Reducing ongoing transmission of tuberculosis.
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Humans↗
Biomedical subjects
P F Barnes
Publications and source records attributed to P F Barnes.
Isolation of mycobacterium-reactive CD1-restricted T cells from patients with human immunodeficiency virus infection.
Because CD1-restricted T cells lack CD4 but produce IFN-gamma in response to nonpeptide mycobacterial antigens, they could play a unique role in immunity to tuberculosis. We studied CD1-restricted T cells in the context of HIV infection by expanding CD4(-) T cell lines from 10 HIV-infected patients. Upon stimulation with Mycobacterium tuberculosis antigen or upon exposure to macrophages infected with M. tuberculosis, these T cell lines proliferated, produced IFN-gamma, and showed cytolytic T cell (CTL) activity against macrophages pulsed with mycobacterial antigen, findings consistent with a protective role against M. tuberculosis. Anti-CD1b antibodies abrogated T cell proliferation, IFN-gamma production, and CTL activity, demonstrating that these T cells are CD1 restricted. IFN-gamma production in response to M. tuberculosis was enhanced by antitransforming growth factor-beta in 8/10 lines, and by IL-15 in 2/10 lines. IFN-gamma production was augmented in a nonantigen-specific manner by IL-12 in 4/8 lines. When live HIV was cocultured with CD1-restricted T cell lines, p24 antigen and proviral DNA were not detected, indicating that the T cells were not infectable with HIV. Vaccination strategies aimed at activation and expansion of M. tuberculosis-reactive CD1-restricted T cells in HIV-infected patients may constitute a novel means to provide protection against tuberculosis, while minimizing the risk of enhancing HIV replication through stimulation of CD4(+) cells.
Antigens, CD1↗
Growth of virulent and avirulent Mycobacterium tuberculosis strains in human macrophages.
Mycobacterium tuberculosis H37Rv causes progressive disease in animals, whereas the H37Ra strain does not. The relevance of this difference in virulence to human infection is uncertain because these strains have been shown to have similar growth rates in human macrophages. To evaluate the intracellular growth of M. tuberculosis strains in macrophages under conditions similar to those encountered in vivo, we infected human monocyte-derived macrophages with H37Ra, H37Rv, or one of four isolates from tuberculosis patients at a low bacillus-to-macrophage ratio. H37Rv and the patient isolates grew significantly faster than H37Ra, based on the numbers of CFU and acid-fast bacilli. These findings did not result from extracellular mycobacterial growth, differential macrophage viability, or bacillary clumping. In contrast to other published results, these findings indicate that the virulence characteristics of M. tuberculosis strains in animal models are relevant to human tuberculosis infection.
Cytokines↗
Chemokine production by a human alveolar epithelial cell line in response to Mycobacterium tuberculosis.
To investigate the role of chemokines during the initial local response to Mycobacterium tuberculosis in the human lung, we studied chemokine production by the human alveolar epithelial cell line A549 after infection with M. tuberculosis. M. tuberculosis-infected A549 cells produced mRNAs and protein for monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8) but not mRNAs for macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES. Chemokine production in response to M. tuberculosis was not dependent on production of tumor necrosis factor alpha, IL-1beta, or IL-6. Two virulent clinical M. tuberculosis isolates, the virulent laboratory strain H37Rv, and the avirulent strain H37Ra elicited production of comparable concentrations of MCP-1 and IL-8, whereas killed M. tuberculosis and three Mycobacterium avium strains did not. The three virulent M. tuberculosis strains grew more rapidly than the avirulent M. tuberculosis strain in the alveolar epithelial cell line, and the three M. avium strains did not grow intracellularly. These findings suggest that intracellular growth is necessary for mycobacteria to elicit production of MCP-1 and IL-8 by alveolar epithelial cells but that virulence and the rate of intracellular growth do not correlate with chemokine production. Alveolar epithelial cells may contribute to the local inflammatory response in human tuberculosis by producing chemokines which attract monocytes, lymphocytes, and polymorphonuclear cells.
Cell Line↗
Production of monocyte chemoattractant protein 1 in tuberculosis patients.
To investigate the role of monocyte chemoattractant protein 1 (MCP-1) in the immune response to Mycobacterium tuberculosis, we studied MCP-1 production in tuberculosis patients. CD14+ blood monocytes from tuberculosis patients spontaneously expressed higher levels of MCP-1 mRNA and protein than CD14+ monocytes from healthy tuberculin reactors. MCP-1 production in lymph nodes from tuberculosis patients was also markedly increased. These findings suggest that MCP-1 can contribute to the antimycobacterial inflammatory response by attracting monocytes and T lymphocytes.
Chemokine CCL2↗
Diversity of DNA fingerprints of Mycobacterium tuberculosis isolates in the United States.
To investigate the diversity of IS6110 fingerprints of Mycobacterium tuberculosis isolates in the United States and to determine if matching IS6110 fingerprints represent recent interstate tuberculosis transmission, we performed restriction fragment length polymorphism analysis of M. tuberculosis isolates from 1,326 patients in three geographically separated states. Seven hundred ninety-five different IS6110 fingerprint patterns were generated, and pattern diversity was similar in each state. Ninety-six percent of the fingerprint patterns were observed in only one state, demonstrating that most IS6110 fingerprint patterns are confined to a single geographic location. Of the IS6110 fingerprint patterns that were shared by isolates from more than one state, most isolates with 1 to 5 IS6110 copies were separable by pTBN12 fingerprinting whereas those with > 15 copies were not. One high-copy-number M. tuberculosis strain had identical IS6110 and pTBN12 fingerprints and included 57 isolates from three states. Epidemiological data demonstrated significant recent transmission of tuberculosis within each city but not among the states. This suggests that identical fingerprints of isolates from geographically separate locations most likely reflect interstate tuberculosis transmission in the past, with subsequent intrastate spread of disease. Further evaluation of M. tuberculosis strains that cause outbreaks in different geographic locations will provide insight into the epidemiological and bacteriological factors that facilitate the spread of tuberculosis.
DNA Fingerprinting↗
Pediatric tuberculosis: clinical presentation and contact investigation at an urban medical center.
OBJECTIVE: (A) To characterize the clinical presentation of pediatric tuberculosis in Los Angeles County; (B) to determine the efficacy of contact investigation in identifying a source case for children with tuberculosis. METHODS: We reviewed the medical records, chest radiograph and Tuberculosis Control records of 34 children (age < 15 years) evaluated at Los Angeles County from January 1992 through December 1993. RESULTS: All patients were Hispanic. The mean age was 2.2 years. Thirty-three patients (97%) had intrathoracic disease. Eighteen patients (53%) were symptomatic and the most common symptoms were fever and cough. The contact investigation revealed only 4 patients (2%) to be adult source cases with active tuberculosis. CONCLUSION: The clinical features of pediatric tuberculosis in Los Angeles County confirm results previously reported in other parts of the US. In contrast, the identification of adult source cases is suboptimal. Improved methods of contact tracing are needed when evaluating children with tuberculosis.
Academic Medical Centers↗
Tuberculosis among the inner city poor.
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Adult↗
Patterns of tuberculosis transmission in Central Los Angeles.
CONTEXT: Recent studies suggest that many tuberculosis cases in urban areas result from recent transmission. Delineation of the epidemiologic links between patients is important to optimize strategies to reduce tuberculosis transmission. OBJECTIVE: To identify epidemiologic links among recently infected urban patients with tuberculosis. DESIGN: Prospective evaluation of patients with tuberculosis. SETTING: Central Los Angeles, Calif. PATIENTS: A total of 162 patients who had culture-proven tuberculosis. INTERVENTIONS: Patients were prospectively interviewed to identify their contacts and whereabouts. The IS6110-based and pTBN12-based restriction fragment length polymorphism analyses were performed on Mycobacterium tuberculosis isolates. Patients whose isolates had identical or closely related restriction fragment length polymorphism patterns were considered a cluster. Unconditional logistic regression was used to identify independent predictors of clustering. MAIN OUTCOME MEASURES: Relationship of clinical and epidemiologic variables to clustering. RESULTS: A total of 96 (59%) of 162 patients were in 8 clusters. Only 2 of the 96 clustered patients named others in the cluster as contacts. The degree of homelessness was an independent predictor of clustering. Compared with nonclustered patients, patients in 6 clusters were significantly more likely to have spent time at 3 shelters and other locations when at least 1 patient in the cluster was contagious, and these locations were independent predictors of clustering. Among nonhomeless persons, clustered patients were significantly more likely than nonclustered patients to have used daytime services at 3 shelters. CONCLUSIONS: (1) Traditional contact investigation does not reliably identify patients infected with the same M tuberculosis strain, and (2) locations at which the homeless congregate are important sites of tuberculosis transmission for homeless and nonhomeless persons. Measures that reduce tuberculosis transmission should be based on locations rather than on personal contacts.
Adolescent↗
Single-cell cytokine analysis of gamma delta T cell responses to nonpeptide mycobacterial antigens.
TCR gamma delta T cells are considered important in the rapid immune response to intracellular infection. We investigated the early response of peripheral blood gamma delta T cells to the nonpeptide Ag isopentenyl pyrophosphate and to its synthetic analogue ethyl pyrophosphate. In healthy donors, an increase in the number of gamma delta T cells was detected as soon as 4 days after stimulation with the nonpeptide Ags. Single-cell analysis of cytokine production was performed by intracellular staining of IFN-gamma and IL-4. gamma delta T cells were found to rapidly expand and produce IFN-gamma in response to nonpeptide Ags. Furthermore, IL-12 augmented the IFN-gamma response. In contrast, gamma delta T cells from the majority of HIV+ donors did not expand or express IFN-gamma in response to nonpeptide Ags, even in the presence of IL-12. These findings indicate a role for nonpeptide-reactive gamma delta T cells in effective cell-mediated immunity for intracellular pathogens.
Antigens, Bacterial↗
Differential effects of cytolytic T cell subsets on intracellular infection.
In analyzing mechanisms of protection against intracellular infections, a series of human CD1-restricted T cell lines of two distinct phenotypes were derived. Both CD4(-)CD8(-) (double-negative) T cells and CD8(+) T cells efficiently lysed macrophages infected with Mycobacterium tuberculosis. The cytotoxicity of CD4(-)CD8(-) T cells was mediated by Fas-FasL interaction and had no effect on the viability of the mycobacteria. The CD8(+) T cells lysed infected macrophages by a Fas-independent, granule-dependent mechanism that resulted in killing of bacteria. These data indicate that two phenotypically distinct subsets of human cytolytic T lymphocytes use different mechanisms to kill infected cells and contribute in different ways to host defense against intracellular infection.
Antigens, CD1↗
Clinical correlates of interferon gamma production in patients with tuberculosis.
To determine if the capacity to produce interferon (IFN) gamma is related to the clinical manifestations of tuberculosis, we correlated Mycobacterium tuberculosis-induced IFN-gamma production by peripheral blood mononuclear cells (PBMCs) with clinical, radiographic, and laboratory variables for 63 human immunodeficiency virus (HIV)-negative patients and 43 HIV-positive patients with tuberculosis. For HIV-negative patients whose chest radiographs showed moderately advanced disease, the mean IFN-gamma concentration +/- SD was 1,639 +/- 388 pg/mL, whereas that for patients with far-advanced disease was 327 +/- 100 pg/mL (P = .0001). For HIV-infected patients who had only pleuropulmonary disease, the mean IFN-gamma concentration was 1,002 +/- 257 pg/mL, whereas that for patients with disease outside the lungs and pleura was 149 +/- 55 pg/mL (P = .0004). Multivariate analysis confirmed that the radiographic extent of disease and the site of disease were the only independent predictors of IFN-gamma production in HIV-negative and HIV-infected patients (P < or = .001). We conclude that reduced IFN-gamma production by PBMCs is a marker of severe tuberculosis in both HIV-negative and HIV-infected patients with tuberculosis.
AIDS-Related Opportunistic Infections↗
CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis.
We evaluated 85 human immunodeficiency virus (HIV)-negative patients with tuberculosis for clinical features and CD4 cell counts. Thirty-seven patients had low CD4 cell counts (mean +/- SD, 341 +/- 116 cells/microL), and 48 patients had normal CD4 cell counts (mean +/- SD, 830 +/- 254 cells/microL). CD4 cell counts were most strongly correlated with total lymphocyte counts (r = 0.84). If total lymphocyte count was excluded, depressed CD4 cell counts were significantly associated with low serum albumin levels, extensive pulmonary disease, low body-mass index, and low hematocrit. Of these four variables, multivariate linear discriminant analysis revealed that the serum albumin level was the best single predictor of low CD4 cell counts and that the other three variables did not improve predictive value. Because these four variables are markers of severe tuberculosis, these findings suggest that disease severity is associated with greater depression of the total lymphocyte and CD4 cell counts. The CD4 cell counts returned to normal levels in most patients after 1 month of therapy.
Adult↗
Effects of Mycobacterium tuberculosis on the bioelectric properties of the alveolar epithelium.
To investigate the hypothesis that Mycobacterium tuberculosis penetrates the alveolar epithelium by downregulating its barrier properties, we evaluated the interactions between M. tuberculosis and rat alveolar epithelial cell monolayers that are believed to share electrophysiologic properties of the human alveolar epithelium. Nonproteinaceous components of M. tuberculosis caused marked declines in electrical resistance and equivalent short-circuit current of the alveolar epithelial cell monolayers, indicating a reduction in the capacity to maintain tight intercellular junctions and to actively reabsorb sodium. M. tuberculosis elicited production of TNF-alpha mRNA and protein by alveolar epithelial cells, and the effects of recombinant TNF-alpha on the bioelectric properties of the alveolar epithelial paralleled those of M. tuberculosis. Furthermore, the effects of M. tuberculosis on alveolar epithelial resistance were abrogated by neutralizing anti-TNF-alpha antibodies. These results indicate that M. tuberculosis elicits production of TNF-alpha, which in turn reduces the bioelectric barrier properties of the alveolar epithelium. These findings provide insight into potential mechanisms by which M. tuberculosis establishes infection and disease in the lung.
Animals↗
Testing for human immunodeficiency virus infection among tuberculosis patients in Los Angeles.
To investigate patterns of testing for human immunodeficiency virus (HIV) infection in tuberculosis patients, we obtained data from the tuberculosis registry and from medical records of 500 tuberculosis patients in Los Angeles County. Sixty-three percent of tuberculosis patients were tested for HIV infection, and multivariate logistic regression analysis revealed that the likelihood of testing was significantly higher among males, persons between 20 and 49 yr old, individuals with HIV risk factors, and patients treated by public health care providers. A minimum of 12% of the total sample, 2% of females, 2% of those outside the ages of 20 to 49, 7% of patients without recorded HIV risk factors, and 17% of patients treated by private practitioners were infected with HIV. These results suggest that health care providers, particularly private practitioners, do not follow national recommendations for universal HIV testing of tuberculosis patients. Instead, HIV testing is preferentially performed on patients perceived to be at high risk for HIV infection. Because HIV seroprevalence is at least 2 to 7% in "low-risk" groups, failure to test these patients may result in significant missed opportunities for diagnosis and treatment of HIV coinfection.
AIDS Serodiagnosis↗
Rapid diagnostic tests for tuberculosis: progress but no gold standard.
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Bacteriological Techniques↗
Chest radiographic findings in patients with tuberculosis with recent or remote infection.
To determine if chest radiographic findings differ in adult tuberculosis patients with recent and remote infection, we reviewed the chest radiographs of 103 patients with tuberculosis in Los Angeles and performed RFLP analyses of their Mycobacterium tuberculosis isolates. Patients whose isolates had identical or closely related RFLP patterns were considered a "cluster." Most patients in large clusters (more than seven patients) had tuberculosis from recent infection, whereas most unclustered patients had tuberculosis from remote infection. Mediastinal adenopathy or pleural effusions were classified as typical of recent infection, and upper lobe infiltrates, cavitation, or fibrosis were classified as characteristic of remote infection. Radiographic patterns were typical of remote infection in 62% of patients and were characteristic of recent infection in 23% of patients. The distribution of these radiographic patterns was similar in clustered and unclustered patients, both with or without human immunodeficiency virus (HIV) coinfection. However, mediastinal adenopathy and pleural effusions were significantly more common in HIV-infected patients. We conclude that: (1) chest radiographic findings in adults with tuberculosis of recent infection are similar to those in patients with remote infection; (2) the distinctive chest radiographic findings in HIV-infected patients with tuberculosis are not due to an increased frequency of recent infection.
AIDS-Related Opportunistic Infections↗
Human cellular immune responses to Mycobacterium tuberculosis.
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Antigens, Bacterial↗