Even so, our knowing of the signalling pathways which might be stimulated for the duration of mycobacterial infec tion and just how the mycobacteria modulate these pathways is restricted. Latest research suggest that a single feasible strat egy might involve regulation and activation of protein tyrosine kinases that subsequently activate members with the STAT pathway, PI3K Akt pathway and mitogen activated protein kinase loved ones. MAP kinases certainly are a household of serine threonine kinases which might be activated by phosphorylation of conserved tyrosine residues. Various members of this family which include the p42 p44 extracellular signal regulated kinases, c Jun amino terminal kinases, and p38 MAP kinase are reported to become involved in inflammatory mediator manufacturing in response to a wide variety of microbial stimuli.
As an example, ERK activation is concerned in response to Salmonella infection of macrophages, and MAP kinase activation is required for tumor necrosis selleck MS-275 component production in response to Group B strep tococcus infection. Also, many labora tories have proven that MAP kinases are concerned in macrophage activation following publicity to lipopolysac charide and various bacterial cell wall parts. Recent scientific studies have begun to investigate the role of these kinases in mycobacterial signalling. Early studies by Chan et al showed that the cell wall part of mycobacteria lipoarabinomannan stimu lated nitric oxide manufacturing via a pathway involving ERK and JNK. Additionally, several scientific studies have proven that infection of macrophages with intact myco bacteria activate specific MAP kinases.
Additional supporting a role for the value of those read what he said kinases in controlling microbial infection would be the findings that path ogenic strains of various bacteria block inflammatory mediator manufacturing as a result of inhibition of MAP kinases. Following activation, MAP kinases phosphorylate unique transcription factors resulting in modulation of cytokine gene transcription. A essential transcription issue involved during the up regulation of a lot of cytokines and various mediators critical to host defense is nuclear factorB. Genes regulated by this factor encode many pro teins concerned inside the early response to pathogens. A number of groups have recently reported activation of NF?B in response to the two intact mycobacteria and mycobacterial cell wall components, and NF?B activation has been reported in monocytes of sufferers infected with M.
tuberculosis. Our laboratory continues to be studying the role that host components perform in enhancing the innate response to challenge by invading mycobacteria. Among these components is surfactant linked protein A, a member on the C style lectin household that is definitely synthesized and secreted by kind II epithelial cells in the lung. Work from many laboratories has demonstrated that SP A plays a major role while in the clear ance of a range of respiratory pathogens throughout the innate host response. In vitro research have proven that SP A functions as an opsonin and enhances the ingestion of this kind of pathogens as BCG, Mycobacterium tuberculosis, influenza A virus,E. coli, Haemophilus influ enzae, Staphylococcus aureus, Streptococcus pneu moniae, Mycoplasma pulmonis and Klebsiella pneumoniae.
The importance of SP A in in vivo host defense is supported just lately through the demonstra tion that mice deficient in SP A demonstrate decreased resistance to group B streptococcal and Pseudomonas aeruginosa pneumonia, decreased clearance of respiratory syncytial virus, and diminished killing of mycoplasma. In in vitro research, Kabha et al. and Hickman Davis et al. demonstrated that SP A enhances the ingestion and killing of K. pneumoniae and mycoplasma by macrophages. Latest work from our laboratory has shown that SP A enhances clearance of BCG and avirulent Mycobacterium tuberculosis by cultured rat macrophages. This enhanced clearance is accompanied by greater professional duction of nitric oxide and TNF.