Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capacity of Streptococcus pneumoniae to produce capsular polysaccharide (CPS) is essential for virulence. The CPS biosynthesis proteins CpsB, CpsC, and CpsD function to regulate CPS production via tyrosine phosphorylation of CpsD. This mechanism of regulating CPS production is important for enabling S. pneumoniae to cause invasive disease. Here, we identify mutations affecting the attachment of CPS to the cell wall. These mutations were located in cpsC, such that CpsC functioned independently from CpsD tyrosine phosphorylation. These mutants produced WT levels of CPS, but were unable to cause bacteremia in mice after intranasal challenge. This finding suggests that cell-wall attachment of CPS is essential for invasive pneumococcal disease; production of WT levels of CPS alone is not sufficient. We also show that cpsB mutants, which lack the phosphotyrosine-protein phosphatase, produced less CPS than the WT strain, but attached substantially more CPS to their cell wall. Thus, the phosphorylated form of CpsD promotes attachment of CPS to the cell wall.
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PMID:Attachment of capsular polysaccharide to the cell wall of Streptococcus pneumoniae type 2 is required for invasive disease. 1670 78

Kupffer cells are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/Nuclear Factor of Activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. While their effect on lymphocytes has been studied extensively, there is limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs. Here, we investigated the impact of tacrolimus treatment on innate immunity and more specifically on the capability of Kupffer cells to fight infections. Retrospective analysis of data of more than 2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, most bacteria were sequestered in liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus-treated mice. Using imaging we unveiled the mechanism underlying this observation: the reduced capability of Kupffer cells to capture, phagocytose and destroy bacteria in tacrolimus-treated animals. Further, in a gene expression analysis of infected Kupffer cells, the TREM-1 pathway was the one with the most significant downregulation after tacrolimus treatment. TREM-1 inhibition likewise inhibited Kupffer cell bacteria capture. TREM-1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment. Our results indicate that tacrolimus treatment has a significant impact directly on Kupffer cells and on TREM-1, thereby compromising their capacity to fend off infections.
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PMID:Tacrolimus impairs Kupffer cell capacity to control bacteremia: why transplant recipients are susceptible to infection. 3276 29