Heart Health Articles

Journal Of Clinical Investigation Online Early Table Of Contents: May 11, 2009

April 28, 2017

LXR proteins: new target in the war on tuberculosis?

Kris Huygen and colleagues, at the Scientific Institute of Public Health, Belgium, have now identified a role for LXR proteins in the mouse immune response to airway infection with Mycobacterium tuberculosis, the bacterium that causes tuberculosis. As treatment of normal mice with molecules that activate LXRs provided substantial protection from both a new infection and established infections, the authors suggest that LXRs might provide a new target for tuberculosis therapeutics.

In the study, when compared with normal mice, mice lacking both forms of LXR (LXR-alpha and LXR-beta) were more susceptible to airway infection with Mycobacterium tuberculosis and developed more severe disease. Further analysis revealed that these mice did not mount an effective immune response in the airways. For example, there was no accumulation of immune cells known as neutrophils in the lungs and little evidence of Th1 and Th17 immune responses. Importantly, the marked protection from infection seen in normal mice treated with molecules that target LXRs was accompanied by increased Th1 and Th17 immune responses.

TITLE: Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice

Kris Huygen
Scientific Institute of Public Health, Brussels, Belgium.

View the PDF of this article at: https://www.the-jci/article.php?id=35288

GENE THERAPY: Immune cells hold back gene therapy

Individuals with hemophilia B have a genetic mutation in their F9 gene that leads to deficiency in the blood clotting protein Factor IX. A recent gene therapy trial, using the viral vector AAV2 to transfer the F9 gene into liver cells, failed to establish long-lived Factor IX expression. It was suggested that immune responses (specifically CTL responses) against the virus (specifically its capsid protein) destroyed gene-corrected liver cells, thereby preventing long-term Factor IX expression. However, whether the molecular events underlying this mechanistic explanation occur has not been formally demonstrated. But now, Katherine High and colleagues, at Children's Hospital of Philadelphia, Philadelphia, have shown that the required molecular events do occur in AAV-transduced human liver cells. Briefly, they detected on the surface of AAV-transduced human liver cells fragments of the AAV capsid protein bound to the human protein MHCI, and CTL recognition of this protein complex triggered CTL killing of the AAV-transduced cells. As blocking CTL recognition of this protein complex prevented the killing of the AAV-transduced human liver cells, the authors suggest that blocking CTL responses therapeutically might improve the success of liver-targeted AAV-mediated gene therapy.

TITLE: Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors

Katherine A. High
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=36891

INFECTIOUS DISEASE: The LR protein helps meningitis-causing bacteria target the brain

Bacterial meningitis is the potentially fatal bacterial infection of the brain and spinal cord (which together are known as the CNS). While many viruses that can infect nerve cells in the CNS bind the protein LR, and this interaction plays a key role in targeting the viruses to the CNS (a process known as CNS tropism), it is not known whether this protein also mediates the CNS tropism of meningitis-causing bacteria. However, in a new study, Dlawer Ala'Aldeen, Elaine Tuomanen, and colleagues, at Queen's Medical Centre, United Kingdom, and St. Jude Children's Research Hospital, Memphis, have revealed the molecular basis for bacterial interactions with LR. Using several in vitro and in vivo approaches in rodent and human brain cells, the researchers showed that the three common meningitis-causing bacteria bound to the same region of the LR molecule, known as the adhesion recognition site. The authors therefore suggest that interruption of the bacteria/LR interaction may serve as a therapeutic target for bacterial meningitis.

TITLE: Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models

Dlawer A.A. Ala'Aldeen
University Hospital, Queen's Medical Centre, Nottingham, United Kingdom

Elaine I. Tuomanen,
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=36759

IMMUNOLOGY: An explanation for inexplicable severe intracellular viral and bacterial infections

Children that completely lack the protein STAT1, as a result of mutations in both copies of their STAT1 gene, die from infection with intracellular viruses and bacteria. Children with different mutations in one copy of their STAT1 gene have only a partial deficiency in STAT1 protein and are predisposed to mycobacterial infections. Jean-Laurent Casanova and colleagues, at Necker Faculty, France, and The Rockefeller University, New York, have now identified two siblings with a partial STAT1 protein deficiency caused by a specific mutation in both copies of their STAT1 gene. Although these children suffered from severe disease following infection with intracellular viruses and bacteria, they could be cured. Detailed analysis revealed the immune defects underlying the predisposition to bacterial and viral infections and the mechanism by which the STAT1 gene mutation led to the partial deficiency in STAT1 protein. The authors therefore suggest that this partial STAT1 deficiency should be considered as an underlying cause in patients with unexplained, severe intracellular viral and bacterial infections that can be cured.

TITLE: A partial form of recessive STAT1 deficiency in humans

Jean-Laurent Casanova
The Rockefeller University, New York, New York, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=37083

GASTROENTEROLOGY: TAL: Taking A Look at liver failure

Recent reports indicate that children lacking the protein TAL suffer from liver failure. However, all the children were offspring of consanguineous parents, so other defects might have contributed to the liver failure. Andras Perl and colleagues, at the State University of New York, Syracuse, therefore set out to further investigate the role of TAL in liver disease by studying mice either lacking TAL or expressing reduced levels of TAL (Tal-/- and Tal+/- mice, respectively).

In the study, both TAL (Tal-/- and Tal+/- mice showed increased susceptibility to acetaminophen-induced liver failure and spontaneously developed a form of liver cancer known as HCC. Oxidative stress has been implicated in both these conditions and further analysis showed evidence of oxidative stress in the livers of both TAL (Tal-/- and Tal+/- mice and provided insight into the underlying molecular mechanisms. Further, treatment of both TAL (Tal-/- and Tal+/- mice with a potent antioxidant protected them from acetaminophen-induced liver failure and HCC. The authors therefore conclude that TAL provides protection against liver cancer and suggest that the potent antioxidant might be of benefit to individuals who are deficient in TAL.

TITLE: Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Andras Perl
State University of New York, Syracuse, New York, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=35722

HEMATOLOGY: Controlling the early stages of sepsis

Sepsis, a whole-body immune response to infection, is a life-threatening condition. An underlying cause of death from sepsis is multiple organ failure due to small blood clots that form in the blood vessels, blocking blood flow to vital organs. These blood clots form in response to blood vessel damage (which if left unchecked leads to excessive bleeding) caused by the immune response to infection. Daniel McVicar and colleagues, at the National Cancer Institute, Frederick, have now identified a molecule that acts to regulate inflammatory activation of human and mouse blood clot formation in sepsis.

In the study, it was found that unlike healthy individuals, patients with sepsis had substantial amounts of the soluble form of the protein TLT-1 (sTLT-1) in their blood and that its presence correlated with disseminated blood clotting in the blood vessels. Consistent with this observation, human sTLT-1 augmented platelet aggregation (a central step in blood clot formation) in vitro. Further, platelets from mice lacking TLT-1 were impaired in their ability to aggregate in vitro and in vivo (something that led to increased bleeding times). However, these mice were more susceptible to immune response-nduced bleeding and death in models of sepsis. The authors therefore suggest that TLT-1 helps maintain the integrity of blood vessels in the initial phases of sepsis and that the high levels of sTLT-1 detected in patients who die from sepsis probably indicate an aggressive attempt by the body to control immune response-induced bleeding.

TITLE: TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

Daniel W. McVicar
National Cancer Institute, Frederick, Maryland, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=36175

DEVELOPMENTAL BIOLOGY: Developing bile ducts need Foxa proteins

Liver development is a complex process that includes formation of the bile duct. The proteins Foxa1 and Foxa2 are known to have a role in the initial stages of mouse liver development, but what they do in the later stages of this process have not been determined. However, Klaus Kaestner and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now determined that these proteins control bile duct development.

Mice that expressed Foxa1 and Foxa2 during the initial stages of liver development but not the later stages of liver development were generated by the authors and found to have markedly disturbed bile duct development. In particular there was a dramatic increase in the number of bile duct cells (cholangiocytes) and evidence of bile duct scarring (fibrosis). Further analysis revealed how Foxa1 and Foxa2 regulated the expression of a soluble factor known as IL-6, which stimulates cholangiocyte proliferation. These data indicate that by regulating IL-6 expression, Foxa1 and Foxa2 inhibit cholangiocyte proliferation in the adult mouse liver and thereby control bile duct development.

TITLE: Foxa1 and Foxa2 regulate bile duct development in mice

Klaus H. Kaestner
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

View the PDF of this article at: https://www.the-jci/article.php?id=38201

NEPHROLOGY: How the kidneys respond to dehydration

Tonicity is the scientific term for the osmotic pressure exerted on a cells outer membrane, and it is largely affected by the concentration of ions (such as sodium and potassium) in the body. In many animals, including humans, even short-term, mild dehydration leads to increased sodium output in the urine to help prevent a rise in extracellular tonicity, which leads to cellular shrinking. Although the kidney protein Sgk1 is known to be regulated by tonicity, how it is regulated remains unclear. In a new study, Songcang Chen and colleagues, at the University of California at San Francisco, San Francisco, identified the region of the Sgk1 rat gene that responds to extracellular tonicity, the TonE region. Using cultured rat kidney cells and experiments in rodents, the researchers also identified the tonicity-mediated pathway of Sgk1 expression. The authors conclude from this study that Sgk1 may play an important role in mediating the response of kidneys to dehydration and tonicity changes.

TITLE: Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Songcang Chen
University of California, at San Francisco, San Francisco, California

View the PDF of this article at: https://www.the-jci/article.php?id=35314

Karen Honey
Journal of Clinical Investigation