Increased risk of vascular thrombosis in pediatric liver transplant recipients with thrombophilia.

BACKGROUND: Pediatric patients who undergo liver transplantation are at higher risk of developing vascular complications when compared to adult liver transplant recipients. The consequences of hepatic artery thrombosis (HAT) or portal vein thrombosis (PVT) can cause significant morbidity and mortality. We examined pediatric liver transplant recipients who developed vascular thrombosis and the presence of thrombophilia. METHODS: We examined outcome in all pediatric patients who underwent liver transplantation. Recipient, donor demographic data, and outcome data were examined. Categorical differences were compared using the unpaired Student t-test and nominal variables using either the chi-square or the Fischer exact test. A P value of <0.05 was considered significant. RESULTS: Forty-six pediatric patients underwent liver transplantation. Twenty-one recipients were found to have thrombophilia, including 5 with HAT and 2 with PVT. When comparing recipients with or without any vascular thrombosis, those with thrombophilia had a significantly higher incidence of developing a vascular thrombosis (7/21 versus 0/25, P = 0.0017). Five of 42 recipients with artery-to-artery reconstruction developed HAT versus 0 of 4 with a conduit. Recipients who developed any thrombosis were significantly lower in weight than those who did not develop any thrombosis (9.0 ± 1.6 kg versus 22.2 ± 16.0 kg, P = 0.0366). CONCLUSIONS: All pediatric liver transplant recipients who developed any vascular thrombosis were also found to have thrombophilia. Recipients who were smaller in size were at significantly higher risk of developing vascular thrombosis. Lower weight recipients with thrombophilia may benefit from arterial reconstruction with a conduit to decrease the risk of vascular thrombosis.

The antimicrobial peptide-sensing system aps of Staphylococcus aureus.

Staphylococcus aureus is a leading cause of hospital-associated and, more recently, community-associated infections caused by highly virulent methicillin-resistant strains (CA-MRSA). S. aureus survival in the human host is largely defined by the ability to evade attacks by antimicrobial peptides (AMPs) and other mechanisms of innate host defence. Here we show that AMPs induce resistance mechanisms in CA-MRSA via the aps AMP sensor/regulator system, including (i) the d-alanylation of teichoic acids, (ii) the incorporation of lysyl-phosphatidylglycerol in the bacterial membrane and a concomitant increase in lysine biosynthesis, and (iii) putative AMP transport systems such as the vraFG transporter, for which we demonstrate a function in AMP resistance. In contrast to the aps system of S. epidermidis, induction of the aps response in S. aureus was AMP-selective due to structural differences in the AMP binding loop of the ApsS sensor protein. Finally, using a murine infection model, we demonstrate the importance of the aps regulatory system in S. aureus infection. This study shows that while significant interspecies differences exist in the AMP-aps interaction, the AMP sensor system aps is functional and efficient in promoting resistance to a variety of AMPs in a clinically relevant strain of the important human pathogen S. aureus.

Gram-positive three-component antimicrobial peptide-sensing system.

To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta-defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Furthermore, our data indicate that a very short, extracellular loop with a high density of negative charges in the sensor protein is responsible for antimicrobial peptide binding and the observed specificity for cationic antimicrobial peptides. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development.

The human anionic antimicrobial peptide dermcidin induces proteolytic defence mechanisms in staphylococci.

Antimicrobial peptides (AMPs) represent a key component of innate host defence against bacterial pathogens. Bacterial resistance mechanisms usually depend on the characteristic positive charge of AMPs. However, several human cell types also produce anionic AMPs, mechanisms of resistance to which are poorly understood. Here we demonstrate that the skin commensal and leading nosocomial pathogen Staphylococcus epidermidis senses and efficiently inactivates the anionic AMP dermcidin. Dermcidin induced differential expression of global regulatory systems, leading to increased expression of proteases with the capacity to degrade dermcidin, particularly S. epidermidis SepA. A similar induction of extracellular proteolytic activity was found in Staphylococcus aureus, suggesting a common regulatory mechanism in staphylococci. Notably, human cationic AMPs also led to the activation of global regulators, but inactivation of dermcidin by SepA was much more effective than of the tested cationic peptides. The ability to react to the unusual, anionic dermcidin with effective countermeasures likely contributes to the extraordinary success of staphylococci as colonizers and infective agents on human epithelia. Our study indicates that staphylococci can react to human AMPs by specific mechanisms of resistance and establishes a crucial role for staphylococcal proteases in the interaction with human innate host defence.