Historical perspectives on the etiology of tuberculosis

Robert Koch's 1882 demonstration that the tubercle bacillus was the true cause of tuberculosis established a new understanding of causation in medicine. This scientific breakthrough set in motion an etiological revolution with vast implications for the control of infectious disease, and its ramifications are still being felt today.     

Pasteur, Koch and American bacteriology

This study traces American awareness of the work of Louis Pasteur and Robert Koch from the 1860s to the 1890s. In the years before the Civil War, American interest in germ theories had appeared at times of epidemics and persisted to a limited extent among physician-microscopists. Discussions of Pasteur's work occurred primarily in the context of spontaneous generation and antisepsis. Few Americans imitated his work on immunology or studied with Pasteur, but his work on immunity influenced their faith in the potential of bacteriology as a solution to problems of infectious disease. Koch's discoveries of the bacterial agents of tuberculosis and cholera stimulated American medical and public health interest in bacteriology in a more practical way. Americans learned Koch's methods by taking his courses and imported them directly into their own laboratories. A context of enthusiasm for science, educational reform, and problems of infectious disease associated with urbanization and changes in agriculture aided the growth of bacteriology in the American context.     

In vitro cultured Neoparamoeba perurans causes amoebic gill disease in Atlantic salmon and fulfils Koch's postulates

Amoebic gill disease (AGD) in marine farmed Atlantic salmon is of growing concern worldwide and remains a significant health issue for salmon growers in Australia. Until now the aetiological agent, Neoparamoeba perurans, has not been amenable to in vitro culture and therefore Koch's postulates could not be fulfilled. The inability to culture the amoeba has been a limiting factor in the progression of research into AGD and required the maintenance of an on-going laboratory-based infection to supply infective material. Culture methods using malt yeast agar with sea water overlaid and subculturing every 3-4 days have resulted in the establishment of a clonal culture of N. perurans, designated clone 4. Identity of the amoeba was confirmed by PCR. After 70 days in culture clone 4 infected Atlantic salmon, causing AGD, and was re-isolated from the infected fish. Diagnosis was confirmed by histology and the infectious agent identified by PCR and in situ hybridisation using oligonucleotide primers and probes previously developed and specific to N. perurans. This study has fulfilled Koch's postulates for N. perurans as a causative agent of AGD and illustrates its free-living and parasitic nature.     

Koch's postulates and the etiology of AIDS: an historical perspective.

This paper examines the debate over the human immunodeficiency virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) from an historical perspective. The changing criteria for proving the link between putative pathological agents and diseases are discussed, beginning with Robert Koch's research on anthrax in the late nineteenth century. Various versions of 'Koch's postulates' are analyzed in relation to the necessity and sufficiency arguments of logical reasoning. In addition, alterations to Koch's postulates are delineated, specifically those required by the discovery of rickettsiae and viruses in the early twentieth century and by the immunological testing developed after mid-century to demonstrate the links between elusive viral agents and two diseases, hepatitis B and infectious mononucleosis. From this perspective, an examination of the AIDS debate is constructed. Molecular biologist Peter Duesberg's argument that HIV is not the cause of AIDS is analyzed in light of his contention that a version of Koch's postulates has not been satisfied. Additional research findings through 1990 relating to the etiology of AIDS are also noted.     

Robert Koch and the invention of the carrier state: tropical medicine, veterinary infections and epidemiology around 1900

This paper reassesses Robert Koch's work on tropical infections of humans and cattle as being inspired by an underlying interest in epidemiology. Such an interest was developed from the early 1890s when it became clear that an exclusive focus on pathogens was insufficient as an approach to explain the genesis and dynamics of epidemics. Koch, who had failed to do so before, now highlighted differences between infection and disease and described the role of various sub-clinical states of disease in the propagation and--consequently--in the control of epidemics. Studying pathologies of men and cattle in tropical countries eventually facilitated the application of such measures in Europe through the screening of healthy carriers of typhoid, which was carried out in 1902. The concept of the carrier state can be understood as a spin-off from tropical medicine into the study and control of infectious disease in Europe. With it travelled assumptions that were typical for colonial and veterinary medicine where the health of indigenous individuals or cattle would be a secondary objective compared to the control of diseases in populations.     

Polymicrobial challenges to Koch's postulates: Ecological lessons from the bacterial vaginosis and cystic fibrosis microbiomes

Koch's postulates have shaped our understanding of infectious diseases; however, one of the tangential consequences of them has been the emergence of a predominantly monomicrobial perspective concerning disease aetiology. This orthodoxy has been undermined by the growing recognition that some important infectious diseases have a polymicrobial aetiology. A significant new development in our understanding of polymicrobial infections is the recognition that they represent functional ecosystems and that to understand such systems and the outcome and impact of therapeutic interventions requires an understanding of how these communities arise and develop. Therefore, it is timely to explore what we can learn from other fields. In particular, ecological theory may inform our understanding of how polymicrobial communities assemble their structure and their dynamics over time. Such work may also offer insights into how such communities move from stable to unstable states, as well as the role of invasive pathogens in the progression of the disease. Ecological theory offers a theoretical framework around which testable hypotheses can be developed to clarify the polymicrobial nature and dynamics of such infections in the face of environmental change and therapeutic interventions.     

Causation and Disease: The Henle-Koch Postulates Revisited

The Henle-Koch postulates are reviewed in terms of their full validity in Koch's day and in light of subsequent developments. The changing guidelines developed for viral diseases, for viruses in relation to cancer and to chronic central nervous system infection, and for causative agents in chronic diseases are discussed chronologically. A set of guidelines for both acute infectious and chronic diseases is presented. The need for recognizing the role of the host and the spectrum of host responses, for sound biologic sense in evaluating causal roles of agents in disease, and for flexibility in adapting our guidelines to new knowledge are emphasized.     

The contribution of plant biology to the concept of virus (1886-1917).

Between 1860 and 1880 the so-called "theory of the infective germ", which stated in final way that every infectious disease was produced by a living pathogen agent, achieved great consent. The criteria of determining the presence of infectious pathogens (fungi, bacteria, protozoa) were established by "Koch's postulate", a set of experimental procedures conceived for isolating and determining single pathogens. In the last quarter of the 19th century became however evident that the agents of severe infectious diseases could not be identified through the "postulates". These agents could not be seen in light microscopy nor cultured in vitro but could pass through the thin pores of filters which hold back cellular micro-organisms. This last characteristic became a selective method to recognise these peculiar agents, from then named "filterable viruses". Most microbiologists considered the filterable viruses as living micro-organisms because of their extraordinary capacity of in vivo proliferation, and the impossibility of pointing out their structures was due to limits of the experimental techniques. Between the end of the 19th century and 1917, four plant biologists suggested that the filterable viruses were complex chemical substances rather than cellular microorganisms. Their contribution, not appreciated by the contemporary colleagues, laid the foundation of the modern concept of virus.     

Robert Koch

This article traces the origins of bacteriological research, with particular attention to the role of Robert Koch, and his postulates, on infectious agents. By chronologically following Koch's work on anthrax, germ photography and tuberculosis, it shows how the visual representation of germs transformed laboratory research in medical science.     

Robert Koch and the white death: from tuberculosis to tuberculin

The German medical bacteriologist Robert Koch is commonly considered one of the founding fathers of medical bacteriology. His investigations into the aetiology of tuberculosis uncovered the pathogen of this condition, the tubercle bacillus today known as Mycobacterium tuberculosis, in 1882. This work can be seen as a cornerstone of contemporary medical bacteriology, its technologies and methods. It has often been asked how such successful research connected to the tuberculin episode of 1890/91, when Koch produced a medicine for that disease, which spectacularly failed when applied in practice. The analysis concentrates on the path of mostly experimental investigations which Koch followed between 1882 and 1890. From Koch's laboratory notes it becomes clear that tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else. The clue to this contradictory picture lies in the peculiar nature of Koch's understanding of tuberculosis as a disease e.g. his reliance an animal experiments, which essentially differed from what many of his contemporaries held as essentials of that condition.     

Sweepoviruses cause disease in sweet potato and related Ipomoea spp.: fulfilling Koch's postulates for a divergent group in the genus begomovirus

Sweet potato (Ipomoea batatas) and related Ipomoea species are frequently infected by monopartite begomoviruses (genus Begomovirus, family Geminiviridae), known as sweepoviruses. Unlike other geminiviruses, the genomes of sweepoviruses have been recalcitrant to rendering infectious clones to date. Thus, Koch's postulates have not been fullfilled for any of the viruses in this group. Three novel species of sweepoviruses have recently been described in Spain: Sweet potato leaf curl Lanzarote virus (SPLCLaV), Sweet potato leaf curl Spain virus (SPLCSV) and Sweet potato leaf curl Canary virus (SPLCCaV). Here we describe the generation of the first infectious clone of an isolate (ES:MAL:BG30:06) of SPLCLaV. The clone consisted of a complete tandem dimeric viral genome in a binary vector. Successful infection by agroinoculation of several species of Ipomoea (including sweet potato) and Nicotiana benthamiana was confirmed by PCR, dot blot and Southern blot hybridization. Symptoms observed in infected plants consisted of leaf curl, yellowing, growth reduction and vein yellowing. Two varieties of sweet potato, 'Beauregard' and 'Promesa', were infected by agroinoculation, and symptoms of leaf curl and interveinal loss of purple colouration were observed, respectively. The virus present in agroinfected plants was readily transmitted by the whitefly Bemisia tabaci to I. setosa plants. The progeny virus population present in agroinfected I. setosa and sweet potato plants was isolated and identity to the original isolate was confirmed by sequencing. Therefore, Koch's postulates were fulfilled for the first time for a sweepovirus.     

Development of anin situ assay to detect bacterial pathogens of the red algaGracilaria gracilis (Stackhouse) Steentoft,Irvine et Farnham

Since current protocols were found to be inadequate for the identification of bacteria pathogenic toGracilaria gracilis, an assay was developed which made use of axenic algae in order to attribute disease symptoms directly to the presence of a specific bacterial isolate. However, this assay proved to be as unreliable as existing procedures and failed to satisfy Koch's postulates. A second pathogenicity assay was developed which proved more reliable in that each bacterial strain consistently induced a particular symptom in the infected algal thallus. The bacterial strain LS2i was identified as a possible pathogen ofG. gracilis using this assay. However, this assay did not satisfy Koch's criteria for establishing an unequivocal link between the observed disease symptoms and strain LS2i, since significant bacterial contamination of the test alga occurred. A third protocol generated consistent results and satisfied Koch's postulates, enabling the identification of six pathogens ofG. gracilis. All the pathogenic bacterial strains were agarolytic.     

Bringing Koch's postulates to the table in IBD

In this issue of Cell Host & Microbe, Bloom and colleagues elegantly show that commensal Bacteroides species fulfill Koch's postulates for inflammatory bowel disease in a host-genotype-specific way. This study showcases the use of a non-germ-free mouse model to identify specific members of the microbiota involved in disease development.     

Was there a Bacteriological Revolution in late nineteenth-century medicine?

That there was a 'Bacteriological Revolution' in medicine in the late nineteenth-century, associated with the development of germ theories of disease, is widely assumed by historians; however, the notion has not been defined, discussed or defended. In this article a characterisation is offered in terms of four linked rapid and radical changes: (i) a series of discoveries of the specific causal agents of infectious diseases and the introduction of Koch's Postulates; (ii) a reductionist and contagionist turn in medical knowledge and practice; (iii) greater authority for experimental laboratory methods in medicine; (iv) the introduction and success of immunological products. These features are then tested against developments in four important but previously neglected diseases: syphilis, leprosy, gonorrhoea and rabies. From these case-studies I conclude that the case for a Bacteriological Revolution in late nineteenth-century medicine in Britain remains unproven. I suggest that historians have read into the 1880s changes that occurred over a much longer period, and that while there were significant shifts in ideas and practices over the decade, the balance of continuities and changes was quite uneven across medicine. My argument is only for Britain; in other countries the rate and extent of change may have been different.     

A 25 nm virion is the likely cause of transmissible spongiform encephalopathies

The transmissible spongiform encephalopathies (TSEs) such as endemic sheep scrapie, sporadic human Creutzfeldt-Jakob disease (CJD), and epidemic bovine spongiform encephalopathy (BSE) may all be caused by a unique class of "slow" viruses. This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch's postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and "amplified" prions have failed to produce significant infectivity. Moreover, the "wealth of data" claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain-specific forms of "infectious PrP" are proposed to explain the incompatible data. The ability of many "slow" viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host-immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1-5 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25-35 nm in diameter. This particle size can accommodate a viral genome of 1-4 kb, sufficient to encode a protective nucleocapsid and/or an enzyme required for its replication. Host PrP acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain-specific molecules so important for diagnosis, prevention, and fundamental understanding.     

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease

The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively reisolated them in culture. The bacteria colonized IBD-susceptible and -nonsusceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease, but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD.     

Helicobacter pylori. One bacterium and a broad spectrum of human disease! An overview.

Since the historical rediscovery of gastric spiral Helicobacter pylori in the gastric mucosa of patients with chronic gastritis by Warren and Marshall in 1983, peptic ulcer disease has been largely viewed as being of infectious aetiology. Indeed, there is a strong association between the presence of H. pylori and chronic active gastritis in histology. The bacterium can be isolated in not less than 70% of gastric and in over 90% of duodenal ulcer patients. Eradication of the organism has been associated with histologic improvement of gastritis, lower relapse rate and less risk of bleeding from duodenal ulcer. The bacterium possesses several virulence factors enabling it to survive the strong acid milieu inside the stomach and possibly damaging host tissues. The sequence of events by which the bacterium might cause gastric or duodenal ulcer is still not fully elucidated and Koch's postulates have never been fulfilled. In the majority of individuals, H. pylori infection is largely or entirely asymptomatic and there is no convincing data to suggest an increase in the prevalence of peptic ulcer disease among these subjects. An increasingly growing body of literature suggests an association between colonization by H. pylori in the stomach and a risk for developing gastric mucosa-associated lymphoid tissue (MALT), MALT lymphoma, gastric adenocarcinoma and even pancreatic adenocarcinoma. The bacterium has been implicated also in a number of extra-gastrointestinal disorders such as ischaemic heart disease, ischaemic cerebrovascular disease, atherosclerosis, and skin diseases such as rosacea, but a causal role for the bacterium is missing. Eradication of H. pylori thus seems to be a beneficial impact on human health. Various drug regimens are in use to eradicate H. pylori involving the administration of three or four drugs including bismuth compounds, metronidazole, clarithromycin, tetracyclines, amoxycillin, ranitidine, omeprazole for 1-2 weeks. The financial burden, side effects and emergence of drug resistant strains due to an increase in the use in antibiotics for H. pylori eradication therapy need further reconsideration.     

Alzheimer's amyloid story finds its star

Beta-amyloid peptides (Abeta) have been genetically implicated as the cause of Alzheimer's disease, but the causality of amyloid deposited as plaques has been challenged. The controversial role of amyloid peptides in Alzheimer's disease has been highlighted in a recent paper from Lesne and colleagues, who applied Koch's postulates to cast a specific memory-deficit-inducing oligomer species as a central player causing memory loss. These authors used a transgenic mouse model to identify a specific type of aggregate that emerges with cognitive deficits and is capable of transmitting a spatial memory defect to unimpaired animals.     

Borna disease virus: immunoelectron microscopic characterization of cell-free virus and further information about the genome.

The etiological agent of Borna disease, a persistent virus infection of the central nervous system with differently expressed symptomatology, was morphologically unknown. Here we provide the first convincing data on its phenotypic architecture. Salt-released virus comprising the biological parameters of Koch's postulates has an unsegmented single-stranded RNA. A dense band (1.22 g/cm3) in CsCl contains 90-nm particles which appear to be enveloped and a fraction of 50- to 60-nm particles. Labeling of the virions with neutralizing antisera and colloidal gold conjugates indicates that the 90-nm particles most likely represent the causative agent.     

Koch is dead

Although the foundation of Koch's postulates, that "if an agent is the cause of disease in one individual it should be capable of causing disease in a second individual," is basically sound, the ritual that has evolved into present day experimental studies has obscured almost completely what occurs in natural processes outside the laboratory. Through a series of examples, it is emphasized that just bringing the host and the parasite together is not enough, but that the circumstances under which this is done is equally important. These circumstances include: the prior history of the host; the host's behavioral patterns, environmental conditioning, and disease history; the circumstances of exposure; and the environmental factors related to the host and the parasite. Of equal importance is the individual variation (genetic, physiologic, immunologic, etc.) of the host and the individual variation (strains, immunogenicity, pathogenicity, virulence, etc.) of the parasite. Because the rigor of the present day "scientific method" demands clearcut and reproducible results and investigations require predictable performance of the parasite in an evenly maintained host that is in a highly constrained environment, we should not wonder why we cannot produce the events of nature. If we are going to understand diseases of wildlife, we must consider the genetic heterogenicity of the host and parasite population, and recognize the complexity of the environment in which both exist. Koch's postulates, in the narrow sense, will help us to identify parasitisms but will not provide us with an understanding of information about diseases in wildlife; the real significance of these parasitisms to the health of the individual and to the size of the population.(ABSTRACT TRUNCATED AT 250 WORDS)