Virology and Microbiology Articles:
This article orginally appeared in several parts on the ProMED-mail email list. It is reproduced here with permission of Dr. Nash.
Chronic Diseases With Possible Infectious Etiologies
by Hal Nash, Ph.D.
Introduction
In 1979, curved bacterial cells (vibrios) were isolated from stomach biopsies from patients with gastric ulcers. Researchers J. Robin Warren and Barry J. Marshall succeeded in inoculating themselves with Helicobacter pylori and consequently developed transient gastritis. They then hypothesized that many if not most cases of gastric ulcers were the result of an infectious etiology rather than of organic etiology. Such an hypothesis rocked the medical as well as the microbiological communities. The method of "doing science" put Warren and Marshall's hypothesis to the test. In the ensuing two decades, their hypothesis has been supported.
This discovery was a landmark case for the search for infectious etiologies for chronic diseases, although such an idea has existed for many years. Such a search has been waiting for particular developments in molecular biology. From the late 70s to the present, dramatic advances in the study, isolation, and function of molecular entities have occurred. In the space of less than a generation, the tools necessary to engineer molecules, splice, excise, and change those molecules have become commonplace. This is the moment that the search for infectious etiologies has been waiting for. An excellent article by David A. Relman, "Detection and Identification of Previously Unrecognized Microbial Pathogens," contains an excellent, general treatise of the subject of molecular biology and its application to microbial identification. The article can be found at (http://www.cdc.gov/ncidod/EID/vol4no3/relman.htm).
Chronic diseases are by definition, as well as by nature, much more subtle than acute diseases. The obvious is not present. Rather, the subtleties require the exquisite abilities of molecular biology to detect incredibly small evidences of microbial activity, or the remnants of such activity. Prior to this generation, the tools for such detection simply did not exist or were not available to a large extent. Borrowing from the language of nuclear physics, we have reached a critical mass for the study of chronic diseases with suspected infectious etiologies.
What follows are brief synopses of several chronic diseases whose causes are suspected to be microbial in origin. It would be foolish to assume that this is an exhaustive compilation. Rather, I have started with recent postings on ProMED-mail and other sources for information on emerging diseases. I wish to thank everyone who responded to my requests for information on the various diseases addressed here. I believe it is noteworthy that everyone to whom I wrote responded with useful information. And in light of that, it is unmistakeable evidence of the service provided by SatelLife and ProMED-mail.
Chlamydia and neurological complications
Three species of Chlamydia have been implicated in the production of neurological symptoms.
Chlamydia pneumoniae has been reported to have caused cases of meningitis/meningoencephalitis, Guillain-Barre syndrome, and cerebellar ataxia, all of these on the heels of respiratory infections. Additional serological evidence exists for central nervous system involvement.
Chlamydia psittaci is implicated in encephalitis involving several cranial nerves. Additionally, Guillain-Barre syndrome, transverse myelitis, and cerebellar ataxia have been associated with this organism. Subsequent refinement of molecular techniques has attributed a significant number of C. psittaci cases to C. pneumoniae .
Chlamydia trachomatis , most infamous for the sexually-transmitted diseases it causes, has also been associated with meningo-encephalitis. Such accounts are not just recent ones, but some are from over 50 years ago. However, the advent of modern molecular biology techniques is enabling more rapid and accurate identification today.
References:
Korman TM, Turnidge JD, Gra\yson ML. Clin Infect Dis 1997; 25:847-851.
Koskiniemi M, et al. Eur Neurol. 1996; 36(3):160-163.
Koskiniemi M, et al. Eur J Pediatr. 1997; 156:541-545.
Chlamydia and cardiovascular disease
The link between Chlamydia pneumoniae and at least a portion of cardiovascular disease is likely to be as striking as was the infectious link to ulcers. Cardiovascular disease has generally been viewed as a "lifestyle disease," one associated with diet and sedentary living. From several places around the globe, evidence exists that antibodies to C. pneumoniae occur at higher levels than expected in coronary artery disease and heart attack patients.
Additionally, C. pneumoniae has been isolated from diseased coronary arteries.
Animal studies indicate that deliberate infection of test animals result in the production of atherosclerotic plaques. Moreover, antibiotic therapy prevents atherosclerosis in test animals. Normal arteries fail to yield C. pneumoniae upon sampling.
Chlamydia is an obligate intracelluar parasite and by its nature potentially typifies the difficulty of providing unambiguous evidence for its role in cardiovascular disease. A few responses I received described some of the problems in Chlamydia testing. Due to its intracellular chronic behavior, often amplification of genome fractions is required by PCR. Failure to find C. pneumoniae DNA does not necessarily mean the organism is absent. Its antigen could well be present. A few respondents mentioned the need for a "gold standard" in Chlamydia detection. One test, the microimmuno-fluoresence (MIF) test, was suggested for consideration.
These comments are not to minimize the link between C. pneumoniae and cardiovascular disease. Rather, they are evidence of the process of science.
References:
F. Blasi, et al. 1996. Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms. J Clin Microbiol 34:2766-2769.
Muhlestein JB, et al. J Am Coll Cardiol. 1996; 27(7):1555-1561. (demonstrates presence via direct immunofluorescence)
The following five references demonstrate the lack of C. pneumoniae in normal arteries:
Shor A, et al. S Afr Med J. 1992; 82(3):158-161.
Kuo CC, et al. J Infect Dis. 1993;167(4):841-9.
Kuo CC, et al. Arterioscler Thromb. 1993; 13(10)1501-1504.
Campbell LA, et al. J Infect Dis. 1995; 172(2): 585-588.
Grayston JT, et al. Circulation. 1995; 92(12):3397-3400
Ramirez JA, et al. Ann Intern Med. 1996;125:979-982. (Isolation from samples of atherosclerosis)
Maass M, et al. J am Coll Cardiol. 1998;31(4):827-832. (Isolation from samples of atherosclerosis)
Fong IW, et al. J Clin Microbiol. 1997; 35:48-52. (Nasal inoculation of test animals with appearance of atherosclerosis)
Muldowney III JAS. Chlamydia pneumoniae: A Treatable Cause of Atherosclerosis? Antimicrobics and Infectious Diseases Newsletter, Vol 16 Number 1 (March 1998) p. 1-4.
Laitinen K, et al. Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits. Inf and Imm. 1997. Vol 65, p. 4832-4835.
Coxsackie B4 and Diabetes Type I
Evidence exists for a link between prior enterovirus infection and the onset of type I diabetes. The enterovirus most often implicated is Coxsackie B4. Study is underway to determine which, if any, of the viral proteins elicits the autoimmune response typical of this form of diabetes.
It appears that it still cannot be said that Coxsackie B4 virus causes type I diabetes. However, the evidence seems to have established this virus as a trigger to the development of diabetes.
In addition, a study was done in which eight individuals with chronic fatigue syndrome were positive for enteroviral sequences related to the Coxsackie B-like viruses.
References:
Galbraith DN, et al., Evidence for enteroviral persistence in humans. J Gen Virol 1997 Feb; 78 (Pt 2):307-312.
Schmidt WA, et al., Course of coxsackie B antibodies during juvenile diabetes. Med Microbiol Immunol (Berl) 1978;164(4):291-298.
Turzkiewicz-Misztal E, Epidemiologic factors and serum antibody titer to Coxsackie B-4 virus in patients with type I diabetes. Kinderarztl Prax 1991 Mar,59(3):88-91. (article in German)
Retrovirus implicated in Type I Diabetes
A retroviral antigen, produced from an integrated retrovirus, has been shown to trigger lymphocyte activation and the subsequent destruction of beta cells in pancreatic islets (Islands of Langerhans) leading to diabetes.
Comments from some respondents indicated that the etiology of diabetes type I is likely not one agent, but rather multifactorial. The addition of a retrovirus to the list of suspected etiologic agents of diabetes type I lends weight to the recent pronouncement by the World Health Organization that by the year 2010, there will be 240 million diabetics, with the majority in developing nations.
References:
Conrad, B, et al. A Human Endogenous Retroviral Superantigen as Candidate Autoimmune Gene in Type I Diabetes. Cell 1997, 90:303-313.
Borna virus and mental illness
Perhaps as challenging to organic disease dogma as were H. pylori and C. pneumoniae is Borna disease virus and its suspected role in causing mood disorders and schizophrenia.
The virus was initially isolated from a variety of domestic and wild animals, mostly mammals but also ostriches. A wide variety of behavioral, mental, and motor symptoms have been observed. Typically, the virus targets peripheral neurons and spreads toward the central nervous system. In animal studies, the virus targets the limbic system and hypothalamus. In humans, recent data revealed the presence of genetic traces of the borna virus in the blood of a schizophrenic patient. Researchers cautioned that borna virus in the blood does not prove that the virus causes psychiatric symptoms.
Also, borna virus was recently isolated from monocytes from patients with mood disorders. Viral markers coincided with acute episodes of mood disorders. The researchers proposed that such findings might pave the way for new treatment strategies should evidence continue to mount supporting borna virus as a contributor to at least some mental illness.
References:
Bode L, et al., Molecular Psychiatry 1996; Vol 1, Issue 3 (July 1996). (Borna virus and mood disorders)
Bode L, et al., Proc Natl Acad Sci USA 1994 May 10;91 (10): 4362-6. (Genomic organization of Borna virus)
Bode L, et al., Nat Med 1995 Mar; 1(3):232-6. (Genomic organization of Borna virus)
The Lancet 1998; 352:623. (Genetic traces of borna virus in schizophrenic patient)
Hatalski CG, et al., Borna disease. Emerging Infectious Diseases, April-June 1997, Vol 3 No 2. (http://www.cdc.gov/ncidod/EID/vol3no2/hatalski.htm)
Escherichia coli and colorectal cancer
Certain studies provide evidence that some colorectal cancers are the result of infectious agents. One group found that bacterial methyltransferases induced mutations in tumor suppressor genes. Another group focused on the presence and absence of certain intestinal bacteria concluding the possibility that some microflora might serve as promoters while others might serve as anti-promoters of colorectal carcinogenesis. Finally, a third group concentrated their studies on colicins, which are antibiotically active substance, some of which have been found to exert antitumor effects. This group found that the absence of colicinogenic E. coli might be a contributing factor in the development of colorectal carcinoma.
Further implication of E. coli in colorectal cancer was found when researchers concluded that in their sample, the patients with colorectal cancer had mucosal, intracellular invasion by E. coli while those with no colorectal cancer had no such mucosal invasion.
References:
Swidsinski A, et. al. 1998. Association between intraepithelial Escherichia coli and colorectal cancer. Gastroenterology 1998. Aug:115(2):281-286.
Bures J, et. al. 1986. Colicinogeny in colorectal cancer. Neoplasma. 1986;33(2):233-237.
Onoue M, et. al. 1997. Specific species of intestinal bacteria influence the induction of aberrant crypt foci by 1,2-dimethylhydrazine in rats. Cancer Lett. Feb 26;113(1-2):179-186.
Schmutte C, et. al. 1996. Mechanisms for the involvement of DNA methylation in colon carcinogenesis. Cancer Res. May 15;56(10):2375-2381.
Human papilloma virus and anal cancer
In a report about a year old, researchers made a strong connection between human papilloma virus and the development of anal cancer. The viral DNA was detected via PCR in 84% of anal cancer tissues, while none of the rectal adenocarcinomas [control group] were positive for the viral nucleic acid. Sexual transmission, high numbers of sex partners, and male were all associated in increased risk of development of this disease.
Reference:
Frisch M, et. al. 1997. Sexually transmitted infection as a cause of anal cancer. New England Journal of Medicine. Nov. 6; 337(119):1350-1358.
Mycobacterium paratuberculosis and Crohn's / Johne's Disease
In the few respondents regarding Crohn's Disease (CD), the consensus was that there was no consensus. One respondent was so confident that the link between Mycobacterium paratuberculosis and Crohn's Disease was so clear that it warranted an end of discussion comment. Another respondent indicated that there was an obvious connection but one which needed heavy funding to finally hammer out the details of the organism's involvement in the disease. A third respondent confessed that the organism plays a role in the disease but that its role is, as understood now, tenuous at best.
Such comments, from people who should know, illustrate the insidiousness and ambiguity that chronic infectious agents display in causing human pathology. I make this comment not toward the researchers, but rather to the organisms for the subtleties they are capable of displaying. Mycobacterial species are well known for their cell wall structure and composition. But interestingly, M. paratuberculosis both with and without cell walls (in other words, as spheroplasts) has been isolated from CD patients. This immediately highlights the need for other detection methods.
Genetic probes, epidemiologic evidence, and antimicrobial therapeutic evidence exist for implicating M. paratuberculosis as an etiologic agent in CD. Most of the evidence contains at least some conflicting data, yet the supporting evidence is strong enough to suggest M. paratuberculosis is a significant complicating factor in CD.
Johne's Disease is a chronic intestinal disease of ruminant animals resulting in wasting and diarrhea. M. paratuberculosis appears to have been clearly implicated in this animal disease. A goat was infected with the organism taken from a human patient with Crohn's Disease and showed progression to Johne's Disease.
In the United Kingdom, enough evidence for a causal relationship between the organism and CD exists for the Government to conduct health tests on milk after it was shown that M. paratuberculosis was surviving pasteurization.
References:
Tremaine, WJ. 1996. Pathology and pathophysiology of symptoms, p. 93-112. In C. Prantera and BI Korelitz (ed.), Crohn's Disease, 1 ed. Marcel Dekker, Inc., New York.
Van Kruiningen, HJ, et. al. 1986. Experimental disease in infant goats induced my a Mycobacterium isolated from a patient with Crohn's disease. A preliminary report. Digest Dis. and Sci. 31:1351-1360.
Chiodini, RJ. 1989. Crohn's disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev. 2:90-117.
Collins, MT and E Manning. 1995. Johne's disease: An international perspective, p. 313-316. In Anonymous 99th ed.
Polycystic kidney disease
Polycystic kidney disease (PKD) occurs as an autosomal dominant or autosomal recessive disease. The autosomal recessive form is quite rare and frequently causes high mortality during the first month of life. In PKD, fluid-filled cysts form within the kidneys encroaching upon the kidney’s ability to filter the blood. Numerous cysts are possible and range in size from grains of sand to grapefruit.
The emergent infectious character of the disease was revealed in a 1984 study in which PKD[-prone] mice survived long into adulthood when raised under germ-free conditions, but their litter mates exposed to the environment developed cysts early and succumbed soon after. This obviously suggested an environmental contributing factor in the triggering of the disease. Additional studies showed that administration of lipopolysaccharide (LPS), also commonly referred to as gram negative bacterial endotoxin, produced higher rates of cyst formation than commonly seen when the genetic trait is left to act alone.
Current research has detected endotoxin in kidney cyst fluid in addition to a constituent of fungal and yeast cell walls. Through immunologic assay, the endotoxin was found to be reactive with several enterobacteriaceae and has led to a recently proposed hypothesis of a "leaky gut component" in PKD pathophysiology. Up to 80% of PKD patients demonstrate colon pathophysiology. Analysis of the fungal component also implicated seeding of renal tissue from the gut.
References:
Miller-Hjelle MA, Hjelle T et. al. 1997. Polycystic Kidney Disease: An unrecognized emerging infectious disease? Emerging Infectious Diseases, April-June; 3(2):113-127.
Miller-Hjelle MA, Hjelle T et. al. 1998. Polycystic Kidney Disease: An emerging infectious disease in genetically vulnerable persons? Current Anti-Infective Therapy. 18(3):4-5.
An adenovirus linked to obesity
Alterations in metabolic pathways manifest themselves in altered function, regardless of what caused the alteration. Researchers have reported that chickens notably low in serum cholesterol and triglycerides, after being infected with human adenovirus-36, developed visceral obesity to a degree that would not be expected.
Eighteen percent of the obese chickens, and zero percent of the lean, showed neutralizing antibodies to adenovirus-36. Repeated results were found in mice infected with human adenovirus AD-36P.
When screening human sera for an avian adenovirus it was found that the body mass index was higher for those positive for the adenovirus than for those who were negative.
Researchers are still in the early stages of linking at least a portion of obesity cases to an infectious etiology. Questions still remain regarding the mechanism by which the virus might disrupt metabolism and cause increased adiposity.
References:
Dhurandhar NV, et. al. 1997. Evidence for an association of a virus with obesity in humans. The FASEB Journal. Feb. 28, 1997. 11(3).
Atkinson RL, et. al. 1997. Production of obesity in mice with a human virus. The International Journal of Obesity. June. Vol. 21, Supplement 2.
Dhurandhar NV, et. al. 1996. Development of obesity in chickens after infection with a human adenovirus. Obesity Research. October. Vol. 4, Supplement 1. Page 248.
Dhurandhar NV, et. al. 1992. Screening of human sera for avian adenovirus antibody. International Congress on Obesity. Lake Geneva, Wisconsin. July 1994.
Dhurandhar NV. 1992. Effect of adenovirus infection on adiposity in chickens. Veterinary Microbiology, 31:101-107.
Conclusion:
Even a cursory examination of this sort reveals the enormous complexity facing the elucidation of the pathophysiology of chronic infectious disease states. Chronic disease, by definition and by nature, will always present the greater challenge to the researcher. But with today's molecular biological tools, research has the ability to provide answers.
The tremendous strides made by infectious disease research since the days of Robert Koch have led to great expectations of the infectious disease control community. Time and again, that community of researchers has delivered. However, acute disease lends itself to easier discovery than that of chronic disease, as has been seen by the easier application of Koch's postulates to acute disease. And so it was that acute diseases were more naturally dealt with in the history of microbiology. It might not be fair to expect the same from chronic infectious disease research.
Some respondents to my queries made occasional references to Koch's postulates. In having to read between the lines, it appears that perhaps those who determine funding, or those who determine projects worthy of funding, might be trying to apply Koch's postulates to the study of chronic diseases. This might not be a fair thing to do. >From the diseases addressed in this synopsis, it is clear that when investigating chronic diseases, by their very nature they cannot be made to fit into the framework of Koch's postulates. Those postulates cast an enormous light on our understanding of infectious diseases ... of the acute type.
The earliest forms of life on Earth were of a prokaryotic nature, bacteria which [now] live on and in and occasionally parasitize virtually every life form on the planet. It should not be surprising that, considering that they were here first, they should colonize human bodies in nearly unimaginable ways. And it should not be surprising that some of those ways be subtle. And that the subtleties have varying degrees depending on the nature of the host (and just how varied that alone can be!). This realization is a necessity for those in positions of funding and decision-making regarding research into chronic diseases.
Hal B. Nash, Ph.D.
Assistant Professor of Biology
Western Wyoming College Rock Springs WY 82901
E-mail: hnash@wwcc.cc.wy.us
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