Immunological basis of early clearance of Mycobacterium tuberculosis infection: the role of natural killer cells.

Tuberculosis (TB) kills more people than any other single infectious disease globally. Despite decades of research, there is no vaccine to prevent TB transmission. Bacille Calmette-Guérin (BCG) vaccine, developed a century ago, is effective against childhood (disseminated and miliary) TB. However, its protective efficacy against pulmonary TB varies from 0 to 80% in different populations. One of the main reasons for the lack of an effective vaccine against TB is the lack of complete understanding about correlates of protective immunity on which to base vaccine design and development. However, some household contacts who are extensively exposed to Mtb infection remain persistently negative to tuberculin skin test and interferon-gamma assay. These individuals, called 'resisters', clear Mtb infection early before the development of acquired immunity. The immunological basis of early Mtb clearance is yet to be established; however, innate lymphocytes such as monocytes/macrophages, dendritic cells, neutrophils and natural killer cells, and innate-like T cells such as mucosal-associated invariant T cells, invariant natural killer (NK) T cells and gamma-delta (γδ) T cells, have been implicated in this early protection. In recent years, NK cells have attracted increasing attention because of their role in controlling Mtb infection. Emerging data from animal and epidemiological studies indicate that NK cells play a significant role in the fight against Mtb. NK cells express various surface markers to recognize and kill both Mtb and Mtb-infected cells. This review presents recent advances in our understanding of NK cells in the fight against Mtb early during infection, with emphasis on cohort studies.

Association of ESAT-6/CFP-10-induced IFN-γ, TNF-α and IL-10 with clinical tuberculosis: evidence from cohorts of pulmonary tuberculosis patients, household contacts and community controls in an endemic setting.

Mycobacterium tuberculosis (Mtb) early secreted protein antigen 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are among candidate vaccines against tuberculosis (TB). Results of experimental animal models show that these antigens are associated with induction of strong T cell immunity [interferon (IFN)-γ production], while others report that these proteins as virulent factors involved in pathogenicity of Mtb infection. However, the role of ESAT-6/CFP-10 during natural Mtb infections in humans has not been established. In this paper we present results of a longitudinal study from an Mtb-infected human population from an endemic setting. Whole blood assay was used to determine levels of IFN-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-10 against rESAT-6/CFP-10 in TB patients, household contacts and community controls. The levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 at baseline were significantly higher in patients and community controls than in household contacts. In patients, no significant difference was observed in the level of these cytokines before and after chemotherapy whereas, in contacts, the level of these cytokines increased significantly and progressively over time. The study shows that the levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are depressed during Mtb infection or exposure but are elevated during clinical TB. Our findings from a study of naturally infected human population suggest that IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are markers for clinical TB but not for protective immunity.

-174G/C polymorphism in the interleukin-6 promoter is differently associated with prostate cancer incidence depending on race.

Interleukin-6 (IL-6), a pro-inflammatory cytokine, is involved in prostate cancer progression, including androgen independence. Serum IL-6 levels also correlate with prostate tumor burden, prostate-specific antigen levels and metastasis. Since circulating cytokine levels vary considerably inter-individually, such variation could be linked to genetic factors, including genetic polymorphism. The -174G>C/rs1800795 polymorphism in the IL-6 promoter is functionally relevant in terms of transcriptional regulation and disease association. We investigated a possible association of the -174G/C polymorphism with prostate cancer. Since significant racial disparities exist in prostate cancer incidence, we also investigated this association between the -174G/C polymorphism and prostate cancer in Caucasians and African-Americans, separately. Direct sequencing of the PCR amplicon from genomic DNA was used for genotyping rs1800795 in all subjects [age-matched controls (N = 140) and prostate cancer patients (N = 164)]. Sample size and power was calculated using the PGA software. We found the GG genotype to be associated with increased risk of prostate cancer in Caucasian subjects, whereas the CC genotype was associated with increased risk in the African-American sample set. Such a dimorphic genotypic association with cancer and race is unique and suggests a complex gene-gene and gene-environment interaction.

IgA response to ESAT-6/CFP-10 and Rv2031 antigens varies in patients with culture-confirmed pulmonary tuberculosis, healthy Mycobacterium tuberculosis-infected and non-infected individuals in a tuberculosis endemic setting, Ethiopia.

Little attention has been given to the role of antibodies against Mycobacterium tuberculosis (Mtb) infection. We have compared the levels of IgA and IgG against ESAT-6/CFP-10 and Rv2031c antigens in sera of patients with culture-confirmed pulmonary tuberculosis (PTB), healthy Mtb-infected and non-infected individuals in endemic TB settings. Venous blood samples were collected from 166 study participants; sera were separated and assayed by an enzyme-linked immunosorbent assay (ELISA). QuantiFERON-TB Gold In-Tube (QFTGIT) assay was used for the screening of latent TB infection. The mean optical density (OD) values of IgA against ESAT-6/CFP-10 and Rv2031 were significantly higher in sera of patients with culture-confirmed PTB compared with healthy Mtb-infected and non-infected individuals (P < 0.001). The mean OD values of IgG against ESAT-6/CFP-10 and Rv2031 were also significantly higher in sera of patients with culture-confirmed PTB compared with healthy Mtb-infected and non-infected individuals (P < 0.05). The mean OD values of IgA against both antigens were also higher in sera of healthy Mtb-infected cases compared with non-infected individuals. There were positive correlations (P < 0.05) between the level of IFN-γ induced in QFTGIT assay and the OD values of serum IgA against both antigens in healthy Mtb-infected subjects. This study shows the potential of IgA response against ESAT-6/CFP-10 and Rv2031 antigens in discriminating clinical TB from healthy Mtb-infected and non-infected cases. Nevertheless, further well-designed cohort study is needed to fully realize the full potential of this diagnostic marker.

Is interferon-gamma the right marker for bacille Calmette-Guérin-induced immune protection? The missing link in our understanding of tuberculosis immunology.

Bacille Calmette-Guérin (BCG), developed a century ago, is the only licensed tuberculosis (TB) vaccine in use to date. The protective efficacy of BCG against TB varies with no apparent protection in some population, and mechanisms of its immune protection is poorly known, and yet BCG is the most widely used vaccine, with more than 4 billion BCG-vaccinated children globally. BCG is probably the only licensed vaccine currently in use believed to mediate immune protection through the production of interferon (IFN)-γ by CD4 T cells, which in turn activates macrophages to kill Mycobacterium tuberculosis (Mtb). Currently, a number of new TB candidate vaccines are in different phases of clinical trial. The majority of these new vaccines are either recombinant forms of BCG or prime boosters of BCG (rBCG) and their immunogenicity is tested using BCG as a benchmark by measuring specific IFN-γ produced by CD4(+) T cells as a protective immune marker. However, some recent studies that examined mechanisms of immune protection of BCG in animals and humans have reported a lack of correlation between IFN-γ production by CD4 cells and BCG-induced immune protection. These studies point to the fact that there is a missing link in our understanding of TB immunology. Conversely, there is emerging evidence that other T cell subsets (gammadelta, γδ), CD8(+) T cells and natural killer (NK) cells may play a vital role in immune protection against Mtb infection and BCG-induced immune protection. γδ T cells and NK cells, which were considered to be part of the innate immunity in the past, have been shown to develop immunological memory upon re-encounter with the same pathogen. In this paper, the controversy over the role of IFN-γ as a marker for protective immunity against TB, and emerging data on the role of γδ T cells, CD8(+) and NK cells in TB immunology, will be presented.

Protective effect of chondroitin sulfate nano-selenium on chondrocyte of patients with Kashin-Beck disease.

OBJECTIVE: To investigate the protective effect of chondroitin sulfate nano-selenium (SeCS) on chondrocyte of Kashin-Beck disease (KBD). METHODS: Chondrocyte samples were isolated from the cartilage of three male KBD patients (54-57 years old). The chondrocytes were respectively divided into four groups: (a) control group, (b) SeCS supplement group (100 ng/mL SeCS), (c) T-2 + SeCS supplement group (20 ng/mL T-2 + 100 ng/mL SeCS), and (d) T-2 group (20 ng/mL T-2). Live/dead staining and transmission electron microscopy (TEM) were used to observe cell viability and ultrastructural changes in chondrocytes respectively. Expressions of Caspase-9, cytochrome C (Cyt-C), and chondroitin sulfate (CS) structure-modifying sulfotransferases including carbohydrate sulfotransferase 3, 15 (CHST-3, CHST-15), and uronyl 2-O-sulfotransferase (UST) were examined by quantitative real-time polymerase chain reaction. RESULTS: After one- or three-days intervention, the number of living chondrocytes in the SeCS supplement group was higher than that in the control group, while it is opposite in the T-2 + SeCS supplement group and T-2 group. The cellular villi number in the surface increased in the SeCS supplement group compared with the control group. Mitochondrial morphology density was improved in the T-2 + SeCS supplement group compared with the T-2 group. Expressions of CHST-3, CHST-15, UST, Caspase-9, and Cyt-C on the mRNA level significantly increased in the T-2 + SeCS supplement group and T-2 group compared with the control group. CONCLUSIONS: SeCS supplement increased the number of living chondrocytes, improved the ultrastructure, and altered the expressions of CS structure-modifying sulfotransferases, Caspase-9, and Cyt-C.

The protective role of antibody responses during Mycobacterium tuberculosis infection.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the most important infectious diseases globally. Immune effector mechanisms that lead to protection or development of clinical disease are not fully known. It is generally accepted that cell-mediated immunity (CMI) plays a pivotal role in controlling Mtb infection, whereas antibody responses are believed to have no protective role. This generalization is based mainly on early classical experiments that lacked standard protocols, and the T helper type 1 (Th1)/Th2 paradigm. According to the Th1/Th2 paradigm Th1 cells protect the host from intracellular pathogens, whereas Th2 cells protect form extracellular pathogens. During the last two decades, the Th1/Th2 paradigm has dominated not only our understanding of immunity to infectious pathogens but also our approach to vaccine design. However, the last few years have seen major discrepancies in this model. Convincing evidence for the protective role of antibodies against several intracellular pathogens has been established. Studies of B cell-deficient mice, severe combined immunodeficiency (SCID) mice, passive immunization using monoclonal (mAb) and polyclonal antibodies and immune responses against specific mycobacterial antigens in experimental animals reveal that, in addition to a significant immunomodulatory effect on CMI, antibodies play an essential protective role against mycobacterial infections. In this review, our current understanding of the essential role of antibodies during Mtb infections, limitations of the Th1/Th2 model and the unfolding interdependence and mutual regulatory relationships between the humoral and CMI will be presented and discussed.

Control of Biomphalaria pfeifferi population and schistosomiasis transmission in Ethiopia using the soap berry endod (Phytolacca dodecandra), with special emphasis on application methods.

The endod (Phytolacca dodecandra)-based schistosomiasis mansoni control project was implemented in Ethiopia between 1994 and 1999. The aim was to develop an effective, cheap and sustainable method of controlling schistosomiasis. First, different formulations of the Ethiopian endod strain 44 (E-44) were compared for potency in the laboratory. Secondly, spray and drip-feeding methods were compared for simplicity and effectiveness in the field. Lastly, the efficacy of endod powder soap was compared with the endod spray method. In Bati stream, endod powder soap was distributed to the residents every weekend at laundry sites. In Worke stream, endod was sprayed along a 1-km stretch of the stream at 3-month intervals. No endod was applied in Harbu stream. The immediate and long-term effects of endod application on the snail population and schistosomal infection were determined. Using the spray method, 100% snail mortality could be obtained, and it was simpler and more effective than the drip-feeding method. Snail mortality ranged from 20 to 100% using endod soap. There was a progressive decline in the snail population and infection in Bati stream compared with Worke stream, mainly due to sustained use of endod soap. The advantages and disadvantages of the different endod delivery systems are discussed.

Differences in prevalence, intensity of infection and parasite-specific antibody levels do not predict different age-infection profiles.

Acquired immunity is believed to influence the age-infection profile of Schistosoma infections. We compared antibody responses against Schistosoma mansoni adult worm antigen (AWA) and soluble egg antigen (SEA) in 164 residents of two communities with different levels of infection. IgG, IgA, IgM, IgE, and IgG subclass 1 to 4 antibodies were determined by ELISA. Seventy-five of the subjects were from Harbu, an area with a prevalence of 39% and an intensity of infection of 116 eggs per gram of stool (EPG), whereas 89 subjects were from Bati, with a prevalence of 66% and intensity of infection of 256 EPG. In both communities the prevalence and the intensity of infection were highest in the age group 10-14 years, although both were significantly higher in Bati than in Harbu. Mean levels of AWA-specific IgA, IgM, IgG, IgG1 and IgG2, and of SEA-specific IgG, IgM, IgG2 and IgG3 were significantly higher in Bati than in Harbu. However, mean levels of IgE against worm and egg antigens were significantly higher in Harbu than in Bati. Significant differences were detected in the levels of IgA, IgE, IgG, IgM, IgG1 and IgG2 against AWA, and in IgE, IgM, IgG2 and IgG3 against SEA according to the place of residence. The levels of anti-AWA IgG, IgG1 and IgG2 and anti-SEA IgG, IgG1 and IgG4 were significantly associated with the intensity of infection. Anti-AWA IgM levels were associated with age, whereas sex and age had interacting effects on the levels of AWA-specific IgG1 and SEA-specific IgG and IgM. Antibody responses exhibited different age-related patterns in the two communities. This may indicate that differences in history of exposure influence the evolution of immune responses. However, the study did not support the view that differences in antibody levels between communities subject to different levels of infection result in a systematic deviation in age-infection profile (the "peak shift").

Age- and sex-related differences in antibody responses against Schistosoma mansoni soluble egg antigen in a cohort of school children in Ethiopia.

Acquired immunity is believed to be the main factor in the age-related differences in prevalence and intensity of Schistosoma infections. We studied antibody responses against S. mansoni soluble egg antigen (SEA) by ELISA in children before treatment, 5 weeks and one year after treatment. After screening for S. mansoni infection, positive children were treated with praziquantel (40 mg per kg body weight). Infection rate was significantly higher in boys younger than 12 years than in girls in the same age group. Levels of all antibody isotypes, except IgG1 (before treatment) or IgA (one year after treatment), were higher in children older or equal to 12 years than in those younger. The difference between age groups was significant for IgE, IgM, IgG3 and IgG4 (before treatment) and IgE (one year after treatment). Similarly, all antibody isotypes, except IgE, before treatment were higher in boys than in girls. At 5 weeks after treatment, IgG, IgE and IgG1 showed an increasing tendency, whereas IgM and IgG3 tended to decrease. One year after treatment, significant decreases were observed in IgG, IgG1 and IgG4 and a significant increase in IgG2 levels. The study presents further evidence for the difference in acquired immunity between younger and older children, and between boys and girls. The study also suggests that praziquantel differentially affects antibody responses against S. mansoni SEA.

The relationships between dehydroepiandrosterone sulphate (DHEAS), the intensity of Schistosoma mansoni infection and parasite-specific antibody responses. A cross-sectional study in residents of endemic communities in north-east Ethiopia.

There are speculations that the puberty-related hormone dehydroepiandrosterone sulphate (DHEAS) might influence the intensity of infection and immune responses during Schistosoma infections. We studied the relationships between DHEAS, intensity of Schistosoma mansoni infection and humoral immune responses in 135 residents of Ethiopia. Serum levels of eight antibody isotypes against worm and egg antigens were determined by ELISA. DHEAS was measured with an immunoluminometric assay. There was a significant negative correlation between serum levels of DHEAS and intensity of S. mansoni infection. A significant increase in serum levels of DHEAS in the age group 15-19 years was accompanied by a progressive decline in the intensity of infection. Peak level of DHEAS coincided with the lowest intensity of infection in the age group 20-29 years. Multiple regression analysis showed that DHEAS alone had a significant (p<0.0001) negative effect when the effect of age was removed. Age also had a significant (p<0.0001) negative effect on the intensity of infection, after removing the effect of DHEAS. The two predictive variables accounted for 34.4% of the decline in the intensity of infection. Age accounted for 24.9%, whereas DHEAS accounted for 15.2% when the effect of each of the variables was removed. DHEAS had significant negative effects on AWA-specific IgG (p=0.02) and IgG1 (p=0.018) and SEA-specific IgG1 (p=0.009), after adjusting for the effect of age.

Praziquantel side effects and efficacy related to Schistosoma mansoni egg loads and morbidity in primary school children in north-east Ethiopia.

A total of 611 Schistosoma mansoni infected primary school children from three schools in north-east Ethiopia were treated with praziquantel at 40 mg/kg body weight in a single dose. Pre-treatment, 40.4% had no presenting symptoms and 30-40% had nausea, abdominal cramps and/or bloody-mucoid diarrhoea. None of the pre-treatment symptoms was related to nutritional status, intensity of S. mansoni egg excretion, or to the presence of other concomitant intestinal parasitic infections. During the first 4-6 h post-treatment observation period, 90 (14.7%) children self-presented with severe gastro-intestinal symptoms. Children who self-presented with severe symptoms had a higher mean age and mean S. mansoni egg excretion compared with children who did not self-present. The following day a total of 529 (86.6%) children, including all who self-presented during the first 4-6 h post-treatment, reported for clinical check-up and were subjected to a structured questionnaire interview on symptoms they had experienced over the time lapse following treatment. Among these, 91.5% reported one or more treatment related symptoms which were at times severe. Abdominal cramps (86.9%), diarrhoea with blood and/or mucus (49.5%), dizziness (31.2%) and vomiting (24.9%) were the most common treatment related symptoms. Skin rash with oedema were observed in four cases. Among treatment related symptoms, the combination of abdominal cramps with vomiting, bloody diarrhoea, vomiting alone and general weakness were significantly higher among the malnourished. A proportion of these symptoms increased with increasing categories of S. mansoni egg excretion before and after adjusting for nutritional status and concurrent intestinal parasitic infections. Overall, the cure rate of praziquantel, among 541 children who had stool examination 5 weeks after treatment was 83.2% and this rate decreased with increasing pre-treatment egg counts. In conclusion, most of the treatment related symptoms were mild. However, some of the objective symptoms were at times severe and may reduce drug compliance in primary health care based population chemotherapy.

Control of Schistosoma mansoni by the soapberry Endod (Phytolacca dodecandra) in Wollo, northeastern Ethiopia: post-intervention prevalence.

OBJECTIVES: To record the effect of Endod soap and spraying of soaked Endod suspension on the prevalence of human schistosomiasis. DESIGN: A cross-sectional epidemiological study in which pre- and post-intervention parasitological results were compared. SETTING: Kemise, Bati and Harbu towns in northeastern Ethiopia. SUBJECTS: The study subjects included all members of the five per cent households systematically selected from the three towns. RESULTS: In Kemise town, where suspension of ground Endod was sprayed on the stream containing infected snails, the prevalence of the disease was reduced from 59% to 53% and the mean intensity of infection was reduced from 239 eggs per gram (EPG) of faeces to 99 EPG (p < 0.05). In Bati town where Endod soap approach was used, the respective reduction in the prevalence and intensity of infection was from 51% to 43% and from 195 EPG to 162 EPG (p < 0.05). There was also a significant reduction of the disease in the control town probably due to the effects of praziquantel treatment and other factors. CONCLUSION: The reduction achieved in the prevalence and intensity of schistosomiasis after an intervention period of four years was limited. This observation corroborates the fact that molluscicides must always be considered as supplementary to chemotherapy in the control of schistosomiasis. Although both approaches can be used, the spraying approach appears to be simpler and more feasible because two or three times yearly application of Endod suspension would suppress snail population and reduce transmission. Nevertheless, the choice as to what approach to use must be made on the basis of community preference, and for some soap-effect of Endod would be attractive

The efficacy of oxamniquine in selective population chemotherapy in Ethiopia.

Oxamniquine, at 40 mg/kg body weight, was used in a pilot schistosomiasis control programme in an endemic community in Ethiopia. After mass screening of the population using Kato's thick smear method, 1556 positive patients were treated in divided doses over two consecutive days. However, only 1183 (76%) persons completed the total dose. Three months later stool examination of about 20% of those who completed the total dose showed a cure rate of 68% and a significant reduction in the geometric mean egg counts. In those still positive redistribution of grades of infection took place; heavy infection, > 800 egg count per gram (epg), was reduced from 22.7% to 7.9% (p < .001) and light infection increased from 27.7% to 57.3% (p < .001) and light infection increased from 27.7% to 57.3% (p < .0001). The implications of this experience in the control of schistosomiasis in Ethiopia is discussed.

Epidemiology of schistosomiasis mansoni in three endemic communities in north-east Ethiopia: baseline characteristics before endod based intervention.

As part of a pre-intervention baseline data collection the epidemiological characteristics of schistosomiasis mansoni were studied in 3 endemic communities (Kemise, Harbu and Bati towns) in northeast Ethiopia in April and May 1994. The objective was to generate data based on which post-intervention differences (in changes), if any, in transmission level could partly be explained for the 3 towns. After calculating the sample size required for each town 132, 75, 158 households were selected by systematic random sampling from Kemise, Harbu and Bati, respectively and all members of the selected households stool was examined by the Kato's thick smear method. Eighty eight and 85% of the houses harboured one or more cases of Schistosoma mansoni in Kemise and in Bati, respectively, all members of the households being positive in 27% in Kemise and in 28% in Bati. The overall prevalences were 59%, 33% and 51% in Kemise, Harbu and Bati, respectively, with the corresponding geometric mean egg counts (epg) of 240, 123 and 195 for positives and 26.5 and 15 for the whole populations. All ages combined, there were no significant differences due to sex both in prevalence and intensity of infection. By age, children in the 10-14 years age group were most affected (p = 0.007), their prevalences reaching 86%, 52% and 66% in Kemise, Harbu and Bati, respectively and their corresponding geometric mean epg being 377, 157 and 401, respectively. Heavy infection (> 100 epg) reached 42%, 32% and 16% in Kemise, Bati and Harbu, respectively, reaching an average of 55% among the 10-14 years of age. The implications of the epidemiological findings and the possible use of the household approach for rapid assessment of schistosomiasis magnitude in an area are discussed.

Prevalence of pulmonary tuberculosis and associated risk factors in Eastern Ethiopian prisons.

OBJECTIVES: To determine the prevalence of pulmonary tuberculosis (PTB) and associated risk factors among inmates in three major prison settings of Eastern Ethiopia. DESIGN: Between July and November, 2008, 371 prisoners with a history of cough of ≥ 2 weeks were screened for PTB using direct smear microscopy and culture. Data were analysed using descriptive statistics and multivariable logistic regression. RESULTS: Of 371 PTB suspects identified by active screening, 33 (8.9%) were confirmed as smear- or culture-positive PTB. Together with the 11 PTB patients already on treatment, the point prevalence of PTB was 1913 per 100,000 (95%CI 1410-2580), about seven times higher than that of the general population. Eleven newly diagnosed PTB patients were sharing a cell with known TB patients. Factors significantly associated with PTB were young age (15-44 years of age) (OR 3.73), urban residence (OR 3.59), having a cough >4 weeks (OR 3.15), and sharing a cell with a TB patient (OR 3.39) or a prisoner with chronic cough (OR 4.5). CONCLUSIONS: The study documented a high prevalence of PTB among Ethiopian prisoners. Socio-demographic and TB management factors were identified to be underlying causes of the high transmission rate and the acquisition of new cases. Active surveillance of TB and implementing prevention and control guidelines are imperative.

Assessment of knowledge and practice about tuberculosis among eastern Ethiopian prisoners.

OBJECTIVE: To assess the level of knowledge and practice related to TB and identify predictive factors in three prisons in eastern Ethiopia: Dire Dawa, Jijiga and Harar. DESIGN: Between July and November 2008, 382 TB patients and suspects were interviewed using a structured questionnaire. Data were analysed using descriptive statistics and ordinal logistic regression. RESULTS: Only six (1.6%) prisoners described the cause of TB as being bacterial, while a wind locally known as 'nefas' was frequently mentioned (36.1%); nearly 75% of the prisoners correctly described breath as a mode of TB transmission; 116 (30.7%) did not know any measures for TB prevention and control; and half of the participants did not know that anti-tuberculosis drugs were provided free of charge. Significant predictors of TB knowledge were: incarceration in the Jijiga (OR 9.62, P < 0.001) and Dire Dawa (OR 2.14, P = 0.016) prisons, those who did not consult and receive treatment for TB symptoms (OR 2.46, P < 0.001), and prisoners without a past history of TB (OR 2.72, P = 0.002). CONCLUSION: The study demonstrates that prisoners have a modest level of biomedical knowledge. As part of the National TB Programme, health education programmes need to be implemented to enhance prisoners' knowledge of TB.

Progress in serodiagnosis of Mycobacterium tuberculosis infection.

One-third of the world population is estimated to have Mycobacterium tuberculosis infection. Accurate and timely identification of infected individuals is critical for treatment and control. The current diagnostic methods lack the desired sensitivity and specificity, require sophisticated equipment and skilled workforce or take weeks to yield results. Diagnosis of extrapulmonary TB, TB-HIV co-infection, childhood TB and sputum smear-negative pulmonary TB pose serious challenges. Interest in developing serodiagnostic methods is increasing because detection of antibody is rapid, simple and relatively inexpensive, and does not require a living cell for detection. Three types of tests, namely screening tests to overcome diagnostic delay, specific tests for diagnosis of extrapulmonary TB and other bacteriologically negative cases, and tests for vaccine-induced immunity need critical consideration. Several factors must be considered to develop serodiagnostic methods for TB. Antigen recognition by infected individuals is highly heterogeneous due to stage of disease, differences in HLA types, strain of the bacilli, health of the patient and bacillary load. With advances in molecular biological techniques, a number of novel antigens have been identified. Some of these antigens have proven valuable in detecting specific antibodies in some of the most challenging TB patients. The best example is a fusion protein containing several M. tuberculosis proteins (e.g. CFP-10, MTB8, MTB48, MTB81 and the 38-kDa protein) which showed encouraging results in detecting antibodies in sera of patients, including TB-HIV co-infection. This review presents progress made in the serodiagnosis of TB during the last decade.

The emergence of Beijing family genotypes of Mycobacterium tuberculosis and low-level protection by bacille Calmette-Guérin (BCG) vaccines: is there a link?

The world is confronted with major tuberculosis (TB) outbreaks at a time when the protection of bacillus Calmette-Guérin (BCG) vaccine has become inconsistent and controversial. Major TB outbreaks are caused by a group of genetically similar strains of Mycobacterium tuberculosis (Mtb) strains, including the Beijing family genotypes. The Beijing family genotypes exhibit important pathogenic features such high virulence, multi-drug resistance and exogenous reinfection. These family strains have developed mechanisms that modulate/suppress immune responses by the host, such as inhibition of apoptosis of infected macrophages, diminished production of interleukin (IL)-2, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and elevated levels of IL-10 and IL-18. They demonstrate distinct expression of proteins, such as several species of alpha-crystallin (a known Mtb virulence factor), but decreased expression of some antigens such as heat shock protein of 65 kDa, phosphate transport subunit S and a 47-kDa protein. In addition, the Beijing family strains specifically produce a highly bioactive lipid (a polyketide synthase)-derived phenolic glycolipid. This altered expression of proteins/glycolipids may be important factors underlying the success of the Beijing family strains. The Beijing family strains are speculated to have originated from South-east Asia, where BCG vaccination has been used for more than 60 years. The hypothesis that mass BCG vaccination may have been a selective factor that favoured genotypic and phenotypic characteristic acquired by the Beijing family strains is discussed.

Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease.

Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection.