scholarly journals Stereological analysis of bacterial load and lung lesions in nonhuman primates (rhesus macaques) experimentally infected with Mycobacterium tuberculosis

2011 ◽  
Vol 301 (5) ◽  
pp. L731-L738 ◽  
Author(s):  
Paul A. Luciw ◽  
Karen L. Oslund ◽  
Xiao-wei Yang ◽  
Lourdes Adamson ◽  
Resmi Ravindran ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rhesus Macaques ◽  
Bacterial Load ◽  
Three Dimensional ◽  
Tuberculosis Infection ◽  
Clinical Strain ◽  
Stereological Analysis ◽  
Three Dimensional Objects ◽  
Pulmonary Granulomas ◽  
The Impact

Infection with Mycobacterium tuberculosis primarily produces a multifocal distribution of pulmonary granulomas in which the pathogen resides. Accordingly, quantitative assessment of the bacterial load and pathology is a substantial challenge in tuberculosis. Such assessments are critical for studies of the pathogenesis and for the development of vaccines and drugs in animal models of experimental M. tuberculosis infection. Stereology enables unbiased quantitation of three-dimensional objects from two-dimensional sections and thus is suited to quantify histological lesions. We have developed a protocol for stereological analysis of the lung in rhesus macaques inoculated with a pathogenic clinical strain of M. tuberculosis (Erdman strain). These animals exhibit a pattern of infection and tuberculosis similar to that of naturally infected humans. Conditions were optimized for collecting lung samples in a nonbiased, random manner. Bacterial load in these samples was assessed by a standard plating assay, and granulomas were graded and enumerated microscopically. Stereological analysis provided quantitative data that supported a significant correlation between bacterial load and lung granulomas. Thus this stereological approach enables a quantitative, statistically valid analysis of the impact of M. tuberculosis infection in the lung and will serve as an essential tool for objectively comparing the efficacy of drugs and vaccines.

scholarly journals The impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination

AIDS ◽  
2015 ◽  
Vol 29 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Christine E. Jones ◽  
Anneke C. Hesseling ◽  
Nontobeko G. Tena-Coki ◽  
Thomas J. Scriba ◽  
Novel N. Chegou ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Bacille Calmette Guerin ◽  
Hiv Exposure ◽  
The Impact

scholarly journals Correlation between Disease Severity and the Intestinal Microbiome in Mycobacterium tuberculosis-Infected Rhesus Macaques

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Sivaranjani Namasivayam ◽  
Keith D. Kauffman ◽  
John A. McCulloch ◽  
Wuxing Yuan ◽  
Vishal Thovarai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Resistance ◽  
Rhesus Macaques ◽  
Severe Disease ◽  
Predictive Biomarker ◽  
Host Susceptibility ◽  
Intestinal Microbiome ◽  
Metagenomic Sequencing ◽  
Content Type ◽  
The Impact

ABSTRACT The factors that determine host susceptibility to tuberculosis (TB) are poorly defined. The microbiota has been identified as a key influence on the nutritional, metabolic, and immunological status of the host, although its role in the pathogenesis of TB is currently unclear. Here, we investigated the influence of Mycobacterium tuberculosis exposure on the microbiome and conversely the impact of the intestinal microbiome on the outcome of M. tuberculosis exposure in a rhesus macaque model of tuberculosis. Animals were infected with different strains and doses of M. tuberculosis in three independent experiments, resulting in a range of disease severities. The compositions of the microbiotas were then assessed using a combination of 16S rRNA and metagenomic sequencing in fecal samples collected pre- and postinfection. Clustering analyses of the microbiota compositions revealed that alterations in the microbiome after M. tuberculosis infection were of much lower magnitude than the variability seen between individual monkeys. However, the microbiomes of macaques that developed severe disease were noticeably distinct from those of the animals with less severe disease as well as from each other. In particular, the bacterial families Lachnospiraceae and Clostridiaceae were enriched in monkeys that were more susceptible to infection, while numbers of Streptococcaceae were decreased. These findings in infected nonhuman primates reveal that certain baseline microbiome communities may strongly associate with the development of severe tuberculosis following infection and can be more important disease correlates than alterations to the microbiota following M. tuberculosis infection itself. IMPORTANCE Why some but not all individuals infected with Mycobacterium tuberculosis develop disease is poorly understood. Previous studies have revealed an important influence of the microbiota on host resistance to infection with a number of different disease agents. Here, we investigated the possible role of the individual’s microbiome in impacting the outcome of M. tuberculosis infection in rhesus monkeys experimentally exposed to this important human pathogen. Although M. tuberculosis infection itself caused only minor alterations in the composition of the gut microbiota in these animals, we observed a significant correlation between an individual monkey’s microbiome and the severity of pulmonary disease. More importantly, this correlation between microbiota structure and disease outcome was evident even prior to infection. Taken together, our findings suggest that the composition of the microbiome may be a useful predictor of tuberculosis progression in infected individuals either directly because of the microbiome’s direct influence on host resistance or indirectly because of its association with other host factors that have this influence. This calls for exploration of the potential of the microbiota composition as a predictive biomarker through carefully designed prospective studies.

scholarly journals Microstructured liposome subunit vaccines reduce lung inflammation and bacterial load after Mycobacterium tuberculosis infection

Vaccine ◽  
2014 ◽  
Vol 32 (34) ◽  
pp. 4324-4332 ◽  
Author(s):  
Monalisa Martins Trentini ◽  
Fábio Muniz de Oliveira ◽  
Marilisa Pedroso Nogueira Gaeti ◽  
Aline Carvalho Batista ◽  
Eliana Martins Lima ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Lung Inflammation ◽  
Bacterial Load ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Subunit Vaccines

scholarly journals Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

2020 ◽  
Author(s):  
Uma Shanmugasundaram ◽  
Allison N Bucsan ◽  
Shashank R. Ganatra ◽  
Chris Ibegbu ◽  
Melanie Quezada ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Double Positive ◽  
Cell Responses ◽  
Ifn Γ

AbstractMycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and memory CD4 and CD8 T cells producing IFN-γ in the airways compared to peripheral blood, which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-17/IFN-γ double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb burden. Our findings provide novel insights into antigen-specific T cell responses associated with asymptomatic Mtb infection that are relevant for developing better strategies to control TB.

scholarly journals Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis

2014 ◽  
Vol 22 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Marcela Henao-Tamayo ◽  
Andrés Obregón-Henao ◽  
Elizabeth Creissen ◽  
Crystal Shanley ◽  
Ian Orme ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Vaccine Efficacy ◽  
Disease Process ◽  
Bcg Vaccine ◽  
Clinical Strain ◽  
Interleukin 17 ◽  
Content Type ◽  
The Impact

ABSTRACTThe global epidemic caused by the bacterial pathogenMycobacterium tuberculosiscontinues unabated. Moreover, the only available vaccine against tuberculosis,Mycobacterium bovisbacillus Calmette-Guérin (BCG), demonstrates variable efficacy. To respond to this global threat, new animal models that mimic the pathological disease process in humans are required for vaccine testing. One new model, susceptible C3Heb/FeJ mice, is similar to human tuberculosis in that these animals are capable of forming necrotic tubercle granulomas, in contrast to resistant C3H/HeOuJ mice. In this study, we evaluated the impact of prior BCG vaccination of C3Heb/FeJ and C3H/HeOuJ mice on exposure to a low-dose aerosol ofMycobacterium tuberculosisW-Beijing strain SA161. Both BCG-vaccinated murine strains demonstrated reduced bacterial loads 25 days after infection compared to controls, indicating vaccine efficacy. However, during chronic infection, vaccine efficacy waned in C3H/HeOuJ but not in C3Heb/FeJ mice. Protection in vaccinated C3Heb/FeJ mice was associated with reduced numbers of CD11b+Gr1+cells, increased numbers of effector and memory T cells, and an absence of necrotic granulomas. BCG vaccine efficacy waned in C3H/HeOuJ mice, as indicated by reduced expression of gamma interferon (IFN-γ) and increased expressions of interleukin-17 (IL-17), IL-10, and Foxp3 by T cells compared to C3Heb/FeJ mice. This is the first murine vaccine model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy.

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