VIROLOGY: Successfully modeling hepatitis B and C virus infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect liver cells, and persistent infection can lead to cirrhosis of the liver and/or a form of liver cancer known as hepatocellular carcinoma. Current small animal models of HBV and HCV infection are not particularly good, and new models are needed if we are to learn more about how these viruses operate and test new potential therapeutics. Inder Verma and colleagues, at the Salk Institute for Biological Studies, La Jolla, have now developed a human liver chimeric mouse model by transplanting a large number of human liver cells into mice lacking three proteins (Fah, Rag2, and Il-2r-gamma) to generate mice with livers in which 95% of the liver cells are human. Importantly, these mice could be infected with HBV and HCV, and mice infected with HCV were responsive to antiviral therapy. As mentioned by the authors and, in an accompanying commentary, Alexander Ploss and Charles Rice, at Rockefeller University, New York, this mouse model should prove useful not only for studying HBV and HCV infection and testing antiviral therapies but also for studying other infections microorganisms that target the liver such as malaria.

TITLE: Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

Inder M. Verma
Salk Institute for Biological Studies, La Jolla, California, USA.

View this article at: jci/articles/view/40094?key=88d7139eef5794adc164

TITLE: New horizons for studying human hepatotropic infections

Alexander Ploss
The Rockefeller University, New York, New York, USA.
Charles M. Rice
The Rockefeller University, New York, NY, USA.

View this article at: jci/articles/view/42338?key=4238dhsm34ikjw9xu2k3

VIROLOGY: New insight into Chikungunya virus infection from nonhuman primates

Chikungunya virus (CHIKV) is transmitted to humans from mosquitos. It causes a severely debilitating disease characterized by fever, rash, and pain in muscles and joints. Chikungunya disease is emerging as a considerable health problem in Africa, Asia, and the islands of the Indian Ocean. CHIKV infection is currently modeled in mice, but mouse models do not accurately mimic the disease seen in humans and are not useful for the development of vaccines and immune cell-based therapeutics. Now, Pierre Roques and colleagues, at the Commissariat à l'Energie Atomique, France, have successfully modeled CHIKV infection in cynomolgus macaques. Specifically, CHIKV infection in cynomolgus macaques was found to recapitulate the viral, clinical, and pathological features observed in CHIKV infected humans. Importantly, using this model of CHIKV infection, the authors determined that CHIKV infection persisted long term in joints, muscles, lymphoid organs, and liver, and that during this long-term infection the virus resided in immune cells known as macrophages. The authors hope this model of CHIKV infection will be useful to develop new therapeutic and/or prophylactic strategies, a sentiment echoed by Stephen Higgs and Sarah Ziegler, at the University of Texas Medical Branch, Galveston, in an accompanying commentary.

TITLE: Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

Pierre Roques
Service d'immunovirologie, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.

View this article at: jci/articles/view/40104?key=4803265af26198f13cd3

TITLE: A nonhuman primate model of chikungunya disease

Stephen Higgs
University of Texas Medical Branch, Galveston, Texas, USA.

View this article at: jci/articles/view/42392?key=5s874984222348f4s89e

NEPHROLOGY: New gene linked to kidney disease

Nephronophthisis (NPHP) is the most common genetic cause of kidney failure in children. Ten causative genes (NPHP1-NPHP9 and NPHP11), all of which generate proteins that localize to a cellular complex known as the primary cilia-centrosome complex, have been identified previously. A team of researchers, at the University of Michigan Health System, Ann Arbor, and Duke University Medical Center, Durham, has now identified an association between mutations in the XPNPEP3 gene and an NPHP-like nephropathy in two consanguineous families, one in northern Finland and one in Turkey. Unlike all the known NPHP proteins, XPNPEP3 protein localizes to cellular compartments known as mitochondria. However, in vivo analysis in zebrafish indicated that XPNPEP3 protein has a role in ciliary function, as it degraded several ciliary cystogenic proteins. The authors therefore conclude that there is a link between mitochondria and ciliary dysfunction, a key component of NPHP. As highlighted by Erwin Böttinger, at Mount Sinai School of Medicine, New York, these data provide exciting new avenues of research for understanding ciliopathies, genetic disorders caused by damage to cellular structures known as primary cilia.

TITLE: Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Friedhelm Hildebrandt
University of Michigan Health System, Ann Arbor, Michigan, USA.
Nicholas Katsanis
Duke University Medical Center, Durham, North Carolina, USA.

View this article at: jci/articles/view/40076?key=2670edbdb460768b2251

TITLE: Lights on for aminopeptidases in cystic kidney disease

Erwin P. Böttinger
Mount Sinai School of Medicine, New York, New York, USA.

View this article at: jci/articles/view/42378?key=54ejkhkif89845v6831f

DERMATOLOGY: Breaching the barrier: too much of the protein ELA2 impairs skin barrier function

Our skin has two crucial barrier functions: it protects against water loss and it prevents penetration of infectious agents and allergens. By studying mice and humans, a team of researchers, led by Alain Hovnanian and colleagues, at CHU Necker-Enfants Malades, France, has now generated data that indicate an important role for the protein elastase 2 (ELA2) in maintaining skin barrier function and suggest that ELA2 might have a role in the development of the rare genetic skin disease Netherton syndrome.

Netherton syndrome is caused by the inefficient inhibition of proteins known as serine proteases, which causes severe skin redness and scaling. In this study, the serine protease ELA2 was found to be expressed in both mouse and human skin cells (keratinocytes). Importantly, ELA2 was found to be hyperactive in skin from patients with Netherton syndrome. Further, transgenic mice overexpressing ELA2 in the epidermal layer of the skin exhibited cellular abnormalities characteristics of Netherton syndrome and these led to dehydration. As these data indicate that ELA2 is likely to have an important role in the skin barrier defect seen in patients with Netherton syndrome, the authors suggest that ELA2 might provide a new target for the treatment of Netherton syndrome.

TITLE: Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

Alain Hovnanian
CHU Necker-Enfants Malades, Department of Genetics, Paris, France.

View this article at: jci/articles/view/41440?key=6487f1d61ce6104ea750

DERMATOLOGY: Watching immune cell movement to and from the skin

Immune cells known as Tregs have an important role in preventing other immune cells from attacking the cells of our body and causing autoimmune diseases such as rheumatoid arthritis. A team of researchers, at Kyoto University Japan, and the Research Center for Allergy and Immunology, RIKEN, Japan, has now used mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light, to track Treg movement under physiologic conditions and during immune responses in the skin.

In the study, Tregs were found to move from the skin to designated regions for immune cell clustering known as draining lymph nodes. The extent of this trafficking was enhanced by skin inflammation but balanced under these conditions by movement of Tregs from the draining lymph nodes to the skin. As discussed by Hironori Matsushima and Akira Takashima, at the University of Toledo College of Medicine, in an accompanying commentary, these data provide new insight into the regulation of immune responses in the skin.

TITLE: Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Kenji Kabashima
Kyoto University, Kyoto, Japan.
Michio Tomura
Research Center for Allergy and Immunology, RIKEN, Yokohama City, Japan.

View this article at: jci/articles/view/40926?key=e05d84d8cce3f4f282a7

TITLE: Bidirectional homing of Tregs between the skin and lymph nodes

Akira Takashima
University of Toledo College of Medicine, Toledo, Ohio, USA.

View this article at: jci/articles/view/42280?key=ij489s9cn2jkcxs98433

Karen Honey
Journal of Clinical Investigation

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