News From The Journal Of Clinical Investigation: Aug. 25, 2010
Ticks can carry and transmit to humans disease-causing bacteria. For example, the black-legged tick, Ixodes scapularis, can transmit several bacteria that cause disease in humans, including Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis, a disease characterized by fever, severe headache, muscle aches, chills, and shaking. If bacteria can in any way enhance the survival of the ticks that transmit them, this increases their likelihood of infecting a human, thereby impacting human health. A team of researchers, led by Erol Fikrig, at Yale University School of Medicine, New Haven, has now determined that Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze molecule that enhances tick survival in the cold. As Ixodes scapularis ticks overwinter in the US in the Northeast and Upper Midwest, this likely increases the number of Anaplasma phagocytophilum available to infect humans. As noted by Stephen Dumler, at The Johns Hopkins University School of Medicine, Baltimore, in an accompanying commentary, these data highlight how important understanding ecology and tick biology can be to unraveling the intricacies of human disease.
Title: Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze glycoprotein gene that enhances their survival in the cold
Accompanying Commentary Title: Fitness and freezing: vector biology and human health
BACTERIOLOGY: Immune interference, an explanation for vaccine failure?
Infection with Staphylococcus aureus bacteria is a major cause of bloodstream, lower respiratory tract, and skin and soft tissue infections. Given the dramatic increase in the number of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), a Staphylococcus aureus vaccine is much needed. However, vaccines developed thus far have failed to induce protection in clinical trials, and even prior infection with the bacterium fails to engender protection against subsequent infection. A team of researchers, led by Gerald Pier, at Brigham and Women's Hospital, Harvard Medical School, Boston, has now generated data in mice to explain why vaccines and prior infection do not provide individuals with protection from Staphylococcus aureus.
In the study, immune molecules known as antibodies that target the Staphylococcus aureus components CP and PNAG were each shown to indirectly mediate bacterial killing in vitro and to provide protection in mouse models of Staphylococcus aureus infection. However, when mixed together, in vitro killing and in vivo protection were markedly reduced because the antibodies interfered with each other. Further analysis indicated that interference occurred because the parts of the antibodies that bound CP and PNAG interacted with each other in a process known as idiotype-anti-idiotype binding. Similar binding was observed for antibodies isolated from humans with Staphylococcus aureus bloodstream infections. As noted by the authors, and Liise-anne Pirofski, at Albert Einstein College of Medicine, New York, in an accompanying commentary, this identification of a mechanism to explain the inability of humans to mount good protective antibody responses to Staphylococcus aureus should help in the design of future candidate vaccines.
Title: Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice
Accompanying Commentary Title: Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue
PULMONARY: New cystic fibrosis models teach us about disease
Cystic fibrosis (CF) is caused by genetic mutations that disrupt the function of the protein CFTR. Although many organs are affected in cystic fibrosis, the most life-threatening aspect of the disease is lung disease. To understand this more deeply, animal models of cystic fibrosis that more closely mimic the human disease than do mouse models are needed. To this end, three independent research groups - one led by Kevin Foskett, at the University of Pennsylvania, Philadelphia; one led by John Engelhardt, at the University of Iowa, Iowa City; and one led by Jeffrey Wine, at Stanford University, Stanford - have analyzed pig and ferret models of cystic fibrosis and determined that they represent good models of lung disease in individuals with cystic fibrosis. As concluded by each of the authors and noted by Jonathan Widdicombe, at the University of California Davis, Davis, in an accompanying commentary, these animals will prove valuable models to both further understanding of the mechanisms underlying lung disease in individuals with cystic fibrosis and test potential therapies.
Title: cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways
Accompanying Article: Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs
Accompanying Article Title: Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis
Accompanying Commentary Title: Transgenic animals may resolve a sticky situation in cystic fibrosis
REPRODUCTIVE BIOLOGY: Long standing question in sperm biology answered
Nahum Sonenberg, Bernard Robaire, and colleagues, at McGill University, Montreal, have generated data in mice that provides insight into a long unanswered question in sperm biology. Specifically, how protein expression is regulated in the late stages of sperm development. The importance of these data are outlined in an accompanying commentary by Stephen Liebhaber and colleagues, at the University of Pennsylvania, Philadelphia.
A protein in a cell is made from a template known as an mRNA molecule, which in turn is a copy of the information contained in a gene. About half way through sperm development, mRNA formation ceases so the mRNA templates for proteins needed in the late stages of sperm development must be made early in development and stored. Understanding of the mechanisms that underlie mRNA storage and subsequent activation has been long sought after. In the study, Sonenberg, Robaire, and colleagues find that mice lacking the protein Paip2a and mice lacking Paip2a and Paip2b exhibit male infertility associated with impaired activation of stored mRNAs. Further analysis indicated that aberrant increased expression of the protein Pabp caused the impaired activation of stored mRNAs, leading the authors to conclude that mRNA activation in late sperm development requires an optimal concentration of Pabp, as determined by Paip2a.
Title: The poly(A)-binding protein partner Paip2a controls translation during late spermiogenesis in mice
Accompanying Commentary Title: Too much PABP, too little translation
Journal of Clinical Investigation