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Meg Mangin R.N.
Research Team
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Posted: Thu Sep 14th, 2006 01:56 |
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How inflammation overpowers the immune system
(filelink)
I think the way the Th1 inflammation initially overpowers the immune system, is that the level of infection gets to a critical value, and then an incident occurs (eg, sun-holiday, pregnancy, acute infection) which causes extra 1,25-D production, leading to a breakdown of the negative-feedback mechanisms which normally control the 1,25-D production in the phagocytes. From that point onwards those control mechanisms are not able to reliably maintain control. The patient enters a "relapsing-remitting" phase of the disease process.
Additionally, the TACO membrane protein, through which Mycobacteria infect the phagocyte (and possibly L-forms too), is down-regulated by VDR. So the actual entry of the bacteria into the phagocyte may be facilitated by excess ingested 25-D or Vitamin D causing the VDR to shut down.
http://tinyurl.com/nkb7x
Cholesterol is also involved in the expression of TACO:
http://tinyurl.com/l8rzj
..Trevor..
Too much 1,25-D means reduced immune response
http://tinyurl.com/bxjnu
Q: Do high levels of 1,25 vitamin D facilitate entry and exit of th1 pathogens?
A: Who knows? I have focused on transcription, not ingress and egress. I suspect that the Th1 microbiota can enter and exit the cells essentially unhindered, however (based on the microscopy we have seen).
..Trevor...
Last edited on Tue May 20th, 2008 04:54 by Meg Mangin R.N.
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Meg Mangin R.N.
Research Team
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Posted: Tue Dec 19th, 2006 23:05 |
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Measles Virus-induced Immunosuppression
(filelink)
"MV infection, while inducing lifelong immunity, also suppresses the immune system leading to an increase in susceptibility to other, secondary infections (24, 67, 91). In vitro research has shown that MV infection of cell cultures makes the cells more susceptible to a secondary bacterial invasion (13) "
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Meg Mangin R.N.
Research Team
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Posted: Wed Jan 10th, 2007 19:45 |
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(filelink)
Low doses of antibiotics more effective
Bull Math Biol. 2005 Jul;67(4):831-53. Epub 2004 Dec 15. Cogan NG, Cortez R, Fauci L.
Modeling physiological resistance in bacterial biofilms.
Mathematics Department, Tulane University, 6823 St. Charles Avenue, New Orleans, LA 70118, USA.
A mathematical model of the action of antimicrobial agents on bacterial biofilms is presented. The model includes the fluid dynamics in and around the biofilm, advective and diffusive transport of two chemical constituents and the mechanism of physiological resistance. Although the mathematical model applies in three dimensions, we present two-dimensional simulations for arbitrary biofilm domains and various dosing strategies. The model allows the prediction of the spatial evolution of bacterial population and chemical constituents as well as different dosing strategies based on the fluid motion. We find that the interaction between the nutrient and the antimicrobial agent can reproduce survival curves which are comparable to other model predictions as well as experimental results. The model predicts that exposing the biofilm to low concentration doses of antimicrobial agent for longer time is more effective than short time dosing with high antimicrobial agent concentration. The effects of flow reversal and the roughness of the fluid/biofilm are also investigated. We find that reversing the flow increases the effectiveness of dosing. In addition, we show that overall survival decreases with increasing surface roughness.
PMID: 15893555 [PubMed - indexed for MEDLINE]
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"High dose minocycline is an immunosuppressive therapy, one that will allow you to feel better in the short term, but in the longer term, 5-10 years, cause relapse.
This is because the antibiotic-resistant biofilm communities are only attacked by subinhibitory doses of antibiotics. That is the science." ..Trevor..
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1: Eur J Clin Microbiol. 1982 Apr;1(2):97-101. Links
Effect of subinhibitory antibiotic concentrations on the phagocytosis of Staphylococcus aureus.
Milatovic D.
The effect of subinhibitory antibiotic concentrations on the phagocytosis of Staphylococcus aureus was studied by pretreating 3H-thymidine labelled bacteria with one-third the minimal inhibitory concentration of clindamycin, doxycyclin, cefotiam, vancomycin, piperacillin and penicillin G, respectively. Pretreatment with clindamycin and doxycyclin resulted inenhanced uptake of the bacteria by polymorphonuclear leukocytes compared to the untreated control. The augmented phagocytosis was still observed at 1/32 the MIC of clindamycin and 1/64 the MIC of doxycyclin, and when the serum was diluted to a concentration of 1%. Pretreatment of the bacteria with penicillin, cefotiam, piperacillin and vancomycin had no effect on phagocytosis. Inhibitors of bacterial protein synthesis induce alterations of Staphylococcus aureus leading to increased phagocytosis, whereas antibiotics acting on cell wall synthesis are without effect.
PMID: 6293812 [PubMed - indexed for MEDLINE]
Last edited on Thu Feb 28th, 2008 18:32 by Meg Mangin R.N.
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Meg Mangin R.N.
Research Team
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Posted: Wed Jan 10th, 2007 20:07 |
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(filelink)
Cell-wall-deficient bacterial forms may be involved in the pathogenesis of chronic and latent lung infections.
FEMS Microbiol Lett. 2006 Dec 13; [Epub ahead of print]
Persistence of Staphylococcus aureus L-form during experimental lung infection in rats.
Michailova L, Kussovsky V, Radoucheva T, Jordanova M, Markova N. Department of Morphology of Microorganisms, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
The course of pulmonary infection in rats infected by intranasal inoculation with a Staphylococcus aureus stable protoplast L-form was studied. Blood and bronchoalveolar samples were taken on days 3, 7, 14 and 30 after challenge and were investigated by microbiological, electron microscopic, cytochemical and cytometric methods. The electron microscopic data and isolation of L-form cultures from bronchoalveolar samples at all experimental times demonstrated the ability of S. aureus L-form cells to internalize, replicate and persist in the lungs of infected
rats to the end of the observation period, in contrast to the S. aureus parental form. It was found that persisting L-form evoked ineffectual phagocytose by alveolar macrophages and low but long-lasting inflammatory reaction in rats. The experimental model of pulmonary infection with S. aureus L-form suggests that the cell-wall-deficient bacterial forms may be involved in the pathogenesis of chronic and latent lung infections.
PMID: 17168999 [PubMed - as supplied by publisher]
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1,25-dihydroxyvitamin D3 is a potent suppressor of interferon-mediated macrophage activation
This study indicates there may be no immune dysfunction at all in Th1 disease - just the pathogenic bacteria which have bypassed the defenses.This is a very important piece of the puzzle, I think. The abstract is above. the full text is behind a "pay me" wall 
..Trevor..
Last edited on Thu Jul 26th, 2007 00:35 by Meg Mangin R.N.
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Meg Mangin R.N.
Research Team
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Posted: Wed Jan 10th, 2007 20:16 |
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(filelink)
Interspecies microbial interactions may alter the course of disease, the response to therapy and the population structure of bacterial communities
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19890-5. Epub 2006 Dec 15.
Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa.
Hoffman LR, Deziel E, D'Argenio DA, Lepine F, Emerson J, McNamara S, Gibson RL, Ramsey BW, Miller SI.
Departments of *Pediatrics, Microbiology, Medicine, and Genome Sciences, University of Washington, Seattle, WA 98195.
Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunistic pathogens of humans, Pseudomonas aeruginosa and Staphylococcus aureus, frequently are coisolated from infections of catheters, endotracheal tubes, skin, eyes, and the respiratory
tract, including the airways of people with cystic fibrosis (CF). Here, we show that suppression of S. aureus respiration by a P. aeruginosa exoproduct, 4-hydroxy-2-heptylquinoline-N-oxide (HQNO), protects S. aureus during coculture from killing by commonly used aminoglycoside antibiotics such as tobramycin. Furthermore, prolonged growth of S. aureus with either P. aeruginosa or with physiological concentrations of pure HQNO selects for typical S. aureus small-colony variants (SCVs), well known for stable aminoglycoside resistance and persistence in chronic infections, including those found in CF. We detected HQNO in the sputum of CF patients infected
with P. aeruginosa, but not in uninfected patients, suggesting that this HQNO-mediated interspecies interaction occurs in CF airways. Thus, in all coinfections with P. aeruginosa, S. aureus may be underappreciated as a pathogen because of the formation of antibiotic-resistant and difficult to detect small-colony variants. Interspecies microbial interactions, analogous to those mediated by HQNO, commonly may alter not only the course of disease and the response to therapy, but also the population structure of bacterial communities that promote the health of host animals, plants, and ecosystems.
PMID: 17172450 [PubMed - in process]
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Meg Mangin R.N.
Research Team
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Posted: Thu Jan 11th, 2007 18:29 |
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(filelink)
Antibiotic Minimun Inhibitory Concentration (MIC)
In-vitro MIC bears no relation whatsoever to an antibiotic's effectiveness in-vivo. Here are studies proving examples of that:
http://tinyurl.com/6dac9
http://tinyurl.com/ylty4s
..Trevor..
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Meg Mangin R.N.
Research Team
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Posted: Thu Jun 21st, 2007 18:35 |
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(filelink)
Bacteria Sneaks and Hides in Cells
Reported June 18, 2007
(Ivanhoe Newswire) -- Researchers have found Staphylococcus aureus bacteria may elude the immune system by sneaking into cells and hiding out to avoid detection.
Researchers from University Hospital of Geneva in Switzerland and the Institute of Food Research in Norwich, UK, embarked on a study to find out just what S. aureus does in human lung epithelial cells. S. aureus is a major cause of human and animal infections.
Just like a villainous shape-shifter, shortly after S. aureus entered the lung cells, researchers found the bacteria's gene expression profile changed dramatically. They found the gene expression for bacterial metabolic functions and transport actually shut down, leaving the infectious bug in a dormant state. At the same time, researchers discovered the production of toxins that can kill epithelial cells became strictly controlled to limit cell damage. Then, the mechanisms that help the bacteria survive resumed.
Results of the study could pave the way to a better understanding of these types of infections as well as help researchers come up with better antibacterial drugs to fight them. It could also help them better understand what goes on at the molecular level that makes S. aureus so persistent. Researchers say the bacteria can re-surface and cause another infection years after the initial episode was "cured."
Patrice Francois, from University Hospital in Geneva, was quoted as saying, "S. aureus intracellular survival appears related to its capability to adopt a discrete behavior instead of actively duplicating. S. aureus then benefits from natural or programmed cell death to re-emerge and trigger another episode of infection, leading to chronicity."
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University of Michigan Health System
Microbes start immune response by sneaking inside cells
New insights could lead to better vaccines, treatments for rheumatoid arthritis, study suggests
Immune cells that are the body’s front-line defense don’t necessarily rest quietly until invading bacteria lock onto receptors on their outside skins and rouse them to action, as previously thought. In a new paper, University of Michigan scientists describe their findings that bacteria can barge inside these guard cells and independently initiate a powerful immune response.
The study, published online ahead of print in the April issue of the journal Immunity and accompanied by a special commentary, adds important new details to an emerging picture of how the body recognizes invading bacteria and responds. The work of the U-M team and researchers elsewhere — now taking place in laboratory animal studies — offers a different way of thinking about how best to design future human vaccines, as well as drugs that could more precisely target the body’s inflammatory response in rheumatoid arthritis and some other autoimmune diseases.
“In our study, the presence of bacterial microbes inside the cell is what triggers the immune response. That creates a new perspective for developing new drugs,” says senior author Gabriel Nunez, M.D., the Paul H. de Kruif professor of pathology at the U-M Medical School and a member of the U-M Comprehensive Cancer Center.
For years, scientists have believed that when bacteria invade the body, they set off alarms in the immune system by interacting with receptors on a cell’s surface. But, now new studies are revealing that bacteria can also plunge inside immune system cells and trigger the immune response there. In the new study, Nunez’ team sheds light on one major pathway in which this process occurs.
When invading bacteria enter immune system cells, a protein called cryopyrin, present in the fluid inside the cells, responds and activates a key pathogen-fighting molecule, Nunez’ team reported last year in Nature. Cryopyrin is implicated in the development of several inflammatory syndromes characterized by recurrent fever, skin rash and arthritis.
Cryopyrin triggers a key enzyme involved in the body’s inflammatory response, capsase-1, which in turn causes production of IL-1beta, a powerful molecule which signals the immune system to attack pathogens and induces fever to help the body fend off infection. IL-1beta plays an important role, too, in excessive immune system activity in inflammatory diseases.
The researchers report in the new paper how cryopyrin is activated to start the process. In experiments that exposed mouse immune cells called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-M research fellow, the study’s co-first authors, find that cryopyrin’s call to action inside the cells occurs without requiring a well-known set of cell-surface receptors called Toll-like receptors or TLRs. ”We prove that these TLRs are not required to activate cryopyrin. That is a major step,” says Nunez.
Instead, bacteria were able to enter the cells through a pore in the cell membrane, and stimulate the cryopyrin-initiated immune response without activating TLRs. The researchers discovered that a protein called pannexin-1 creates the pore, like a devious undersea diver drilling a hole in a ship hull.
The team’s work joins a growing body of research revealing the importance of recently discovered receptors such as cryopyrin inside cells, known collectively as NOD-like receptors. Knowledge about NOD-like receptors is moving forward rapidly and will contribute to a fuller understanding of the human immune system, say the U-M researchers.
Public release date: 13-Apr-2007
Last edited on Sun Jul 8th, 2007 22:06 by Meg Mangin R.N.
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Meg Mangin R.N.
Research Team
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Posted: Tue Dec 4th, 2007 18:06 |
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[filelink]
Microbiota
We have found that chronic inflammatory disease is caused by a hitherto poorly documented Microbiotia of intra-phagocytic biofilm-dwelling bacteria, a microbiota which was documented to exist in Stem Cells by the late Emil Wirostko (Columbia Uni, ca.1988).
I have fleshed out at least one molecular mechanism whereby this Microbiota can disable the Nuclear Receptor transcribing the 5 copies of the MTSS1 gene, and the 3 copies of the MTUS1 gene. ..Trevor..
The diversity of bacteria is hard to fathom
National Public Radio recently aired an interview explaining how the tools of molecular genomics have expanded our perspective of living things.
It used to be thought there were simply: "animals, vegetables and fungi." Now, since we can observe things on a molecular level, scientific classification has changed.
We know the animal kingdom is actually a very small branch in the tree of life, dwarfed by the vastness of microbes. If you listen to the program (less than 10 minutes), it reviews how our perspective has developed but it also seems to point to how far we have to go in understanding microbiota.
National Public Radio, Science Out of the Box
'Animal, Vegetable, Fungi ' Lesson Revised by Angela Seabrook
aired on All Things Considered Dec. 1, 2007
http://tinyurl.com/36t5aw
This interview with Carl Zimmer includes such topics as the controversy caused in the late 1970's when Dr. Carl Woese at the University of Illinois redefined the "Tree of Life" classification by defining a new domain, Archaea.
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A somewhat similar perspective, if a little more forcefully and controversially put forth, can be found at URL
http://rpvss.ucsd.edu:8080/ramgen/calit2/metagenomics/doolittle.rm
W.Ford Doolittle: Metagenomes and Metaspecies
"I will submit that there is no such thing as a microbial species"
Phagocytosis
The immune system destroys pathogens by a process of phagocytosis, where the macrophages engulf the pathogen and then digest it by breaking its DNA up into fragments. At that point it is no longer a viable organism.
The Th1 microbiota has developed a mechanism to avoid phagocytosis, and live inside the same cytoplasm that would normally digest the individual organisms. ..Trevor..
Last edited on Thu Jul 17th, 2008 19:44 by Meg Mangin R.N.
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Meg Mangin R.N.
Research Team
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Posted: Thu Feb 14th, 2008 04:06 |
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[filelink]
This graphic illustrates The Disease Process of Cell Wall Deficient (CWD) Bacteria
Thanks to Gary Kays.....
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