Biomedical subjects

Barun Mathema

Publications and source records attributed to Barun Mathema.

At least 19 recordsLinked to original sources

PubMed2026

Assessment of differentially culturable tubercle bacteria assays for the detection of tuberculosis infection in asymptomatic household contacts and the implications for intra-household transmission: a longitudinal cohort study.

BACKGROUND: Conventional culture methods for tuberculosis diagnosis miss differentially culturable tubercle bacteria (DCTB), which grow only in liquid assays supplemented with growth-enhancing factors. This limitation, combined with inadequate contact tracing and screening, often fails to identify asymptomatic individuals, with live bacilli detectable by enhanced culture methods. This shortfall results in undiagnosed reservoirs of bacteria, potentially fuelling ongoing transmission. In this study, we aimed to investigate whether DCTB assays provide greater sensitivity by detecting more Mycobacterium tuberculosis infections than conventional culture and whether this enhanced detection improves the resolution of intrahousehold transmission mapping. In addition, we sought to evaluate whether DCTB populations can progress to conventional culture positivity, thereby highlighting their clinical and epidemiological relevance. METHODS: In this prospective observational longitudinal cohort study, drug-susceptible or rifampicin-resistant tuberculosis index participants aged 12 years or older, were recruited from primary healthcare clinics from two South African districts. Inclusion criteria were informed consent, Xpert MTB/RIF Ultra-positive results, tuberculosis symptoms (>2 weeks), provision of baseline samples, at least one consenting household contact, and documented HIV status. Household contacts of the index patients and control households were also recruited. Sputum specimens were collected at baseline and 2, 4, 8, 12, and 16 months from the index participants and household contacts. Samples were analysed by conventional mycobacterial growth indicator tube (MGIT) culture, and colony-forming unit assays to identify viable bacteria. Enhanced culture to detect DCTB involved serial dilution of sputum in liquid culture, supplemented with M tuberculosis culture filtrate as a source of growth stimulatory factors. Whole-genome sequencing (WGS) of cultured isolates was performed to trace household transmission. FINDINGS: Between June 1, 2020, and Feb 6, 2024, 293 index participants (183 [62%] male), 701 household contacts (453 [65%] female), and 122 control participants (67 [55%] female) were enrolled. At baseline, 249 (85%) of 293 index participants and 110 (16%) of 701 household contact sputum samples were positive for M tuberculosis by MGIT conventional culture. For baseline MGIT-negative specimens, DCTB assays detected M tuberculosis in an additional 21 (7%) of 293 index participants and 26 (4%) of 701 household contacts. Over 16 months of follow-up, DCTB assays identified 61 (8·7%) of 701 additional tuberculosis-positive household contacts not detected by conventional culture. WGS-guided transmission mapping using conventional culture identified transmission in 16 (15%) of 104 households, whereas DCTB assays detected an additional 19 (18%) of 104 transmission events. No evidence of intrahousehold transmission was found in the remaining 69 (66%) of 104 tuberculosis-positive households. Over the 16-month follow-up period, conventional culture identified 233 positive household contacts, of which 195 (84%) were asymptomatic. DCTB assays detected an additional 94 cases of M tuberculosis positivity in household contacts, of which 79 (84%) were asymptomatic. In control households, tuberculosis prevalence at baseline was two (2%) of 122, with an additional three (3%) of 122 identified during follow-up. INTERPRETATION: DCTB assays provide substantial value by detecting asymptomatic individuals missed by conventional culture, revealing a potentially important reservoir of subclinical infection, which could sustain transmission. In addition, DCTB detection uncovers transmission linkages missed by conventional culture, providing a more comprehensive understanding of M tuberculosis transmission dynamics and highlighting the need to incorporate enhanced culture methods into diagnostic and surveillance strategies, to strengthen early case identification and tuberculosis control efforts. FUNDING: National Institutes of Health.

Humans↗

PubMed2025

Integrating genomic and spatial analyses to describe tuberculosis transmission: a scoping review.

Tuberculosis remains a leading cause of infection-related mortality, and efforts to reduce its incidence have been hindered by an incomplete understanding of local Mycobacterium tuberculosis transmission dynamics. Advances in pathogen sequencing and spatial analysis have created new opportunities to map M tuberculosis transmission patterns more precisely. In this scoping review, we searched for studies combining pathogen genetics and location data to analyse the spatial patterns of M tuberculosis transmission and identified 142 studies published between 1994 and 2024. Secular changes in genetic methods were observed, with genome sequencing approaches largely replacing lower-resolution genotyping methods since 2020. The included studies addressed four primary research questions: how are tuberculosis cases and M tuberculosis transmission clusters geographically distributed; do spatially concentrated M tuberculosis clusters exist, and where are these areas located; when spatial concentration occurs, what host, pathogen, or environmental factors contribute to these patterns; and do identifiable relationships exist between the spatial proximity of tuberculosis cases and the genetic similarity of the M tuberculosis isolates infecting these individuals? Collectively, in this Review, we examined the available study data, evaluated the analytical requirements for addressing these questions, and discussed opportunities and challenges for future research. We found that the integration of spatial and genomic data can inform a detailed understanding of local M tuberculosis transmission patterns, but improved study designs and new analytical methods to address gaps in sampling completeness and to integrate additional movement data are needed to fully realise the potential of these tools.

Humans↗

PubMed2006

Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiological studies to community-associated MRSA (CA-MRSA) disease. However, the role that PVL plays in the pathogenesis of CA-MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL-positive with that of PVL-negative CA-MRSA representing the leading disease-causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL-negative (lukS/F-PV knockout) strains of USA300 and USA400 were as lethal as wild-type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild-type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA-MRSA strains, we conclude that PVL is not the major virulence determinant of CA-MRSA.

Abscess↗

PubMed2006

Molecular epidemiology of tuberculosis: current insights.

Molecular epidemiologic studies of tuberculosis (TB) have focused largely on utilizing molecular techniques to address short- and long-term epidemiologic questions, such as in outbreak investigations and in assessing the global dissemination of strains, respectively. This is done primarily by examining the extent of genetic diversity of clinical strains of Mycobacterium tuberculosis. When molecular methods are used in conjunction with classical epidemiology, their utility for TB control has been realized. For instance, molecular epidemiologic studies have added much-needed accuracy and precision in describing transmission dynamics, and they have facilitated investigation of previously unresolved issues, such as estimates of recent-versus-reactive disease and the extent of exogenous reinfection. In addition, there is mounting evidence to suggest that specific strains of M. tuberculosis belonging to discrete phylogenetic clusters (lineages) may differ in virulence, pathogenesis, and epidemiologic characteristics, all of which may significantly impact TB control and vaccine development strategies. Here, we review the current methods, concepts, and applications of molecular approaches used to better understand the epidemiology of TB.

Animals↗

PubMed2006

Evaluation of the Mtb72F polyprotein vaccine in a rabbit model of tuberculous meningitis.

Using a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F+AS02A) or Mtb72F formulated in AS01B (Mtb72F+AS01B) was protective against central nervous system (CNS) challenge with Mycobacterium tuberculosis H37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F+AS02A-vaccinated rabbits. In addition, protection against M. tuberculosis H37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F+AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.

Adjuvants, Immunologic↗

PubMed2005

Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites.

We studied genetic relationships among 5069 Mycobacterium tuberculosis strains recovered from patients enrolled in 4 population-based studies in the United States and Europe, by analysis of 36 synonymous single-nucleotide polymorphisms (SNPs). All strains were assigned to 1 of 9 major genetic clusters based on sSNP profile. The same 9 genetic clusters were revealed by analysis of 227 nonsynonymous SNPs, 121 intergenic SNPs, and concatenated profiles of 578 SNPs available for a subset of 48 representative strains. IS6110 profiles, spoligotypes, and mycobacterial interspersed repetitive unit patterns were nonrandomly associated with SNP-based phylogenetic lineages, together indicating a strongly clonal population structure. Isolates of the 9 genetic clusters were not distributed with equal frequency in all localities, reflecting geographic subdivision. The SNP-based phylogenetic framework provides new insight into the worldwide evolution of M. tuberculosis and a gateway for investigating genotype-disease phenotype relationships in large samples of strains.

Bacterial Typing Techniques↗

PubMed2005

Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli.

Infection with Mycobacterium tuberculosis in humans results in active disease in approximately 10% of immune-competent individuals, with the most-severe clinical manifestations observed when the bacilli infect the central nervous system (CNS). Here, we use a rabbit model of tuberculous meningitis to evaluate the severity of disease caused by the M. tuberculosis clinical isolates CDC1551, a highly immunogenic strain, and HN878 or W4, 2 members of the W/Beijing family of strains. Compared with infection with CDC1551, CNS infection with HN878 or W4 resulted in higher bacillary loads in the cerebrospinal fluid and brain, increased dissemination of bacilli to other organs, persistent levels of tumor necrosis factor-alpha , higher leukocytosis, and more-severe clinical manifestations. This pathogenic process is associated with the production by HN878 of a polyketide synthase-derived phenolic glycolipid (PGL), as demonstrated by reduced virulence in rabbits infected with an HN878 mutant disrupted in the pks1-15 gene, which is required for PGL synthesis.

Animals↗

PubMed2005

Targeted hybridization of IS6110 fingerprints identifies the W-Beijing Mycobacterium tuberculosis strains among clinical isolates.

Targeted IS6110-based RFLP genotyping can be applied to rapidly identify specific groups of biomedically/epidemiologically relevant Mycobacterium tuberculosis clinical isolates. One such group is the W-Beijing strain family (also known as Beijing/W), implicated in significant nosocomial and community outbreaks worldwide. Using previously defined criteria, we developed a simple and accurate method to identify members of the W-Beijing family, based on rehybridization of Southern blot membranes used previously in routine IS6110 DNA fingerprint analysis. The hybridization probe constructed ("W-Beijing polyprobe") contains the PCR-amplified fragments specific for three M. tuberculosis chromosomal loci used for the identification of W-Beijing strains. The targets include the dnaA-dnaN and NTF regions and the direct repeat locus. A total of 526 selected clinical isolates (representative of 253 different IS6110-defined strain types) were analyzed using the W-Beijing polyprobe. A total of 148 isolates from this collection were found to be members of the W-Beijing phylogenetic lineage, comprising 106 strains from the W-Beijing family (46 clusters) and 42 related isolates. Rehybridization results were confirmed by computer-assisted analysis. The sensitivity and specificity of this method were estimated at 98.7% and 99.7%, respectively. This study demonstrates that the W-Beijing polyprobe can accurately and reliably discriminate members of the W-Beijing phylogenetic lineage and the W-Beijing family of M. tuberculosis strains.

Base Sequence↗

PubMed2005

Differential distribution and expression of Panton-Valentine leucocidin among community-acquired methicillin-resistant Staphylococcus aureus strains.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat worldwide. CA-MRSA strains differ from hospital-acquired MRSA strains in their antibiotic susceptibilities and genetic backgrounds. Using several genotyping methods, we clearly define CA-MRSA at the genetic level and demonstrate that the prototypic CA-MRSA strain, MW2, has spread as a homogeneous clonal strain family that is distinct from other CA-MRSA strains. The Panton-Valentine leucocidin (PVL)-encoding genes, lukF and lukS, are prevalent among CA-MRSA strains and have previously been associated with CA-MRSA infections. To better elucidate the role of PVL in the pathogenesis of CA-MRSA, we first analyzed the distribution and expression of PVL among different CA-MRSA strains. Our data demonstrate that PVL genes are differentially distributed among CA-MRSA strains and, when they are present, are always transcribed, albeit with strain-to-strain variability of transcript levels. To directly test whether PVL is critical for the pathogenesis of CA-MRSA, we evaluated the lysis of human polymorphonuclear leukocytes (PMNs) during phagocytic interaction with PVL-positive and PVL-negative CA-MRSA strains. Unexpectedly, there was no correlation between PVL expression and PMN lysis, suggesting that additional virulence factors underlie leukotoxicity and, thus, the pathogenesis of CA-MRSA.

Bacterial Proteins↗

PubMed2004

Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem because treatment is complicated, cure rates are well below those for drug-susceptible tuberculosis (TB), and patients may remain infectious for months or years, despite receiving the best available therapy. To gain a better understanding of MDR-TB, we characterized serial isolates recovered from 13 human immunodeficiency virus-negative patients with MDR-TB, by use of IS6110 restriction fragment-length polymorphism analysis, spacer oligonucleotide genotyping (i.e., "spoligotyping"), and sequencing of rpoB, katG, mabA-inhA (including promoter), pncA, embB, rpsL, rrs, and gyrA. For all 13 patients, chronic MDR-TB was caused by a single strain of Mycobacterium tuberculosis; 8 (62%) of the 13 strains identified as the cause of MDR-TB belonged to the W-Beijing family. The sputum-derived isolates of 4 (31%) of the 13 patients had acquired additional drug-resistance mutations during the study. In these 4 patients, heterogeneous populations of bacilli with different resistance mutations, as well as mixtures of drug-susceptible and drug-resistant genotypes, were observed. This genetic heterogeneity may require treatment targeted at both drug-resistant and drug-susceptible phenotypes.

Adult↗

PubMed2004

Evolution of epidemiologic methods and concepts in selected textbooks of the 20th century.

Textbooks are an expression of the state of development of a discipline at a given moment in time. By reviewing eight epidemiology textbooks published over the course of a century, we have attempted to trace the evolution of five epidemiologic concepts and methods: study design (cohort studies and case-control studies), confounding, bias, interaction and causal inference. Overall, these eight textbooks can be grouped into three generations. Greenwood (1935) and Hill (first edition 1937; version reviewed 1961)'s textbooks belong to the first generation, "early epidemiology", which comprise early definitions of bias and confounding. The second generation, "classic epidemiology", represented by the textbooks of Morris (first edition 1957; version reviewed 1964), MacMahon & Pugh (first edition 1960; version reviewed 1970), Susser (1973), and Lilienfeld & Lilienfeld (first edition 1976; version reviewed 1980), clarifies the properties of cohort and case-control study designs and the theory of disease causation. Miettinen (1985) and Rothman (1986)'s textbooks belong to a third generation, "modern epidemiology", presenting an integrated perspective on study designs and their measures of outcome, as well as distinguishing and formalizing the concepts of confounding and interaction. Our review demonstrates that epidemiology, as a scientific discipline, is in constant evolution and transformation. It is likely that new methodological tools, able to assess the complexity of the causes of human health, will be proposed in future generations of textbooks.

Epidemiologic Methods↗

PubMed2004

Differential monocyte activation underlies strain-specific Mycobacterium tuberculosis pathogenesis.

In vitro infection of monocytes with Mycobacterium tuberculosis HN878 and related W/Beijing isolates preferentially induced interleukin-4 (IL-4) and IL-13, which characterize Th2 polarized immunity. In contrast, CDC1551 induced more IL-12 and other molecules associated with phagocyte activation and Th1 protective immunity. The differential cytokine-chemokine response was mediated by extracted lipids, suggesting that these molecules regulate host responses to infection.

Cell Differentiation↗

PubMed2003

Persistence of a highly resistant strain of tuberculosis in New York City during 1990-1999.

One multidrug-resistant Mycobacterium tuberculosis (MDRTB) strain, strain W, caused several nosocomial outbreaks in New York City (NYC) during 1 January 1990-31 July 1993. We reviewed all MDRTB cases verified during 1 August 1993-31 December 1999 that had isolates with either this DNA pattern or a variant of this strain, and we compared them to the outbreak cases. Of 427 DNA-confirmed cases from 1990-1999, 161 (37%) were from 1 August 1993-31 December 1999; these 161 cases, from 56 hospitals and 2 correctional sites, constituted 28% of all MDRTB cases in NYC during this period. Compared with those from 1 January 1990-31 July 1993, patients from 1 August 1993-31 December 1999 were less likely to be infected with human immunodeficiency virus, to have been born in the United States, to be homeless, to have been incarcerated, and to have epidemiological links; 16% of patients had nosocomial- and 9% had community-exposure links. This strain was disseminated widely in the community during the outbreaks; postoutbreak cases likely represent reactivated disease among individuals infected during the outbreak periods in the community.

Adult↗

PubMed2003

Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen.

The prevalence of MRSA in the nosocomial setting has been well studied, and its control remains a challenge for infection control professionals. Complicating this problem is the increasing number of reports on the spread of community-acquired MRSA (CA-MRSA). CA-MRSA strains differ from hospital-acquired MRSA (HA-MRSA) strains in that they are generally susceptible to most antibiotics. These strains share the presence of staphylococcal cassette chromosome mec (SCCmec) type IV in their genomes, are frequently virulent, and predominantly cause skin and soft tissue infections. The genome sequence of the prototypic CA-MRSA strain, MW2, revealed the presence of additional virulence factors not commonly present in other S. aureus strains. We determined the genetic relatedness of 30 geographically diverse CA-MRSA isolates clustered based on SCCmec type IV by sequence analysis of the polymorphic repeat region of the protein A gene (spa typing). These results indicated that most strains shared a common spa type (131), identical to MW2. Because this group tends to infect healthy individuals with no known risk factors for nosocomial acquisition of MRSA, we refer to it as CA-MRSA without risk factors. A second group, CA-MRSA with risk factors, consists of two related genotypes, spa types 1 and 7, which differ by one nucleotide change. These strains have caused severe infections in HIV-positive patients in Los Angeles and New York. Although CA-MRSA strains share genetic determinants, they are not clonal but rather are derived from different genetic backgrounds. The genetic characteristics and the epidemiology of CA-MRSA with and without risk factors are discussed.

Communicable Diseases, Emerging↗

PubMed2003

Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity.

Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated.

Adolescent↗

PubMed2002

Identification and evolution of an IS6110 low-copy-number Mycobacterium tuberculosis cluster.

A cohort of 56 patients infected with related strains of Mycobacterium tuberculosis, the S75 group, was identified in a New Jersey population-based study of all isolates with a low number of copies of the insertion element IS6110. Genotyping was combined with surveillance data to identify the S75 group and to elucidate its recent evolution. The S75 group had similar demographic and geographic characteristics. Seventeen persons (30%) were linked epidemiologically. The S75 group was segregated from other low-copy-number isolates on the basis of several independent molecular methods. This group included 3 IS6110 genotype variants: BE, H6, and C28, containing 1, 2, and 3 IS6110 insertions, respectively. IS6110 insertion site mapping and comparative sequence analysis strongly suggest a stepwise acquisition of IS6110 elements from BE to H6 to C28. S75 represents a locally produced strain cluster that has recently evolved. The combination of multiple molecular tools with traditional epidemiology provides novel insights into dissemination, local transmission, and evolution of M. tuberculosis.

DNA Transposable Elements↗

PubMed2002

Global dissemination of the Mycobacterium tuberculosis W-Beijing family strains.

A large, genetically related group of Mycobacterium tuberculosis strains, variously called W or Beijing, is distinguished by specific molecular markers and referred to as the W-Beijing family strains. Molecular epidemiological studies suggest that these strains are highly prevalent throughout Asia and the countries of the former Soviet Union and they have also been reported in several other geographical regions, including North America. Although the spread of W-Beijing family strains in diverse populations is well documented, the underlying host-pathogen factors accounting for their continued dissemination and burden of disease have yet to be determined.

Asia, Eastern↗

PubMed2002

Spoligologos: a bioinformatic approach to displaying and analyzing Mycobacterium tuberculosis data.

Spacer oligonucleotide (spoligotyping) analysis is a rapid polymerase chain reaction-based method of DNA fingerprinting the Mycobacterium tuberculosis complex. We examined spoligotype data using a bioinformatic tool (sequence logo analysis) to elucidate undisclosed phylogenetic relationships and gain insights into the global dissemination of strains of tuberculosis. Logo analysis of spoligotyping data provides a simple way to describe a fingerprint signature and may be useful in categorizing unique spoligotypes patterns as they are discovered. Large databases of DNA fingerprint information, such as those from the U.S. National Tuberculosis Genotyping and Surveillance Network and the European Concerted Action on Tuberculosis, contain information on thousands of strains from diverse regions. The description of related spoligotypes has depended on exhaustive listings of the individual spoligotyping patterns. Logo analysis may become another useful graphic method of visualizing and presenting spoligotyping clusters from these databases.

Bacterial Typing Techniques↗