Chlamydia pneumoniae and MS: Questions and Answers

What is the life-cycle of C pneumoniae?

Simplifying slightly, C pneumoniae has two major phases to its life cycle. The infectious form is called the Elementary Body (EB). This spore-like form transmits the organism from person to person and, within a person, from cell to cell. The EB is metabolically inert; it has an external membrane which includes potentially unstable proteins. When it attaches to a susceptible host cell a sudden change takes place; the proteins which are embedded in its external membrane become loose and the host cell wall closes behind the entering EB. Entry may be controlled by subversional proteins injected into the host cell via tiny syringes and needles (The type III secretory system. Proteins associated with the TTSS have been found in the EB proteome.)

Once inside the host cell, the organism expands to become the Reticular Body (RB). It efficiently uses host membrane to make its own environment within a cell. Then it takes up its position around the host's mitochondria to steal the energy-rich molecules fabricated by these organelles, probably by means of small tubes. The RB then begins to control the direction of the host-cell metabolism, again probably using microscopic syringes and needles. Its own nuclear material eventually divides into many separate individuals, which then condense into EBs. The host cell bursts, scattering EBs into the extracellular milieu. This is the picture in cell-culture and is the likely picture in acute infections.

In chronic infections a different pathway is taken. Under pressure from host defences the organism enters into persistent state, where its metabolic processes are diminished. The organism in this state is called the Cryptic Body (CB). This chronic unresolved infection - which can last for several decades - can initiate the malign process of autoimmunity. To a large extent the form of the disease depends on the host's genetic inheritance. This is why many of the chronic disease forms caused by infections with Chl pneumoniae tend to have inherited characteristics. An excellent and readable account of how peristent unresolved infections can initiate chronic diseases with autoimmune aspects can be found in this dissertation by Tiina Sävykoski:

How might Chlamydia pneumoniae reach the brain?

The organism settles on some part of the respiratory lining and then invades. A respiratory infection (sinusitis, bronchitis, pharyngitis or pneumonia) results. Host defence cells mop up the organism; some become parasitized. Chl pneumoniae can travel round the body in the blood monocytes - mobile host defence cells - when these are called to deal with a remote infection - perhaps a transient virus infection. As the monocytes pass through the blood vessel walls, Chl pneumoniae are shed; these infect the lining cells. Microcolonies of Chl pneumoniae are set up. This can happen in the brain, in joints, in the vessels which supply the great arteries themselves, and in the skin. See [Gieffers J, et al., Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature. Eur Respir J. 2004 Apr;23(4):506-10.]

MS is a many-staged and complex disorder. How can a simple bacterial colonisation/infection cause such complexity?

MS has four variants: relapsing-remitting, where neurological deficits occur suddenly and resolve over a few weeks. Resolution is at first usually complete; later, it is less so. Although called relapsing-remitting, most patients gradually accrue deficits. The disease may change to the secondary-progressive form; remissions are now unusual and deterioration is the rule. The third variant is the primary-progressive form, where the disease worsens from the beginning. The fourth, or so-called benign form, describes rare cases where resolution is always complete; the deficits themselves may cease to happen. (It is unwise to use this term as MS can become aggressive twenty years after its first mild appearance.)

All these forms and stages would correspond well with an established Chlamydia pneumoniae infection in the brain. In the relapsing-remitting form the infection is silent until a new respiratory infection provokes a new host response. This tends to become more severe as time goes on. (Parallels are seen in the increasing severity of pneumonias caused by Chlamydia pneumoniae in those who suffer repeated infections after seroconversion: the severity is caused by the increasing strength of the host response.) In the progressive forms the host response is continuously firing, often against an extracerebral bacterial infection; a patient with early SPMS will often mention chronic sinusitis, chronic middle ear disease or new-onset asthma which began some time before the MS began to slide into the progressive phase. Sarah experienced a prolonged respiratory infection followed by new-onset asthma before her illness became progressive.

MS has a genetic component. It also has a marked geographical distribution. How do you account for this, given that Chl pneumoniae is ubiquitous?

MS has a pronounced geographical distribution. It is most common in the cooler latitudes, becoming rarer as the tropics are approached. Migration from temperate to tropical areas confers protection, provided the move is made before adolescence. People who migrate to temperate areas are more likely to develop MS than those who have remained behind.

The epidemiology of MS is not as simple as this, however. The disease has an increased incidence in certain groups of women in the Middle East. The common factor seems to be a seasonal or cultural reduction in exposure to sunlight; in those with a genetic predisposition a relative lack of Vitamin D develops. Vitamin D deficiency is indeed found in those with MS; it is linked to calcium and magnesium deficiency and to osteoporosis. By contrast MS is extremely rare amongst the Inuit, who, though living through arctic winters, derive ample Vitamin D from a fish-rich diet.

Vitamin D is vital for the maintenance of the blood/brain barrier. Not only may a mild Vitamin D deficiency allow ingress of Chl pneumoniae; it may also activate quiescent infections. The number of active white-matter lesions seen on MRI in persons with MS closely follows the seasonal fluctuation of levels of circulating Vitamin D.

Other infectious agents, notably Human Herpesvirus 6, have been put forward as causative agents in MS. How does this square with a primary Chl pneumoniae infection?

Human Herpes Virus 6 may have a secondary input into MS; read a brief note about this on page 5.

Can a chlamydial cause for MS be proved in an individual patient by serology?

Not at the moment. This because Chl pneumoniae is a common organism and infections with the bacterium are common. Antibody levels tend to rise during life, even in people who are asymptomatic. Patients with extracerebral infections of some duration (particularly reactive arthritis) can show high titres in the microimmunofluorescence test; it is generally reckoned that a titre of 1:512 or above, in the presence of appropriate clinical findings, supports a diagnosis of Chl pneumoniae disease. MS is different; the pathology is at the blood-brain barrier. One would not expect an elevation of circulating antibodies unless an extracerebral component to the infection were also present. This may be the case in progressive disease; there is a statistical elevation of antibodies in a group of such patients. This supports the idea of a chlamydial cause for MS, but makes no prediction in an individual. That is why treatment must at the moment be empirical.

Antibiotics have been around for more than sixty years: surely they must have been tried before.

Neurologists have speculated from the late 19th century that MS might have an infective origin. They were used to dealing with infections, particularly syphilis. I’m sure that penicillin, so effective against syphilis, would have been tried in MS. There is unexpected evidence that penicillins have some activity against chlamydiae; however, in the absence of meningitis but they do not achieve high concentrations in the CNS. By the time tetracycline was invented, neurology, and the received beliefs about the cause of MS, had changed. Neurologists now rarely saw patients with underlying infections and MS was considered a primary auto-immune disorder. And, too, there is a battle-weariness in the neurology establishment. So many hopes about finding a treatable cause for MS have been dashed over the decades. The mind-set of the neurological establishment needs to be changed. This will happen.

And, too, MS sufferers are often seen as people who are difficult to help. When I was a student it was customary to speak of the ‘typical mental attitude’ of those with established MS; this included an impression of blunted insight, a kind of insouciance, even euphoria. In these more politically correct days one does not speak like this any more, but there is an element of truth in it. Now that I think of MS as an infection, the answer becomes clear: this ‘typical mental attitude’ is a state of intoxication with bacterial metabolic products. Once seen it's not forgotten. A similar state is seen in other chronic infections. In the days before antibiotics persons with active tuberculosis were said to have a typical mental state. People who were nursing at the time still vividly remember this.

In addition to this (recalcitrant doctors and recalcitrant patients) the beginnings of recovery with antibiotics are not pleasant. The early bacteriolytic reaction can be alarming. And, as Sarah found, as-yet unorganised repair can cause function to worsen in the short term. This could easily lead to an early impression that antibiotics were unhelpful or even harmful and could have led to their discontinuance.

There was a lone voice in the 1950's and 60's who dissented from the strengthening auto-immune school: Dr Paul Le Gac. Page 9 gives links to pdf files of his papers and presentations.

Why doxycycline and roxithromycin (or azithromycin)?

Both are oral, both are active against Chlamydia pneumoniae, both are relatively inexpensive. They are relatively risk-free. They act synergically against test strains of the organism; giving both together would be the equivalent of giving a four-fold increase of each drug were it to be given alone. The drugs work on different steps in the bacterial protein synthesis pathway. Combination therapy reduces the chance of the emergence of resistance. Both drugs pass into the brain. Both reach good levels inside cells. This is very important. Both are well tolerated. Azithromycin is an alternative to roxithromycin. They deplete the organisms slowly: this is very important, as the release of bacterial endotoxins should not be sudden.

Rifampicin may also be considered. It, too, is synergic with doxycycline, penetrates the brain and is active intracellularly. It is not suitable for intermittent use. It is highly active, and, in patients with a large bacterial load, it may give rise to intense reactions.

Why are later short courses of metronidazole to be taken together with these antimicrobials?

Chlamydiae are complex organisms. Long ago their ancestors must once have been free-living bacteria which possessed their own energy-generating pathways. The transformation from EB to RB is an active change, and an active change implies the retention of at least some of these pathways. The ones with the most utility for this purpose would be anaerobic, and thus susceptible to metronidazole.

Doxycycline and roxithromycin block the replicating phase by inhibiting protein synthesis and may be expected to force the organism to maintain itself by using its own primitive anaerobic respiratory mechanisms. In this suspended state it would be susceptible to anti-anaerobic agents such as metronidazole.

This is borne out by clinical evidence. The administration of metronidazole after doxycycline in a patient with likely high-load Chl pneumoniae infection causes a bacteriolytic reaction more severe than that following the original administration of doxycycline.

However, there is a difference: in this leg of treatment there is no risk of the emergence of resistance, for the organism is unable to replicate. Metronidazole need thus be given in courses only as long as can be tolerated.

Five-day courses of metronidazole at three-week intervals, during continuous treatment with doxycycline and roxithromycin, would seem reasonable; at first, metronidazole may be limited to one or two doses on one or two days to judge the severity of reaction.

The eventual aim would be to give all three agents intermittently. This, the final leg of treatment, would entail a 14 day course of doxycycline and roxithromycin, with metronidazole given from day five for five days. (The reason for continuing doxycycline and roxithromycin for a few days after the metronidazole has been stopped is because these drugs both possess anti-inflammatory activity which may prevent a reaction to the organisms killed by metronidazole.) This course would be given once a month. After several months the intervals between the antibiotics would be cautiously extended.

Why this complex antibiotic regime?

The literature is filled with instances of treatment-failure in serologically-proven chronic Chl pneumoniae infections of non-CNS systems, whether macrolides, tetracyclines or rifampicin have been used. When the drug is stopped, even after months of treatment, serology rises, and the patient relapses.

The intensive cyclical regime of combined antimicrobials outlined here corrals the pathogen, initially halting replication, then eliminating stalled intracellular forms. Extracellular forms may be depleted by giving N-acetyl cysteine (see below.)

No single antimicrobial agent can be expected to achieve this effectiveness against every phase of the organism's life.

What are the expected reactions to the antibiotics?

There seems to be two components to the reactions experienced on taking the antibiotics.

The first is caused by elimination of bacterial fragments — endotoxins — and is characterised by shivering, influenzal symptoms and general malaise.

The second is caused by the release of metabolic toxins; waves of giddiness and feelings of unreality are quite common. They are alarming if not known about and understood. The strength and duration of these reactions depends largely on the bacterial load. In MS, particularly early relapsing-remitting MS, the bacterial load is likely to be small, and the reaction brief. In other conditions, particularly those with multi-system involvement, the bacterial load may be large and the reaction to antibiotics unpleasant and prolonged.

It may seem unlikely that doxycycline, roxithromycin and rifampicin can kill chlamydiae; they are, after all, considered to be bacteriostatic agents — normally they inhibit rather than kill bacteria. However, intracellular Chlamydia pneumoniae must continuously elaborate proteins to ensure its own survival within the host-cell.

The reaction to the metronidazole component of treatment is particularly severe as at this stage numerous bacteria are being killed. For this reason it may be best to give an initial course of one single day, followed by review. Prochlorperazine, 10mg orally, may be useful.

The patient can be reassured that a reaction to the antimicrobials are evidence of bacterial destruction and that they will end. And, too, the morale induced by physical improvement has to be set against them.

Isn’t giving antibiotics for a long time is a bad thing?

That depends on the illness. Long-term doxycycline is used fairly routinely for certain kinds of gum disease and for acne. Doxycycline is also used long-term in malaria prophylaxis.

Long-term use of these antibiotics engenders no real risk of an increase of resistance in other bacteria within the wider community.

Does the fact that antibiotics can roll back MS tell us something about the nature of the illness itself?

I think it does. Components of MS, at some stages and in some variants, may be:

A bacterial toxaemia. This may account for the mental fog, blunting of insight, greatly increased reaction times and many other non-specific symptoms which are hard to explain by demyelination alone, including fatigue; indeed, there is evidence of abnormal cortical activity. [Leocani L et al., Neuroimage. 2001;13(6 Pt 1):1186-92.] A toxaemia would be expected to resolve quickly with effective antibiotic treatment, as has happened here.

Early phenomena: local mass oligodendrocyte death and secondary demyelination. This is the sudden stripping away of the insulation of the nerve-fibres in the classical MS relapse. It is reversible, but recovery depends on the replacement of oligodendrocytes, the cells which produce and sustain myelin. Damage to the nerve fibres occurs even in early disease, but becomes more severe with time.

Loss of neurones.
[reviewed by Minagar A et al., Pathogenesis of brain and spinal cord atrophy in multiple sclerosis. J Neuroimaging. 2004; 14(3 Suppl): 5S-10S.] Neurone-loss has been shown to occur in MS and may cause eventual dementia. One might speculate that appropriate antibiotic treatment would prevent further neuronal loss. (Given that neurones are very susceptible to toxins, and that the brain has evolved an elaborate defence system for keeping toxins out, it is possible to speculate that the neuronal loss seen throughout the course of MS might be a direct result of chronic toxaemia maintained from within the brain itself.) Until fairly recently it was considered that, in the adult, lost neurones could not be replaced; there is now a lot of evidence that neuronal replacement occurs throughout life: neural stem cells are known to occur at various loci, including the hippocampus, sub-pial and periventricular area. [reviewed by Taupin P. Adult neurogenesis in the mammalian central nervous system: functionality and potential clinical interest. Med Sci Monit. 2005l; 11(7): RA247-252.] In addition, the brain is known to have considerable functional plasticity.

Many scientists now believe that Multiple Sclerosis to be a heterogenous group of diseases rather than a single disease entity. How does this fit with the idea infection with a single bacterial species?

Some scientists do consider MS to be a collection of different disease types. Lassmann et al. proposed a classification of MS based on the appearances of lesions. [Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. [Review]. Trends Mol Med 2001; 7: 115–21.]

One could argue that these different lesion types represent an immune response dependent on the patient's genetic inheritance: in fact this is a minor piece of evidence that a single pathogenic species is at the root of the disease.

Differences in host immune responses occur in many chronic intracellular infections. One such is leprosy, which can present in numerous different forms which very lesions very different in gross and microscopic appearance.

Can relapses occur after starting antibiotics?

In relapsing-remitting MS the major cause of relapse, a new respiratory infection with Chlamydia pneumoniae, will be prevented by the antibiotics. However, for the first six months or so it is possible for a relapse to occur secondary to a virus infection. This may be particularly likely in a household with young children.

Not all new deficits which occur during treatment are relapses, though: see page 10.

last updated 12th August 2011

return to ms-index page