The INDIVIDUALIST

A Wiki about biochemical individuality

Immunology

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Introduction

Most microbes require some sort of attachment in order to infect. Many of these attachments are the result of lectin-like adhesions between the microbe and the gut, respiratory passages, urinary or reproductive tract. Since many of these lectins latch on to sugars and the most common sugars on our membranes are those of our ABO blood group, it is not surprising to discover that many, if not most, infections have a preference for one blood type or another -another good reason to eat right for your type.

Biofilms


A new approach to controlling bacterial infection involves interfering with their ability of one bacteria to communicate with another. Many bacteria are capable of altering their genetic expression based upon an assessment of their environmental conditions. For example, bacteria will swim freely if genetically stimulated to manufacture a type of structure called a flagella ('whip' in Latin). Flagella are tail-like projections that protrude from their body and provide a type of locomotion. However, under different stimuli, these same bacteria will instead switch to genes that produce pilum ('hairs' in Latin) or fimbriae ('threads' in Latin) tiny appendages found on the surface. Pilum connect bacteria together, allowing for the formation of colonies and the exchange of genetic information, such as that which results in resistance to antibiotics. Fimbriae are used by bacteria to adhere to one another and to adhere to animal cells, and some inanimate objects. The actions of cranberry juice on urinary tract infections is thought to be partially the result of the juice's high concentration of the sugar mannose. Mannose is know to block the attachment of two classes of fimbriae: the 'type 1' and 'p type.' When bacteria adhere to some external object, most species will begin to generate a biofilm, a combination of the bacteria and a variety of branching sugar molecules called exopolysaccharides. Bacteria, exopolysaccharides, stray DNA and other assorted things are what we in the real world politely call slime or when it's on the bottom of your sailboat, fouling. Microbes in biofilms often turn on large numbers of genes that are usually repressed in their free-swimming brethren.

http://www.4yourtype.com/images/biofilm.jpg

"Over 80% of bacterial infections in people are estimated to involve biofilms. If you want to see a biofilm in action don't clean your teeth for a day, that gunky plaque is a biofilm - an appetizing blend of bacteria, sugars, proteins and bacterial DNA."
- Carla Ross, http://www.seedsofwonder.typepad.com/

Quorum sensing


A fascinating example of the level of cooperation that occurs during biofilm formation is a phenomena called quorum sensing. Like an early pioneer of the American West writing home to describe the wonders of California, the first bacterial colonists secrete a variety of signaling molecules which act on receptors of other bacteria, inducing them to alter their own genes to allow them to adhere to the biofilm and produce additional signaling molecules of their own to attract additional followers. Quorum sensing is not limited to bacteria: it can be observed in many social species such as ants and honey bees.

"A bacterial quorum is not unlike the human variety - as soon as enough individuals are gathered together, decisions can be made. For bacteria, these decisions result from the production of signals that switch on genes involved in processes such as virulence."
- Alison Mitchell [Nature Reviews Molecular Cell Biology 2, 488 (July 2001)]



Signaling for biofilms



Biofilms are an object of intense scrutiny in biomedicine and may provide insight into why certain infections, such as chronic Lyme Disease, appear so entrenched and difficult to eradicate in some patients. Most interest centers on discovering substances that interfere with the signaling (called auto-inducers or pheromones) that are involved in quorum sensing. The two most common auto-inducers seen in bacteria are know as AHL (N-Acyl Homoserine Lactones) and Auto-inducer family (AI-2, AI-3).

AHL


AHL are signaling molecules found in many gram negative bacteria. Common gram negative bacteria include H. pylorii (ulcer causing bacteria), Samonella (food poisoning), Neisseria gonorrhoeae (gonorrhea) Spirochetes (Lyme disease), Proteus and E. Coli (urinary tract infections). They are inactivated by an enzyme called lactonase. Interestingly, a major source of lactonase activity is via the PON1 gene, which codes for the enzyme paraoxonase. The main effect of paraoxonase is to provide a way to block the artery clogging effects of LDL (the 'bad') cholesterol by enhancing the antioxidant functions of high-density lipoprotein (HDL).(1) Paraoxonase also blocks the toxic effects of common pesticides called 'organophosphates.' Although speculative, once could surmise that bacterial biofilm activity, requiring the utilization of lactulone to inhibit further quroum sensing, might exhaust paraoxonase activity to the point which it can no longer provide adequate protection against lipid peroxidation: in essence, an additional link between chronic infectious states and cardiovascular disease. Pesticide detoxification also drains paraoxonase activity as well, leading to one researcher speculating that early (prenatal) pesticide exposure and variants of the PON1 gene might explain some of the causes for increased rates of autism. (2)



Several natural products, including quercetin, a ubiquitous plant bioflavanoid, pomegranate juice and NAC (n-acetyl cysteine) have been shown to increase paraoxonase activity, though the studies have been largely done in tissue culture or on rats.(3,4) There is quite a bit of variation (polymorphisms) in the PON1 gene and it is doubtful that the animal quercetin studies are extendable to humans, as each species metabolizes quercetin somewhat differently. (5)



Auto-inducers AI-2, AI-3


The second series of signaling molecules used in quorum sensing are the 'auto-inducer' family, typically number 1 through 3. Unlike the AHL family the auto-inducers work on both gram negative and gram positive bacteria. Common gram positive bacteria include Staphylococcus, Streptococcus, and Clostridium (botulism). The auto-inducers are one of the very few biologically active family of molecules that contain the element boron. Some evidence indicates that foods containing furocoumarins inhibit their signaling. Common furocourmains in the diet include grapefruit juice and bergamot.(6) Some species of seaweed are also being investigated for their ability to 'jam' bacterial signalling. (7)

Stress and biofilms
The stress hormone norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase. The gene for dopamine β-hydroxylase has shown some association linkages with the gene that controls ABO blood type. (8) Norepinephrine can substitute for the AI-3 auto-inducer and result in biofilm growth. Both epinephrine and norepinephrine are present throughout the gastrointestinal tract. Since the major link between ABO and dopamine appears to be via the null alleles (people who are type O blood) we could hypothesize that blood group O individuals who are highly stressed (or otherwise hyper-adrenalized) may have more problems with infections or overgrowth in the gut. This may be especially relevant for those type O individuals who possess the 'Hunter' epigenotype.



Phytomedicinals and Biofilm Inhibition

Andrographis paniculata
Since ancient times, Andrographis has been used in traditional Siddha and Ayurvedic systems of medicine as well as in tribal medicine in India and some other countries. The plant extract exhibits antityphoid and antifungal activities. (9) Andrographis is also reported to possess hepato-protective, antibiotic, antimalarial, and anti-inflammatory properties (10) Andrographolide, the main active component of the herb Andrographis paniculata was recently reported to act by inhibiting the bacterial quorum sensing system. (11) A recent study using variations (analogues) of andrographolide verified this observation. (12) Andrographis has unquestioned activity in chronic respiratory problems. I think the next few years will witness this plant assuming a precedence in infectious disease management that few herbs (with perhaps the exception of Artemesia annua for malaria) ever achieve.

Scutellaria baicalensis
Chinese Skullcap flavonoid is a member of the mint family and has long been used in traditional Chinese herbal medicine, as a digestive aid, and to normalize an over-active digestive system. Scutellaria has been shown to decrease inflammatory cytokine production from human mast cells (immune system hormones which ramp up inflammation). Scutellaria also has a cell-regulating effect; encouraging the body to more efficiently remove cells which have become dysfunctional, either though age or malformation. (13) Baicalein, a flavone found in the leaves of Scutellaria, has been shown to effect the ability of bacteria to adapt to antibiotics.Bacteria become resistant to medication such as antibiotics by maximizing their ability to flush them out of their cell bodies. Scutellaria blocks this by inhibiting the removal (efflux) of the drug though what are called MDR ('multiple drug resistance') pumps. When used with antibiotics, Baicalein noticably increased the efficacy of several antibiotics. (14) Chinese Skullcap has a variety of actions in the body but I've found that the real benefit of the herb in instances of infection is its remarkable ability to limit the ability of microbes to develop resistance to medication. There is also some evidence that Chinese Skullcap is directly damaging to the bacteria outer membrane as well.

Schisandra chinensis
A renowned herb in Chinese medicine, Schisandra invigorates the RNA-DNA molecules to reconstruct cells and enhance the fitness of the adrenal glands. Adaptogenic herbs, like schisandra, have been used in Traditional Chinese Medicine to improve the ability of the body to respond to stress. (15) The major constituents in schisandra are lignans (schizandrin, deoxyschizandrin, gomisins, and pregomisin) found in the seeds of the fruit. Modern Chinese research suggests these lignans have a protective effect on the liver and an immunomodulating effect. (16)

Rhizoma Atractylodis Macrocephalae
Practitioners of Chinese medicine believe that Atractylodes affects the Spleen and Stomach meridians, or energy pathways in the body, serving as a "Spleen Qi tonic," meaning that it rebuilds metabolic function by increasing nutrition, increasing energy, and regulating fluids. White Atractylodes is also thought to have restorative, normalizing effects on the digestive system and liver. (17)



Eleutherococcus senticosus
This herb is also known as Siberian ginseng. The applicable parts of Siberian ginseng are the root and leaf. The lignin constituent sesamin, and the phenylpropanoid syringin seem to have immunostimulatory effects. (18) Long known as an adaptogen, Siberian Ginseng is considered to possess stress modulating effects, including optimization of the HPA (hypothalamus-pituitary-adrenal) 'fight or flight' stress axis. Siberian ginseng and Schisandra chinensis stimulate of expression of chemicals (Hsp70, Hsp72) involved in the chemical defense against stress. (19)



References

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  2. D'Amelio M, Ricci I, Sacco R, Liu X, D'Agruma L, Muscarella LA, Guarnieri V, Militerni R, Bravaccio C, Elia M, Schneider C, Melmed R, Trillo S, Pascucci T, Puglisi-Allegra S, Reichelt KL, Macciardi F, Holden JJ, Persico AM. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.
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  5. You Y, Fu JJ, Meng J, Huang GD, Liu YH. Effect of N-acetylcysteine on the murine model of colitis induced by dextran sodium sulfate through up-regulating PON1 activity.Dig Dis Sci. 2009 Aug;54(8):1643-50. Epub 2008 Nov 26
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  7. University Of New South Wales (2004, December 8). New Weapon In Germ Warfare: 'Jamming' Bacteria Signals Stops Cholera. ScienceDaily. Retrieved March 24, 2010, from http://www.sciencedaily.com /releases/2004/12/041208083233.htm
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  14. Lee Y, Yeo H, Liu SH, Jiang Z, Savizky RM, Austin DJ, Cheng YC. Increased anti-P-glycoprotein activity of baicalein by alkylation on the A ring.J Med Chem. 2004 Oct 21;47(22):5555-66.
  15. Liu KT. Studies on fructus Schizandrae chinensis. Annex 12: Studies on fructus Schizandrae chinensis. Plenary lecture, World Health Organization (WHO) Seminar on the Use of Medicinal Plants in Health Care, Sept 1977
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