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MicrobiomeThe human body is colonized by a vast number of microbes and microbial colonies gain many advantages by parasitizing immune cells and altering nuclear receptor activity. Tissue invasion provides a privileged niche with access to host protein and iron, sequestration from immune response, and a means for persistence. [1] Macrophage microbicidal mechanisms are thought to be responsible for the control and elimination of intracellular pathogens; 1,25(OH)2D production and action in macrophages activates toll-like receptors to increase expression of the AMP cathelicidin and kill the infectious invaders. [2, 3] Consequently, when immune defenses are stimulated Th17 cells mobilize host immunity and contribute to the development of harmful chronic inflammatory conditions. [4, 5]

The Human Microbiome project, which is cataloguing all the microorganisms associated with mankind, has revealed that over 90% of the cells in the human body are not human in origin. The millions of genes carried in the human microbiota greatly outnumber the 23,000 genes in the human genome. When host conditions are favorable, non-pathogenic bacteria in the microbiome may become pathogenic using a panoply of tactics to cause interferences within host cells. Intracellular pathogens are described as often entering an unusual biologic state designated "persistence" and in this form have been associated with engendering several chronic diseases. [6-8] Phagocyte-inflicted tissue damage plays an important role in many chronic diseases. [9] In the arms race of host-microbe co-evolution, successful microbial pathogens have evolved innovative strategies to evade host immune responses and persist in intracellular cytoplasm. For example, 'crosstalkmanipulation' (the proactive microbial interference strategies that instigate, subvert or disrupt the molecular signaling crosstalk between receptors of the innate immune system) undermines host defenses and contributes to microbial adaptive fitness. [10, 11]

Pathogenic microbes also induce stress responses which protect the cell from lethal factors, express proteases that degrade AMPs, use biofilms as a shield, modulate host cell motility to facilitate establishment of an infection, and secrete substances that block the VDR. [12-16] Genetic foreign and host protein interactions alter gene transcription and translation mechanisms and many species survive by horizontal gene transfer. [6, 17, 18] Autoimmune patients acquire a distinct pathogenic microbiota and multi-morbidity often results. [19, 20]Intracellular bacteria modulate cytokine production; and in monocytes and macrophages, cytokine activation markedly inhibits 1,25(OH)2D/VDR gene transcription. [21, 22] When the immune system is fighting a persistent microbe, it continually releases inflammatory molecules in an effort to kill the pathogen. [23] This dysfunctional immunological response produces low-grade inflammation which is a component of many chronic and autoimmune diseases.

References

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2. Nauciel C. Immune Defenses against Intracellular Bacterial Infection. In: Paradise LJ, Friedman H, Bendinelli M, eds. Opportunistic Intracellular Bacteria and Immunity. New York, NY: Kluwer Academic Press; 2002.
3. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. Mar 2006;311(5768):1770-3.
4. McGeachy MJ, McSorley SJ. Microbial-induced Th17: superhero or supervillain? 2012. J Immunol Oct;189(7):3285-3291.
5. Oswald-Richter KA, Beachboard DC, Seeley EH, et al. Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol. Oct 2012(32(5)):1129-40.
6. Smillie CS, Smith MB, Friedman J, Cordero OX, David LA, Alm EJ. Ecology drives a global network of gene exchange connecting the human microbiome. Nature. Oct 2011;480(7376):241-4.
7. Branton WG, Ellestad KK, Maingat F, et al. Brain Microbial Populations in HIV/AIDS: α-Proteobacteria Predominate Independent of Host Immune Status. PLOS one. 2013;8(1):e54673.
8. Eishi Y. Etiologic aspect of sarcoidosis as an allergic endogenous infection caused by Propionibacterium acnes. Biomed Res Int. 2013:2013:935289.
9. Labro M. Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Clin Microbiol Rev. 2000;13(4):615-650.
10. Khan N, Gowthaman U, Pahari S, Agrewala JN. Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici! PLoS Pathog. 2012;8(6):e1002676.
11. Hajishengallis G, Lambris JD. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. Mar 2011(11(3)):187-200.
12. Dörr T, Vulić M, Lewis K. Ciprofloxacin Causes Persister Formation by Inducing the TisB toxin in Escherichia coli. PLoS Biol. 2010;8(2):e1000317.
13. Chakraborty K, Ghosh S, Koley H, et al. Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells. Cell Microbiol. Dec 2008;10(12):2520-37.
14. Thornton RB, Rigby PJ, Wiertsema SP, et al. Multi-species bacterial biofilm and intracellular infection in otitis media. BMC Pediatr. Oct 2011;11:94.
15. Fuks JM, Arrighi RB, Weidner JM, et al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog. Dec 2012;e1003051(8(12)).
16. Godchaux W3, Leadbetter ER. Sulfonolipids of gliding bacteria. Structure of the N-acylaminosulfonates. J Biol Chem 1984. October Mar;259(5):2982-90.
17. Goodacre R. Metabolomics of a superorganism. J Nutr. Jan 2007;137(1 Suppl):259S-266S.
18. Riley DR, Sieber KB, Robinson KM, et al. Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples. PLOS Comp Bio. 2013(tbc).
19. Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. Jan 2011;5(1):82-91.
20. Anderson G, Horvath J. The growing burden of chronic disease in America. Public Health Rep. May-Jun 2004;119(3):263-70.
21. Wang KX, Chen L. Helicobacter pylori L-form and patients with chronic gastritis. World J Gastroenterol. May 2004;10(9):1306-9.
22. Jones G, Prosser DE, Kaufman M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys. Jul 2012;523(1)(9-18):9-18.
23. Allie N, Alexopoulou L, Quesniaux VJ, et al. Protective role of membrane tumour necrosis factor in the host's resistance to mycobacterial infection. Immunology. Dec 2008;125(4):522-34.

Created June 16, 2014