Recent progress in understanding immune activation in the pathogenesis in HIV–tuberculosis co-infection

Bruyn, Elsa Du; Peton, Nashied; Esmail, Hanif; Howlett, Patrick; Coussens, Anna K.; Wilkinson, Robert J.

doi:10.1097/coh.0000000000000501

Cited by 12 publications

(10 citation statements)

References 55 publications

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“…M . tuberculosis pathogenesis and outcome of TB infection are impacted by several factors such as bacterial lineage [ 2 ], drug susceptibility of the strains [ 3 ], co-infection with HIV [ 4 ] or Cytomegalovirus (CMV) [ 5 ], comorbidities like diabetes [ 6 ], genetic predisposing factors (for instance IFN-γ/IL-12 deficiency [ 7 ]) and malnutrition [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Multicenter analysis of sputum microbiota in tuberculosis patients

et al. 2020

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The impact of tuberculosis and of anti-tuberculosis therapy on composition and modification of human lung microbiota has been the object of several investigations. However, no clear outcome has been presented so far and the relationship between M. tuberculosis pulmonary infection and the resident lung microbiota remains vague. In this work we describe the results obtained from a multicenter study of the microbiota of sputum samples from patients with tuberculosis or unrelated lung diseases and healthy donors recruited in Switzerland, Italy and Bangladesh, with the ultimate goal of discovering a microbiota-based biomarker associated with tuberculosis. Bacterial 16S rDNA amplification, high-throughput sequencing and extensive bioinformatic analyses revealed patient-specific flora and high variability in taxon abundance. No common signature could be identified among the individuals enrolled except for minor differences which were not consistent among the different geographical settings. Moreover, anti-tuberculosis therapy did not cause any important variation in microbiota diversity, thus precluding its exploitation as a biomarker for the follow up of tuberculosis patients undergoing treatment.

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Section: Introductionmentioning

confidence: 99%

Multicenter analysis of sputum microbiota in tuberculosis patients

et al. 2020

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“…Mice are the most commonly used models because they are immunologically similar to humans, genetically tractable, and economical. Studies in inbred mice demonstrated the importance of CD4 ϩ T cells, gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣) among other immunological mediators that are clearly relevant to tuberculosis in humans (5)(6)(7)(8)(9)(10). However, M. tuberculosis infection of the most commonly used inbred mouse strains, such as C57BL/6J (B6) or BALB/c, does not result in all aspects of human tuberculosis or outcomes after vaccination.…”

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confidence: 99%

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Kurtz

Rossi

Beamer

et al. 2020

mSphere

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Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis. Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis. Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize “disease” and “protection,” with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people. IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.

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“…Decreased numbers of CD4 + T lymphocytes with significantly increased CD8 + cells in TB granulomas of HIV-positive nodes were observed in our study similar to changes seen by others, in various anatomical sites and models. 5,[21][22][23][24] Lymph nodes from HIV-positive patients with higher CD4 counts showed better formed granuloma formation in contrast to lymph nodes from patients with lower CD4 counts. These findings are all in keeping with current knowledge of CD4 + destruction and depletion in HIV.…”

Section: Discussionmentioning

confidence: 98%

The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas

Wadee

Wadee²

2021

The American Journal of Tropical Medicine and Hygiene

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Granuloma formation is the pathologic hallmark of tuberculosis. Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous (TB) granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (−) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV− granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV− than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV− TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.

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Recent progress in understanding immune activation in the pathogenesis in HIV–tuberculosis co-infection

Cited by 12 publications

References 55 publications

Multicenter analysis of sputum microbiota in tuberculosis patients

Multicenter analysis of sputum microbiota in tuberculosis patients

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas

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