The history of tuberculosis in the United States

Although collection of cause-specific mortality data in the US began in 1900, data from all states were not included until 1933. A rate of 'new' cases of tuberculosis FIG. 2. Funding by the Centers for Disease Control for tuberculosis control. FIG. 2. Funding by the Centers for Disease Control for tuberculosis control. was determined annually beginning in 1930 but this figure did not become an accurate reflection of disease incidence until 1952 when inactive cases were no longer included. As...

Conclusions

The above characteristics of the epidemiology of tuberculosis are well known, and they highlight a number of issues, many of which are directly or indirectly related to genetics. Age- and gender-related differences in tuberculosis The familiar age- and gender-related differences in incidence pose questions, the answers to which might unlock the door to novel means of treatment or better vaccination. During the first year of life a high incidence of tuberculosis is seen and more males than...

Hypermutability

At this point it is worth considering the generation of antibiotic resistance mutations in mycobacteria. For many resistance alleles, the frequency of spontaneous mutation in laboratory studies is relatively low, especially with reference to functions involved in replication (gyrA), transcription (rpoB) or translation (rpsL, rrnA, rrnB), which take place generally at rates of 10_7 per generation (or less) in bacteria. Do mutations conferring antibiotic resistance occur at a more significant...

Prospects for tuberculosis vaccine development

The data presented here and elsewhere (Huygen et al 1996) demonstrate Ag85A DNA vaccination against tuberculosis in animal models. DNA encoding hsp65 and the 38kDa antigen of M. tuberculosis have also been shown to confer protection (Tascon et al 1996, Zhu et al 1997). These data suggest that there may be several protective antigens in M. tuberculosis and that a combination of DNA plasmids encoding discrete antigens should be investigated. But which antigens There are likely to be several...

Therapeutic possibilities

Some therapeutic effect can be observed if animals are treated with a combination of a DHEA metabolite and a glucocorticoid (R. Hernandez-Pando, K. Arriaga, L. Pavon & G. A. W. Rook, unpublished work 1997) intended to mimic the ratio seen during the 'safe school age' (5 10 years) when children are resistant to the TABLE 1 Suggested correlations between dehydroepiandrosterone (DHEA) levels (or DHEA glucocorticoid ratios) and immunopathology of tuberculosis in humans at different ages....

DNA vaccines against tuberculosis

Montgomery, Aimin Tang, Lan Zhu, R. Randall Deck, Corrille DeWitt, Olivier Denis*, Ian Ormef, Jean Content* and Kris Huygen* Department of Virus and Cell Biology, Merck Research Laboratories, WP-16-3 West Point, PA 19486, USA, *Institut Pasteur, 642 rue Engelard, B-1180, Brussels, Belgium and Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA Abstract. DNA plasmids encoding Mycobacterium tuberculosis antigen 85 (Ag85) were tested as...

Immunisations Allergens eg house dust mite

A hypothetical view of factors regulating the balance between T helper (Th) 1 and Th2 immune responses in various communities. & P. G. Bardin, unpublished observations 1997). Perhaps tuberculosis is good treatment for asthma In conclusion, PBMC from healthy children produce markedly less IFN-y than those of adults, but no consistent differences are found in the production of other cytokines. It is tempting to propose that the immunopathology found in adults is not only due to a...

Immunotherapy

Immunotherapy with crude extracts of M. tuberculosis is not possible, and it causes necrosis and disease exacerbation (Anderson 1891, Koch 1891). In contrast to the necrotic skin test responses to the antigens of tuberculosis itself, tuberculosis patients have defective skin-test responses to the common antigens (Kardjito et al 1986), so injection of these antigens, or of environmental saprophytes that contain them, causes trivial local reactions. These antigens can be protective when they...

The genomic approach

By having the complete sequence of the tuberculosis pathogen at our fingertips, it is self-evident that the sequence of every single target is known. The challenge is to identify which of the 4000 open reading frames is essential under any given set of growth conditions. The first step is to build a metabolic map, by comparing the mycobacterial genes present with those genes of known function isolated from other organisms. This may provide a clue to the way that M. tuberculosis survives and...

Tuberculosis during childhood and adulthood

Children with tuberculosis usually present with lymphadenopathy or the complications thereof, or with systemic spread of the organism. In contrast, adults usually have pronounced systemic effects (such as weight loss and high fever) and immunopathology (such as cavitation and fibrosis). Adulthood disease ('secondary' tuberculosis) is usually ascribed to a secondary immune response following re-infection or re-activation (the Koch phenomenon). Other factors may however contribute to the...

Tuberculosis in the homeless

Homelessness is a well-recognized risk factor for tuberculosis, although it is difficult to disassociate housing circumstances from a variety of other factors that overlap in this population (Zolopa et al 1994). Nevertheless, homeless persons probably constitute a 'core group' within the population that has epidemiological significance out of proportion to its absolute size (Barnes et al In San Francisco there are an estimated 10 000 homeless or unstably housed persons, of whom 2774 were in a...

PGRS and MPTR are members of the PE and PPE multigene families

Mycobacterium Tuberculosis Genome Ppe

During a number of molecular epidemiological studies performed to investigate the relatedness of strains of the tubercle bacillus two families of repetitive DNA were detected. MPTR (Hermans et al 1992) was believed to consist of numerous FIG. 1. Distribution of mapped and sequenced insertion sequence elements on the genome of Mycobacterium tuberculosis H37Rv. The positions of the previously mapped IS6110 and IS1081 are shown. Based on analysis of about 70 of the genome sequence, new insertion...

Susceptibility to tuberculosis as a complex genetic trait analysis using recombinant congenic strains of mice

Igor Kramnik, Peter Demant* and Barry B. Bloom Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine ofYeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA and *The Netherlands Cancer Institute, Amsterdam, Netherlands Abstract. Previous advances in the genetics of infectious diseases derived principally from identification of single genes and their isolated effects on the progression of infection. Modern genetic analysis...

References

Ad hoc committee of the scientific assembly on microbiology, tuberculosis and pulmonary infections 1995 Treatment of tuberculosis and tuberculosis infection in adults and children. Clin Infect Dis 21 9-27 Banerjee A, Dubnau E, Quemard A et al 1994 inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263 227-230 Basso LA, Zheng R, Blanchard JS 1996 Kinetics of inactivation of WT and C243S mutant of Mycobacterium tuberculosis enoyl reductase by...

A mechanism for isoniazid resistance

Resistance to isoniazid can occur by mutations that reduce the affinity of InhA enzyme for the NADH cofactor (Quemard et al 1995). Sequence analysis of inhA in resistant clinical isolates found that most of the amino acid substitutions are located within the enzyme's NADH-binding site (Fig. 4 L. Basso, personal communication 1998). These mutations cause lower affinity to NADH, indicated FIG. 3. The proposed pathway for formation of the isonicotinic acyl-NADH inhibitor of InhA (Rozwarski et al...

Mechanisms and development of antibiotic resistance

Several reviews of the mode of action of antimycobacterial drugs and their biochemical mechanisms of resistance have been published recently (Blanchard 1996, Cole 1994, Musser 1995, Webb & Davies 1998). This information is summarized in Table 1 and Fig. 1. Briefly, for most antibiotics available for the TABLE 1 Genetics of resistance to common antimycobacterial antibiotics TABLE 1 Genetics of resistance to common antimycobacterial antibiotics indicates that uncharacterized mechanisms of...

The impact of genomics on the search for novel tuberculosis drugs

Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK Abstract.The emergence of multidrug-resistant strains of Mycobacterium tuberculosis has highlighted the need for new drugs to treat tuberculosis. Drugs that either shorten the overall duration of therapy or that simplify the regimen would significantly improve compliance and hence reduce treatment failure rates. The drug development process begins with identification and...

The epidemiology of tuberculosis in South Africa

Early clinical descriptions oftuberculosis amongst the Black and Khoi San peoples emphasized the acute nature of the disease in those exposed to tuberculosis for the first time there was much discussion of'virgin populations' and their implications for the spread and clinical features of tuberculosis (Cummins 1929). By 1920 observers in Black rural areas considered that tuberculosis had now begun to show certain 'endemic' characteristics and was no longer so acute or extensive in its features....

General discussion II

The biosynthesis of cell wall molecules Brennan Present-day understanding of the architecture of the mycobacterial cell envelope arises from electron microscopic studies that demonstrate alternating zones of electron density and transparency reminiscent of Gram-negative cells (Brennan & Draper 1994). This evidence is in accord with chemical models of a substantial lipid permeability barrier, a staggered, pseudo-outer membrane contributed in one-half by the ca. C50 meromycolate and ca. C25...

Mechanisms for isoniazid action and resistance

Rozwarskif, James C. Sacchettini* and William R. Jacobs, Jr. Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, Department of Biochemistry and Biophysics, Texas A& M University, College Station, TX 77843, fDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA Abstract. Isoniazid is the most widely used...

The endocrine component

There is a further physiological correlate of the events seen in Figs 1 3. During the phase of Th1 dominance, the adrenals increase in weight, presumably because of activation of the hypothalamopituitary-adrenal axis by cytokines (see Fig. 5). However, when the response switches to Th2 the adrenals start to atrophy (Rook & Hernandez-Pando 1996). This is not an acute renal cortical necrosis but rather progressive atrophy with apoptosis. These observations have led to detailed studies of...

Environmental saprophytes the variable efficacy of BCG and the testing of new vaccines

It is important to emphasize that Figs 1 3 demonstrate that heightened susceptibility can be achieved by evoking a Th2 response to an organism that is only distantly related to M. tuberculosis, clearly indicating the crucial role of responses to 'common' antigens, probably including the stress proteins Hernandez-Pando et al 1997 . T cells that recognize these proteins constitute a major part of the T cell repertoire at birth Fischer et al 1992 . There is presumably a genetic component to the...

The choice between Thl and Th2 responses in humans nature versus nurture

Nature Nurture Human Development

Racial differences, twin and adoption studies show that host genetics contribute to susceptibility to infectious diseases such as tuberculosis. HLA-A10, -B8 and DR2 are associated with tuberculosis, whereas recently identified polymorphisms in the vitamin D receptor and mannose binding protein genes confer resistance to FIG. 1. Factors that regulate the development and effector functions of T helper Th 1 and Th2 cells. The most important factor for the induction of Th1 cells is the presence of...

The choice between Thl and Th2 responses animal models

Little is known of genetic influences on cytokine production in animals. BD10.D2 or C57BL 6 mice, which are resistant to Leishmania, have predominantly Thl responses whereas BALB c mice, which are susceptible to Leishmania, produce predominantly Th2 cytokines. The relevant locus maps to a region on chromosome 11, syntenic to human chromosome 5q31.1, a region known to control IgE levels see below Gorham et al 1996 . Cytokines exert a powerful influence on the polarization of naive T cells. Th...

The immunopathology of tuberculosis

Lung Tuberculosis Adaptation

Immunity to M. tuberculosis requires a T helper 1 Th1 pattern of response accompanied by several types of cytotoxic T cell Flynn et al 1993,1995a,b, Rook amp Hernandez-Pando 1996 . A Th2 response is disastrous even a small Th2 component exacerbates the infection in mice Lindblad et al 1997, Rook amp Hernandez-Pando 1996 . Thus, if the animals are pre-immunized so that they have a 'pure' Thl response to culture filtrate antigens of M. tuberculosis, or to the common antigens present in a...

BCG looking for order in chaos

The variable efficacy of BCG vaccines under different conditions has been discussed almost ad nauseam Bloom amp Fine 1994, Fine 1995 . In summary, we know that at least some BCG vaccines perform well, in terms of protection against pulmonary tuberculosis, under certain conditions. But the same vaccines can perform poorly in different contexts, and we remain ignorant of the determinants of this variance. Among the reasons often discussed are several that do not call immediately for genetical...