Visualizing hepatitis C virus infection in humanized mice

Schaewen, Markus von; Ding, Qiang; Ploß, Alexander

doi:10.1016/j.jim.2014.03.006

Cited by 13 publications

(10 citation statements)

References 119 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To study hepatotropic pathogens, human liver chimeras have been developed [Figure 2 and reviewed in (73, 74)]. In all models, the common theme is destruction of murine hepatocytes to permit space for engraftment of human hepatocytes.…”

Section: Human-murine Liver Chimeric Mouse Models For Infectious Diseasementioning

confidence: 99%

Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

433

384

View full text Add to dashboard Cite

Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases.

show abstract

Section: Human-murine Liver Chimeric Mouse Models For Infectious Diseasementioning

confidence: 99%

Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

433

384

View full text Add to dashboard Cite

show abstract

“…We have previously shown that adenoviral delivery or transgenic expression of full-length human CD81 and OCLN is sufficient to enable HCV glycoproteinmediated uptake (21,22,32). To assess the ability of mCD81/hEL2[h/h] mOCLN/ hEL2[h/h] double-knock-in mice to support HCV uptake in vivo, we employed a cellularly encoded reporter which can be activated by coexpression of Cre recombinase (21,32,33). mCD81/hEL2[h/h] mOCLN/hEL2[h/h] mice were intercrossed with the Gt(ROSA)26Sor tm1(Luc)Kaelin (Rosa26-Fluc) mouse strain (34) harboring a loxP-flanked luciferase (luc) reporter.…”

Section: Dose-dependent Uptake Of Hcv Into Mcd81/hel2[h/h] Mocln/hel2mentioning

confidence: 99%

Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

Ding

Schaewen

Hrebikova

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

Hepatitis C virus (HCV) causes chronic infections in at least 150 million individuals worldwide. HCV has a narrow host range and robustly infects only humans and chimpanzees. The underlying mechanisms for this narrow host range are incompletely understood. At the level of entry, differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, the tetraspanin CD81 and the tight junction protein occludin (OCLN), explain, at least in part, HCV's limited ability to enter mouse hepatocytes. We have previously shown that adenoviral or transgenic overexpression of human CD81 and OCLN facilitates HCV uptake into mouse hepatocytes in vitro and in vivo. In efforts to refine these models, we constructed knock-in mice in which the second extracellular loops of CD81 and OCLN were replaced with the respective human sequences, which contain the determinants that are critical for HCV uptake. We demonstrate that the humanized CD81 and OCLN were expressed at physiological levels in a tissue-appropriate fashion. Mice bearing the humanized alleles formed normal tight junctions and did not exhibit any immunologic abnormalities, indicating that interactions with their physiological ligands were intact. HCV entry factor knock-in mice take up HCV with an efficiency similar to that in mice expressing HCV entry factors transgenically or adenovirally, demonstrating the utility of this model for studying HCV infection in vivo.IMPORTANCE At least 150 million individuals are chronically infected with hepatitis C virus (HCV). Chronic hepatitis C can result in progressive liver disease and liver cancer. New antiviral treatments can cure HCV in the majority of patients, but a vaccine remains elusive. To gain a better understanding of the processes culminating in liver failure and cancer and to prioritize vaccine candidates more efficiently, smallanimal models are needed. Here, we describe the characterization of a new mouse model in which the parts of two host factors that are essential for HCV uptake, CD81 and occludin (OCLN), which differ between mice and humans, were humanized. We demonstrate that such minimally humanized mice develop normally, express the modified genes at physiological levels, and support HCV uptake. This model is of considerable utility for studying viral entry in the three-dimensional context of the liver and to test approaches aimed at preventing HCV entry.KEYWORDS animal models, hepatitis C virus, viral entry, viral hepatitis H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus belonging to the Flaviviridae family, genus Hepacivirus (1). HCV progresses to persistent infection in 70 to 80% of those individuals who become acutely infected (2). Chronic carriers are at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) if they remain untreated. Over a few years, very potent directly acting antivirals (DAAs) which can cure

show abstract

“…In vivo models of HCV infection are also questionable, since small rodents cannot be infected with human HCV, and they only transgenically express HCV proteins, in the absence of replicating virus. The best option in this case is to use immunodeficient mice with humanized livers that are able to replicate the human virus, but to our best knowledge, while infection of the liver with HCV is widely reported (5,26,57), HCV-ethanol studies on this expensive and demanding model are very few (37).…”

mentioning

confidence: 99%

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Ganesan

Natarajan

Zhang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV ϩ AB expressed more IL-1␤, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV Ϫ AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression. HCV RNA; acetaldehyde; apoptosis; hepatocytes; macrophages ALCOHOL EXPOSURE EXACERBATES hepatitis C virus (HCV) infection severity, increases liver inflammation, and potentiates liver injury progression. However, the pathogenesis of HCV-alcohol interactions is not clear yet. The major difficulty in HCValcohol studies is related to the lack of adequate models that can recapitulate both viral replication and ethanol metabolism-two important features that potentiate liver injury progression in alcohol-abusing HCV patients. Human liver cell lines permissive for HCV (Huh7.5 or Huh 7.5.1) that are currently used for HCV-alcohol-related in vitro studies do not metabolize ethanol, while ethanol-metabolizing rodent liver cells cannot support HCV replication. Studies conducted with isolated human hepatocytes also have failed, since these cells require at least 4 -5 days to become infected with HCV; however, by this time, hepatocytes lose the expression and functional activity of CYP2E1 and alcohol dehydrogenase (ADH), the main ethanol-metabolizing enzymes (47). In vivo models of HCV infection are also questionable, since small rodents cannot be infected with human HCV, and they only transgenically express HCV proteins, in the absence of replicating virus. The best option i...

show abstract

Visualizing hepatitis C virus infection in humanized mice

Cited by 13 publications

References 119 publications

Humanized Mouse Models of Clinical Disease

Humanized Mouse Models of Clinical Disease

Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Contact Info

Product

Resources

About