-protein boosting vaccine strategy, naïve chimpanzees were immunized against HCV structural proteins (core, E1, and E2) as well as a nonstructural (NS3) protein. Following immunization, exposure to the heterologous HCV 1b J4 subtype resulted in a peak of plasma viremia which was lower in both immunized animals. Compared to the naïve infection control and nine additional historical controls which became chronic, vaccinee 2 (Vac2) rapidly resolved the infection, while the other (Vac1) clearly controlled HCV infection. Immunization induced antibodies, peptide-specific gamma interferon (IFN-γ), protein-specific lymphoproliferative responses, IFN-γ, interleukin-2 (IL-2), and IL-4 T-helper responses in both vaccinees. However, the specificities were markedly different: Vac2 developed responses which were lower in magnitude than those of Vac1 but which were biased towards Th1-type cytokine responses for E1 and NS3. This proof-of-principle study in chimpanzees revealed that immunization with a combination of nonstructural and structural antigens elicited T-cell responses associated with an alteration of the course of infection. Our findings provide data to support the concept that the quality of the response to conserved epitopes and the specific nature of the peripheral T-helper immune response are likely pivotal factors influencing the control and clearance of HCV infection.

scholarly journals The Role of Micronutrients in the Infection and Subsequent Response to Hepatitis C Virus

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 603 ◽  
Author(s):  
Sunil Gupta ◽  
Scott A. Read ◽  
Nicholas A. Shackel ◽  
Lionel Hebbard ◽  
Jacob George ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Vitamin A ◽  
Innate Immune ◽  
Micronutrient Deficiencies ◽  
Strong Immune Response ◽  
Subsequent Response ◽  
Potent Immune Response

Micronutrient deficiencies develop for a variety of reasons, whether geographic, socioeconomic, nutritional, or as a result of disease pathologies such as chronic viral infection. As micronutrients are essential for a strong immune response, deficiencies can significantly dampen both the innate and the adaptive arms of antiviral immunity. The innate immune response in particular is crucial to protect against hepatitis C virus (HCV), a hepatotropic virus that maintains chronic infection in up to 80% of individuals if left untreated. While many micronutrients are required for HCV replication, an overlapping group of micronutrients are also necessary to enact a potent immune response. As the liver is responsible for the storage and metabolism of many micronutrients, HCV persistence can influence the micronutrients’ steady state to benefit viral persistence both directly and by weakening the antiviral response. This review will focus on common micronutrients such as zinc, iron, copper, selenium, vitamin A, vitamin B12, vitamin D and vitamin E. We will explore their role in the pathogenesis of HCV infection and in the response to antiviral therapy. While chronic hepatitis C virus infection drives deficiencies in micronutrients such as zinc, selenium, vitamin A and B12, it also stimulates copper and iron excess; these micronutrients influence antioxidant, inflammatory and immune responses to HCV.

scholarly journals Role of Interferon-gamma and Immune Response Biomarkers in Predicting IFN-alpha Responsiveness and Treatment Outcome in Patients with Hepatitis C Virus

2012 ◽  
Vol 8 (4) ◽  
pp. 288-298 ◽  
Author(s):  
Amira F. Barakat ◽  
Asmaa Hegazy ◽  
Raghda E. Farag ◽  
Azza Abdul Baky ◽  
Lamiaa F. Arafa ◽  
...  
Keyword(s):  
Immune Response ◽  
Treatment Outcome ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Interferon Gamma ◽  
Ifn Alpha ◽  
Response Biomarkers

scholarly journals Role of Circulating Lymphocytes in Patients with Sepsis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Raul de Pablo ◽  
Jorge Monserrat ◽  
Alfredo Prieto ◽  
Melchor Alvarez-Mon
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Host Response ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Potential Biomarker ◽  
Circulating Lymphocytes ◽  
Postmortem Studies

Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.

scholarly journals DDX60L Is an Interferon-Stimulated Gene Product Restricting Hepatitis C Virus Replication in Cell Culture

2015 ◽  
Vol 89 (20) ◽  
pp. 10548-10568 ◽  
Author(s):  
Oliver Grünvogel ◽  
Katharina Esser-Nobis ◽  
Anna Reustle ◽  
Philipp Schult ◽  
Birthe Müller ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Viral Rna ◽  
Type I ◽  
Dead Box ◽  
Ifn Γ ◽  
Ifn Treatment

ABSTRACTAll major types of interferon (IFN) efficiently inhibit hepatitis C virus (HCV) replicationin vitroandin vivo. Remarkably, HCV replication is not sensitive to IFN-γ in the hepatoma cell line Huh6, despite an intact signaling pathway. We performed transcriptome analyses between Huh6 and Huh-7 cells to identify effector genes of the IFN-γ response and thereby identified the DExD/H box helicase DEAD box polypeptide 60-like (DDX60L) as a restriction factor of HCV replication. DDX60L and its homolog DEAD box polypeptide 60 (DDX60) were both induced upon viral infection and IFN treatment in primary human hepatocytes. However, exclusively DDX60L knockdown increased HCV replication in Huh-7 cells and rescued HCV replication from type II IFN as well as type I and III IFN treatment, suggesting that DDX60L is an important effector protein of the innate immune response against HCV. In contrast, we found no impact of DDX60L on replication of hepatitis A virus. DDX60L protein was detectable only upon strong ectopic overexpression, displayed a broad cytoplasmic distribution, but caused cytopathic effects under these conditions. DDX60L knockdown did not alter interferon-stimulated gene (ISG) induction after IFN treatment but inhibited HCV replication upon ectopic expression, suggesting that it is a direct effector of the innate immune response. It most likely inhibits viral RNA replication, since we found neither impact of DDX60L on translation or stability of HCV subgenomic replicons nor additional impact on assembly of infectious virus. Similar to DDX60, DDX60L had a moderate impact on RIG-I dependent activation of innate immunity, suggesting additional functions in the sensing of viral RNA.IMPORTANCEInterferons induce a plethora of interferon-stimulated genes (ISGs), which are our first line of defense against viral infections. In addition, IFNs have been used in antiviral therapy, in particular against the human pathogen hepatitis C virus (HCV); still, their mechanism of action is not well understood, since diverse, overlapping sets of antagonistic effector ISGs target viruses with different biologies. Our work identifies DDX60L as a novel factor that inhibits replication of HCV. DDX60L expression is regulated similarly to that of its homolog DDX60, but our data suggest that it has distinct functions, since we found no contribution of DDX60 in combatting HCV replication. The identification of novel components of the innate immune response contributes to a comprehensive understanding of the complex mechanisms governing antiviral defense.

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