Cpn theory: Effect of pH on Cpn
Cpn theory: Effect of pH on Cpn
For a few years I have considered that lowering intracellular pH (pHi) might be beneficial for treating Cpn. I suspected that this would be a logical signal to induce Cpn into an EB state which should make it more susceptible to antimicrobial agents as it is most vulnerable during its subsequent conversion from EB to RB state and additionally may have to give up its resistance mechanism. The reason I believed that lower pH triggers the EB state was originally based upon observations of the effect of many acidic substances such as ascorbic acid, exercise, NSAIDs, caffeine, ect. And it seemed logical that this would be the trigger that Cpn used as pH would drop in cells where (1) there was an overgrowth of RBs, (2) the cell was undergoing apoptosis, or (3) the cell was dying from necrosis. In all of these cases, it would benefit Cpn to condense down to the EB state.
Interestingly Cpn has Na+/H+ exchangers/pumps. Typically these pumps lower pHi by exchanging hydrogen ions for sodium. IMO it makes little sense for Cpn to have this mechanism as an intracellular pathogen should be able to rely on the host cell's buffering mechanisms. It is also noteworthy that Cpn's genome only has about 36% homology to these pumps. This is surprisingly low as other bacteria average 65% homology. So I suspect these incomplete Na+/H+ pumps actually are used only to monitor pH levels and when it drops to some thresh hold value, produce some other result aside from exchanging hydrogen ions for sodium that induces conversion to the EB state.
For the last couple of years I and a few others have been testing this idea with various agents that help lower pHi. The results have been very good although perhaps not as good as I had originally hoped. This approach seems to work about twice as fast and with about half the side effects as some of the other approaches but it still takes a couple of years for many people.
More recently the lab work has begun to catch up with the clinical testing and Dr. S. has shown in vitro that lowering pH with lactic acid causes an 8 fold decrease in the production of HSP-60. This recovers to the control levels after about 24 hours. The most likely cause of these results seems to be that the lower pH induces the EB state.
There are a variety of ways to lower pHi:
(1) Anaerobic metabolism lowers pH very efficiently. Historically this was thought to be from a build up of lactic acid although that is no longer believed to be true. It is pretty easy to induce anaerobic metabolism in skeletal muscles but more difficult in other parts of the body. However I think that Cpn (like all bacteria) use efflux pumps to remove environmental toxins. I think they pump out most/all antimicrobial agents and this is metabolically expensive. So taking many of the antimicrobial agents can contribute to lowering pH. I also think that it expends energy to pump out nitric oxide as this is the host cell's natural antimicrobial defense. The downside of relying only on this approach is that infected cells are "starved" of ATP for prolonged periods of time. This can cause a number of problems and specifically is probably the cause of secondary porphyria as cells are always producing heme and some of the steps in the process of converting porphyrins to heme require ATP.
(2) Expelling calcium which is a base or buffer is another way to help lower pHi. Caffeine induces this through causing ryanodine receptors to release calcium. This is a very novel way to help lower pH but caffeine does have the drawback of poor penetration in joints and skin. There is a new disease modifying RA drug (tenidap) in the works that appears to also lower pH through expelling calcium. This could be interesting as presumably being used for RA, it penetrates into joints.
(3) Acidic agents can also contribute to lowering pHi although I think there are some caveats. Cells tend to be a little more acidic than the surrounding fluid. So it takes an active mechanism to transport acidic molecules across the gradient. Substances that can contribute to lowering pHi should be ones that cells have a need for (or are molecularly similar to these). Some of the obvious ones are ascorbic acid (pKa 4.17), cobalamin (pKa 2.7), taurine (pKa 1.5), and niacinamide (pKa 0.5). There are a wide range of these that work to some degree or another but I doubt if they can be used alone as it seems unlikely that a cell would just continuously keep taking up something like ascorbic acid. In topical areas it is easy enough to flood cells with an acidic agent which can be very useful. Examples are the various agents used for "peels" such as salicylic acid (pKa 2.98), lactic acid (pKa 3.83), glycolic acid (pKa 3.83), ascorbic acid (pKa 4.17), etc. In sinuses cromolyn (pKa 1.1) (Nasalcrom brand) works well.
As time permits, I will start another forum topic to discuss some possible therapeutic approaches and Cpn's mechanism of resistance.