Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

Azad, Abul K.; Lloyd, Christopher; Sadée, Wolfgang; Schlesinger, Larry S.

doi:10.3389/fcimb.2020.00139

Cited by 6 publications

(9 citation statements)

References 78 publications

(93 reference statements)

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“…All the above operates within the immune consequences of malnutrition especially in children and the elderly [ 70 ], leading to the profound diversity seen in human immune function and parameters [ 70 , 71 , 72 ].…”

Section: A Wider Context To Pathogen Interferencementioning

confidence: 99%

Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

Jones¹,

Ponomarenko

2022

Infectious Disease Reports

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Pathogen interference is the ability of one pathogen to alter the course and clinical outcomes of infection by another. With up to 3000 species of human pathogens the potential combinations are vast. These combinations operate within further immune complexity induced by infection with multiple persistent pathogens, and by the role which the human microbiome plays in maintaining health, immune function, and resistance to infection. All the above are further complicated by malnutrition in children and the elderly. Influenza vaccination offers a measure of protection for elderly individuals subsequently infected with influenza. However, all vaccines induce both specific and non-specific effects. The specific effects involve stimulation of humoral and cellular immunity, while the nonspecific effects are far more nuanced including changes in gene expression patterns and production of small RNAs which contribute to pathogen interference. Little is known about the outcomes of vaccinated elderly not subsequently infected with influenza but infected with multiple other non-influenza winter pathogens. In this review we propose that in certain years the specific antigen mix in the seasonal influenza vaccine inadvertently increases the risk of infection from other non-influenza pathogens. The possibility that vaccination could upset the pathogen balance, and that the timing of vaccination relative to the pathogen balance was critical to success, was proposed in 2010 but was seemingly ignored. Persons vaccinated early in the winter are more likely to experience higher pathogen interference. Implications to the estimation of vaccine effectiveness and influenza deaths are discussed.

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Section: A Wider Context To Pathogen Interferencementioning

confidence: 99%

Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

Jones¹,

Ponomarenko

2022

Infectious Disease Reports

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Section: Introductionmentioning

confidence: 99%

“…While a substantial portion of the human population gets infected with M.tb , only a fraction of infected individuals progress to active TB. To control TB, we must understand the immunopathogenesis of M.tb infection, including host susceptibility or resistance factors, to develop effective diagnostic, therapeutic and vaccine strategies for different individuals and populations(Azad et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted March 16, 2022. ; https://doi.org/10.1101/2022.03.14.484235 doi: bioRxiv preprint factors, to develop effective diagnostic, therapeutic and vaccine strategies for different individuals and populations (Azad et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The host response to M.tb infection ranges from complete clearance of infection to latent infection to active TB(Pai et al, 2016). Therapy and vaccine trials further highlight response variability across populations(Azad et al, 2020, Finan et al, 2008) with BCG vaccination trials attaining only 50% efficacy(Colditz et al, 1994). Evolutionary adaptation of M.tb to the host is considered a main factor modulating virulence, host response, and TB severity(Sousa et al, 2020, Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Human alveolar macrophage response toMycobacterium tuberculosis: immune characteristics underlying large inter-individual variability

Schlesinger

Sadée

Cheeseman

et al. 2022

Preprint

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Mycobacterium tuberculosis (M.tb) establishes residence and growth in human alveolar macrophages (AMs). Large inter-individual variation in M.tb-AM interactions is a potential early indicator of TB risk and efficacy of therapies and vaccines. Herein, we systematically analyze interactions of a virulent M.tb strain with freshly isolated human AMs from healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load at 72h, reflected by large variation of gene expression programs. Systems analysis of differential and variable RNA and protein expression identifies TB-associated genes and networks (e.g., IL1B and IDO1). RNA time profiles document early stimulation of M1-type macrophage gene expression followed by emergence of an M2-type profile. The fine-scale resolution of this work enables the separation of genes and networks regulating early M.tb growth dynamics, and development of potential markers of individual susceptibility to M.tb infection and response to therapies.

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Human alveolar macrophage response to Mycobacterium tuberculosis: immune characteristics underlying large inter-individual variability

Sadee,

Cheeseman,

Papp

et al. 2023

Preprint

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Background: Mycobacterium tuberculosis (M.tb), the causative bacterium of tuberculosis (TB), establishes residence and grows in human alveolar macrophages (AMs). Inter-individual variation in M.tb-human AM interactions can indicate TB risk and the efficacy of therapies and vaccines; however, we currently lack an understanding of the gene and protein expression programs that dictate this variation in the lungs. Results: Herein, we systematically analyze interactions of a virulent M.tb strain H37Rv with freshly isolated human AMs from 28 healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. A large set of genes possessing highly variable inter-individual expression levels are differentially expressed in response to M.tb infection. Eigengene modules link M.tb growth rate with host transcriptional and protein profiles at 24 and 72h. Systems analysis of differential RNA and protein expression identifies a robust network with IL1B, STAT1, and IDO1 as hub genes associated with M.tb growth. RNA time profiles document stimulation towards an M1-type macrophage gene expression followed by emergence of an M2-type profile. Finally, we replicate these results in a cohort from a TB-endemic region, finding a substantial portion of significant differentially expressed genes overlapping between studies. Conclusions: We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load by 72h.The fine-scale resolution of this work enables the identification of genes and gene networks associated with early M.tb growth dynamics in defined donor clusters, an important step in developing potential biological indicators of individual susceptibility to M.tb infection and response to therapies.

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Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

Cited by 6 publications

References 78 publications

Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

Human alveolar macrophage response toMycobacterium tuberculosis: immune characteristics underlying large inter-individual variability

Human alveolar macrophage response to Mycobacterium tuberculosis: immune characteristics underlying large inter-individual variability

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