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5. Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise

Author

Alland, David, Behr, Marcel A, Beko, Busisiwe B, Burhan, Erlina, Churchyard, Gavin, Cobelens, Frank, Denholm, Justin T, Dinkele, Ryan, Ellner, Jerrold J, Fatima, Razia, Haigh, Kate A, Hatherill, Mark, Horton, Katherine C, Kendall, Emily A, Khan, Palwasha Y, MacPherson, Peter, Malherbe, Stephanus T, Mave, Vidya, Mendelsohn, Simon C, Musvosvi, Munyaradzi, Nemes, Elisa, Penn-Nicholson, Adam, Ramamurthy, Dharanidharan, Rangaka, Molebogeng X, Sahu, Suvanand, Schwalb, Alvaro, Shah, Divya K, Sheerin, Dylan, Simon, Donald, Steyn, Adrie J C, Thu Anh, Nguyen, Walzl, Gerhard, Weller, Charlotte L, Williams, Caroline ML, Wong, Emily B, Wood, Robin, Xie, Yingda L, Yi, Siyan, Coussens, Anna K, Zaidi, Syed M A, Allwood, Brian W, Dewan, Puneet K, Gray, Glenda, Kohli, Mikashmi, Kredo, Tamara, Marais, Ben J, Marks, Guy B, Martinez, Leo, Ruhwald, Morten, Scriba, Thomas J, Seddon, James A, Tisile, Phumeza, Warner, Digby F, Wilkinson, Robert J, Esmail, Hanif, and Houben, Rein M G J

Published
2024
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7. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis

Author

Walker, Timothy M, Miotto, Paolo, Köser, Claudio U, Fowler, Philip W, Knaggs, Jeff, Iqbal, Zamin, Hunt, Martin, Chindelevitch, Leonid, Farhat, Maha R, Cirillo, Daniela Maria, Comas, Iñaki, Posey, James, Omar, Shaheed V, Peto, Timothy EA, Suresh, Anita, Uplekar, Swapna, Laurent, Sacha, Colman, Rebecca E, Nathanson, Carl-Michael, Zignol, Matteo, Walker, Ann Sarah, Crook, Derrick W, Ismail, Nazir, Rodwell, Timothy C, Consortium, the SeqTreat Consortium CRyPTIC, Walker, A Sarah, Steyn, Adrie JC, Lalvani, Ajit, Baulard, Alain, Christoffels, Alan, Mendoza-Ticona, Alberto, Trovato, Alberto, Skrahina, Alena, Lachapelle, Alexander S, Brankin, Alice, Piatek, Amy, Cruz, Ana Gibertoni, Koch, Anastasia, Cabibbe, Andrea Maurizio, Spitaleri, Andrea, Brandao, Angela P, Chaiprasert, Angkana, Barbova, Anna, Van Rie, Annelies, Ghodousi, Arash, Bainomugisa, Arnold, Mandal, Ayan, Roohi, Aysha, Javid, Babak, Zhu, Baoli, Letcher, Brice, Rodrigues, Camilla, Nimmo, Camus, NATHANSON, Carl-Michael, Duncan, Carla, Coulter, Christopher, Utpatel, Christian, Liu, Chunfa, Grazian, Clara, Kong, Clare, Wilson, Daniel J, Matias, Daniela, Jorgensen, Danielle, Zimenkov, Danila, Chetty, Darren, Moore, David AJ, Clifton, David A, van Soolingen, Dick, Liu, Dongxin, Kohlerschmidt, Donna, Barreira, Draurio, Ngcamu, Dumisani, Lazaro, Elias David Santos, Kelly, Ellis, Borroni, Emanuele, Roycroft, Emma, Andre, Emmanuel, Böttger, Erik C, Robinson, Esther, Menardo, Fabrizio, Mendes, Flavia F, Jamieson, Frances B, Coll, Francesc, Gao, George Fu, Kasule, George W, Rossolini, Gian Maria, Rodger, Gillian, Smith, E Grace, Meintjes, Graeme, Thwaites, Guy, Hoffmann, Harald, Albert, Heidi, Cox, Helen, Laurenson, Ian F, and Arandjelovic, Irena

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Microbiology, Clinical Sciences, Tuberculosis, Infectious Diseases, Rare Diseases, Antimicrobial Resistance, Orphan Drug, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Ethambutol, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, World Health Organization, CRyPTIC Consortium, Seq&Treat Consortium, Immunology, Medical microbiology
Abstract

BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

Published
2022

8. A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Author

Adolph, Cara, Cheung, Chen-Yi, McNeil, Matthew B., Jowsey, William J., Williams, Zoe C., Hards, Kiel, Harold, Liam K., Aboelela, Ashraf, Bujaroski, Richard S., Buckley, Benjamin J., Tyndall, Joel D.A., Li, Zhengqiu, Langer, Julian D., Preiss, Laura, Meier, Thomas, Steyn, Adrie J.C., Rhee, Kyu Y., Berney, Michael, Kelso, Michael J., and Cook, Gregory M.

Published
2024
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9. Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells

Author

Olmo-Fontánez, Angélica M., Scordo, Julia M., Schami, Alyssa, Garcia-Vilanova, Andreu, Pino, Paula A., Hicks, Amberlee, Mishra, Richa, Jose Maselli, Diego, Peters, Jay I., Restrepo, Blanca I., Nargan, Kievershen, Naidoo, Threnesan, Clemens, Daniel L., Steyn, Adrie J.C., Thacker, Vivek V., Turner, Joanne, Schlesinger, Larry S., and Torrelles, Jordi B.

Published
2024
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10. A mouse model of TB-associated lung fibrosis reveals persistent inflammatory macrophage populations during treatment

Author

Boucau, Julie, primary, Naidoo, Threnesan, additional, Liu, Yuming, additional, Dasgupta, Shatavisha, additional, Jain, Neha, additional, Castillo, Jennie Ruelas, additional, Jacobson, Nicholas E., additional, Nargan, Kievershen, additional, Cimini, Beth A., additional, Eliceiri, Kevin W., additional, Steyn, Adrie J.C., additional, and Barczak, Amy K., additional

Published
2024
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11. Integrating environmental health and genomics research in Africa: challenges and opportunities identified during a Human Heredity and Health in Africa (H3Africa) Consortium workshop.

Author

Joubert, Bonnie R, Berhane, Kiros, Chevrier, Jonathan, Collman, Gwen, Eskenazi, Brenda, Fobil, Julius, Hoyo, Cathrine, John, Chandy C, Kumie, Abera, Nicol, Mark, Ramsay, Michèle, Smith, Joshua, Steyn, Adrie, Tshala-Katumbay, Desire, and McAllister, Kimberly

Subjects
Africa, G x E, H3Africa, environmental health, gene-environment interactions, global environmental health, workshop, Genetics, Prevention, Pediatric Research Initiative, Human Genome, Biotechnology, Aetiology, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being
Abstract

Individuals with African ancestry have extensive genomic diversity but have been underrepresented in genomic research. There is also extensive global diversity in the exposome (the totality of human environmental exposures from conception onwards) which should be considered for integrative genomic and environmental health research in Africa. To address current research gaps, we organized a workshop on environmental health research in Africa in conjunction with the H3Africa Consortium and the African Society of Human Genetics meetings in Kigali, Rwanda. The workshop was open to all researchers with an interest in environmental health in Africa and involved presentations from experts within and outside of the Consortium. This workshop highlighted innovative research occurring on the African continent related to environmental health and the interplay between the environment and the human genome. Stories of success, challenges, and collaborative opportunities were discussed through presentations, breakout sessions, poster presentations, and a panel discussion. The workshop informed participants about environmental risk factors that can be incorporated into current or future epidemiology studies and addressed research design considerations, biospecimen collection and storage, biomarkers for measuring chemical exposures, laboratory strategies, and statistical methodologies. Inclusion of environmental exposure measurements with genomic data, including but not limited to H3Africa projects, can offer a strong platform for building gene-environment (G x E) research in Africa. Opportunities to leverage existing resources and add environmental exposure data for ongoing and planned studies were discussed. Future directions include expanding the measurement of both genomic and exposomic risk factors and incorporating sophisticated statistical approaches for analyzing high dimensional G x E data. A better understanding of how environmental and genomic factors interact with nutrition and infection is also needed. Considering that the environment represents many modifiable risk factors, these research findings can inform intervention and prevention efforts towards improving global health.

Published
2019

13. Pathogenesis of Post-Tuberculosis Lung Disease: Defining Knowledge Gaps and Research Priorities at the Second International Post-Tuberculosis Symposium.

Author

Auld, Sara C., Barczak, Amy K., Bishai, William, Coussens, Anna K., Dewi, Intan M. W., Mitini-Nkhoma, Steven C., Muefong, Caleb, Naidoo, Threnesan, Pooran, Anil, Stek, Cari, Steyn, Adrie J. C., Tezera, Liku, and Walker, Naomi F.

Subjects
LITERATURE reviews, LUNG diseases, MATRIX metalloproteinases, EVIDENCE gaps, TUBERCULOSIS
Abstract

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Author

Adolph, Cara, Hards, Kiel, Williams, Zoe C., Cheung, Chen-Yi, Keighley, Laura M., Jowsey, William J., Kyte, Matson, Inaoka, Daniel Ken, Kita, Kiyoshi, Mackenzie, Jared S., Steyn, Adrie J.C., Li, Zhengqiu, Yan, Ming, Tian, Guo-Bao, Zhang, Tianyu, Ding, Xiaobo, Furkert, Daniel P., Brimble, Margaret A., Hickey, Anthony J.R., and McNeil, Matthew B.

Published
2024
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15. The immunoregulatory landscape of human tuberculosis granulomas

Author

McCaffrey, Erin F., Donato, Michele, Keren, Leeat, Chen, Zhenghao, Delmastro, Alea, Fitzpatrick, Megan B., Gupta, Sanjana, Greenwald, Noah F., Baranski, Alex, Graf, William, Kumar, Rashmi, Bosse, Marc, Fullaway, Christine Camacho, Ramdial, Pratista K., Forgó, Erna, Jojic, Vladimir, Van Valen, David, Mehra, Smriti, Khader, Shabaana A., Bendall, Sean C., van de Rijn, Matt, Kalman, Daniel, Kaushal, Deepak, Hunter, Robert L., Banaei, Niaz, Steyn, Adrie J. C., Khatri, Purvesh, and Angelo, Michael

Published
2022
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16. A high‐resolution 3D atlas of the spectrum of tuberculous and COVID‐19 lung lesions

Author

Wells, Gordon, Glasgow, Joel N, Nargan, Kievershen, Lumamba, Kapongo, Madansein, Rajhmun, Maharaj, Kameel, Perumal, Leon Y, Matthew, Malcolm, Hunter, Robert L, Pacl, Hayden, Peabody Lever, Jacelyn E, Stanford, Denise D, Singh, Satinder P, Bajpai, Prachi, Manne, Upender, Benson, Paul V, Rowe, Steven M, le Roux, Stephan, Sigal, Alex, Tshibalanganda, Muofhe, Wells, Carlyn, du Plessis, Anton, Msimang, Mpumelelo, Naidoo, Threnesan, and Steyn, Adrie J C

Published
2022
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17. Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model

Author

Ahmed, Mohamed, primary, Tezera, Liku B., additional, Herbert, Nicholas, additional, Chambers, Mark, additional, Reichmann, Michaela T., additional, Nargan, Kievershen, additional, Kloverpris, Henrik, additional, Karim, Farina, additional, Hlatshwayo, Mbali, additional, Madensein, Rajhmun, additional, Habesh, Munir, additional, Hoque, Monjural, additional, Steyn, Adrie J.C., additional, Elkington, Paul T., additional, and Leslie, Alasdair J., additional

Published
2024
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19. Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model

Author

Ahmed, Mohamed, Tezera, Liku B., Herbert, Nicholas, Chambers, Mark, Reichmann, Michaela T., Nargan, Kievershen, Kloverpris, Henrik, Karim, Farina, Hlatshwayo, Mbali, Madensein, Rajhmun, Habesh, Munir, Hoque, Monjural, Steyn, Adrie J.C., Elkington, Paul T., Leslie, Alasdair J., Ahmed, Mohamed, Tezera, Liku B., Herbert, Nicholas, Chambers, Mark, Reichmann, Michaela T., Nargan, Kievershen, Kloverpris, Henrik, Karim, Farina, Hlatshwayo, Mbali, Madensein, Rajhmun, Habesh, Munir, Hoque, Monjural, Steyn, Adrie J.C., Elkington, Paul T., and Leslie, Alasdair J.

Abstract

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.

Published
2024

20. A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Author

Adolph, Cara, primary, Cheung, Chen-Yi, additional, McNeil, Matthew B., additional, Jowsey, William J., additional, Williams, Zoe C., additional, Hards, Kiel, additional, Harold, Liam K., additional, Aboelela, Ashraf, additional, Bujaroski, Richard S., additional, Buckley, Benjamin J., additional, Tyndall, Joel D.A., additional, Li, Zhengqiu, additional, Langer, Julian D., additional, Preiss, Laura, additional, Meier, Thomas, additional, Steyn, Adrie J.C., additional, Rhee, Kyu Y., additional, Berney, Michael, additional, Kelso, Michael J., additional, and Cook, Gregory M., additional

Published
2023
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21. Differential skewing of donor-unrestricted and [gamma[delta] T cell repertoires in tuberculosis-infected human lungs

Author

Ogongo, Paul, Steyn, Adrie J.C., Karim, Farina, Dullabh, Kaylesh J., Awala, Ismael, Madansein, Rajhmun, Leslie, Alasdair, and Behar, Samuel M.

Subjects
Antigens, Tuberculosis vaccines, BCG, Tuberculosis, T cells, Vaccines, HIV, Surgery, Comorbidity, Diseases, Health care industry
Abstract

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and [gamma][delta] T cells. We exploited the distinctive nature of DURTs and [gamma][delta] T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCR[delta] in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCR[delta] repertoire, in contrast, was highly skewed in the lungs, where it was dominated by V[delta]1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident [gamma][delta] T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease., Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from an infectious agent (Global Tuberculosis Report, WHO, 2018 (1). Although treatable with antibiotics, there is [...]

Published
2020
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22. B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and putative functional roles

Author

Krause, Rob, primary, Ogongo, Paul, additional, Tezera, Liku, additional, Ahmed, Mohamed, additional, Mbano, Ian, additional, Chambers, Mark, additional, Ngoepe, Abigail, additional, Magnoumba, Magalli, additional, Muema, Daniel, additional, Karim, Farina, additional, Khan, Khadija, additional, Lumamba, Kapongo, additional, Nargan, Kievershen, additional, Madansein, Rajhmun, additional, Steyn, Adrie, additional, Shalek, Alex, additional, Elkington, Paul, additional, and Leslie, Alasdair, additional

Published
2023
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26. Author Correction: The immunoregulatory landscape of human tuberculosis granulomas

Author

McCaffrey, Erin F., Donato, Michele, Keren, Leeat, Chen, Zhenghao, Delmastro, Alea, Fitzpatrick, Megan B., Gupta, Sanjana, Greenwald, Noah F., Baranski, Alex, Graf, William, Kumar, Rashmi, Bosse, Marc, Fullaway, Christine Camacho, Ramdial, Pratista K., Forgó, Erna, Jojic, Vladimir, Van Valen, David, Mehra, Smriti, Khader, Shabaana A., Bendall, Sean C., van de Rijn, Matt, Kalman, Daniel, Kaushal, Deepak, Hunter, Robert L., Banaei, Niaz, Steyn, Adrie J. C., Khatri, Purvesh, and Angelo, Michael

Published
2022
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27. Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis

Author

Ardain, Amanda, Domingo-Gonzalez, Racquel, Das, Shibali, Kazer, Samuel W., Howard, Nicole C., Singh, Alveera, Ahmed, Mushtaq, Nhamoyebonde, Shepherd, Rangel-Moreno, Javier, Ogongo, Paul, Lu, Lan, Ramsuran, Duran, de la Luz Garcia-Hernandez, Maria, K. Ulland, Tyler, Darby, Matthew, Park, Eugene, Karim, Farina, Melocchi, Laura, Madansein, Rajhmun, Dullabh, Kaylesh Jay, Dunlap, Micah, Marin-Agudelo, Nancy, Ebihara, Takashi, Ndung’u, Thumbi, Kaushal, Deepak, Pym, Alexander S., Kolls, Jay K., Steyn, Adrie, Zúñiga, Joaquín, Horsnell, William, Yokoyama, Wayne M., Shalek, Alex K., Kløverpris, Henrik N., Colonna, Marco, Leslie, Alasdair, and Khader, Shabaana A.

Published
2019
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28. Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis

Author

Lee, Bei Shi, Hards, Kiel, Engelhart, Curtis A, Hasenoehrl, Erik J, Kalia, Nitin P, Mackenzie, Jared S, Sviriaeva, Ekaterina, Chong, Shi Min Sherilyn, Manimekalai, Malathy Sony S, Koh, Vanessa H, Chan, John, Xu, Jiayong, Alonso, Sylvie, Miller, Marvin J, Steyn, Adrie J C, Grüber, Gerhard, Schnappinger, Dirk, Berney, Michael, Cook, Gregory M, Moraski, Garrett C, and Pethe, Kevin

Published
2021
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32. Tissue-resident-like [CD4.sup.+] T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung

Author

Ogongo, Paul, Tezera, Liku B., Ardain, Amanda, Nhamoyebonde, Shepherd, Ramsuran, Duran, Singh, Alveera, Ngoepe, Abigail, Karim, Farina, Naidoo, Taryn, Khan, Khadija, Dullabh, Kaylesh J., Fehlings, Michael, Lee, Boon Heng, Nardin, Alessandra, Arlehamn, Cecilia S. Lindestam, Sette, Alessandro, Behar, Samuel M., Steyn, Adrie J.C., Madansein, Rajhmun, Kloverpris, Henrik N., Elkington, Paul T., and Leslie, Alasdair

Subjects
Pulmonary tuberculosis -- Development and progression, CD4 lymphocytes -- Physiological aspects -- Health aspects, Mycobacterium tuberculosis -- Physiological aspects -- Control, Health care industry
Abstract

T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue-resident memory T cells (Trms) are superior at controlling many pathogens, including Mycobacterium tuberculosis (M. tuberculosis), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct [CD4.sup.+] and [CD8.sup.+] Trm-like clusters within TB-diseased lung tissue that were functional and enriched for IL- 17-producing cells. M. tuberculosis-specific [CD4.sup.+] T cells producing TNF-[alpha], IL-2, and IL-17 were highly expanded in the lung compared with matched blood samples, in which [IL-17.sup.+] cells were largely absent. Strikingly, the frequency of M. tuberculosis-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1[beta] levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and was associated with increased NO production. Taken together, these data support an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells in the immune control of M. tuberculosis in the human lung., Introduction Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis), remains a leading cause of death from infectious disease worldwide (1). Despite the availability of anti-TB treatment, difficulties in [...]

Published
2021
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37. Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Author

Beteck, Richard M., Seldon, Ronnett, Coertzen, Dina, van der Watt, Mariëtte E., Reader, Janette, Mackenzie, Jared S., Lamprecht, Dirk A., Abraham, Matthew, Eribez, Korina, Müller, Joachim, Rui, Feng, Zhu, Guang, de Grano, Ruel Valerio, Williams, Ian D., Smit, Frans J., Steyn, Adrie J. C., Winzeler, Elizabeth A., Hemphill, Andrew, Birkholtz, Lyn-Marie, Warner, Digby F., N’Da, David D., and Haynes, Richard K.

Published
2018
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38. Mycobacterium tuberculosis DosS binds H2S through its Fe3+ heme iron to regulate the DosR dormancy regulon

Author

Sevalkar, Ritesh R., primary, Glasgow, Joel N., additional, Pettinati, Martín, additional, Marti, Marcelo A., additional, Reddy, Vineel P., additional, Basu, Swati, additional, Alipour, Elmira, additional, Kim-Shapiro, Daniel B., additional, Estrin, Dario A., additional, Lancaster, Jack R., additional, and Steyn, Adrie J.C., additional

Published
2022
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39. Omicron infection enhances Delta antibody immunity in vaccinated persons

Author

Khan, Khadija, Karim, Farina, Cele, Sandile, Reedoy, Kajal, San, James Emmanuel, Lustig, Gila, Tegally, Houriiyah, Rosenberg, Yuval, Bernstein, Mallory, Jule, Zesuliwe, Ganga, Yashica, Ngcobo, Nokuthula, Mazibuko, Matilda, Mthabela, Ntombifuthi, Mhlane, Zoey, Mbatha, Nikiwe, Miya, Yoliswa, Giandhari, Jennifer, Ramphal, Yajna, Naidoo, Taryn, Sivro, Aida, Samsunder, Natasha, Kharsany, Ayesha B.M., Amoako, Daniel, Bhiman, Jinal N., Manickchund, Nithendra, Abdool Karim, Quarraisha, Magula, Nombulelo, Abdool Karim, Salim S., Gray, Glenda, Hanekom, Willem, von Gottberg, Anne, Harrichandparsad, Rohen, Herbst, Kobus, Jeena, Prakash, Khoza, Thandeka, Kløverpris, Henrik, Leslie, Alasdair, Madansein, Rajhmun, Marakalala, Mohlopheni, Moshabela, Mosa, Naidoo, Kogie, Ndhlovu, Zaza, Ndung’u, Thumbi, Nyamande, Kennedy, Patel, Vinod, Smit, Theresa, Steyn, Adrie, Wong, Emily, and Milo, Ron

Subjects
Multidisciplinary
Abstract

The extent to which Omicron infection1–9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3–9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19–27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.

Published
2022

40. A data compendium associating the genomes of 12,289 Mycobacterium tuberculosis isolates with quantitative resistance phenotypes to 13 antibiotics

Author

Brankin, Alice, Malone, Kerri, Barilar, Ivan, Battaglia, Simone, Borroni, Emanuele, Pires Brandao, Angela, Cabibbe, Andrea Maurizio, Carter, Joshua, Chetty, Darren, Cirillo, Daniela María, Claxton, Pauline, Clifton, David, Cohen, Ted, Coronel, Jorge, Crook, Derrick, Dreyer, Viola, Earle, Sarah, Escuyer, Vincent, Ferrazoli, Lucilaine, Gāo, George Fú, Gardy, Jennifer, Gharbia, Saheer, Teixeira Ghisi, Kelen, Ghodousi, Arash, Gibertoni Cruz, Ana Lúıza, Grandjean, Louis, Grazian, Clara, Groenheit, Ramona, Guthrie, Jennifer, He, Wencong, Hoffmann, Harald, J., Sarah, Hunt, Martin, Ismail, Nazir Ahmed, Jarrett, Lisa, Joseph, Lavania, Jou, Ruwen, Kambli, Priti, Khot, Rukhsar, Knaggs, Jeff, Koch, Anastasia, Kohlerschmidt, Donna, Kouchaki, Samaneh, Lachapelle, Alexander, Lalvani, Ajit, Grandjean Lapierre, Simon, Laurenson, Ian, Letcher, Brice, Lin, Wan-Hsuan, Liu, Chunfa, Liu, Dongxin, Mandal, Ayan, Mansjö, Mikael, Matias, Daniela, Meintjes, Graeme, de Freitas Mendes, Flávia, Merker, Matthias, Mihalic, Marina, Millard, James, Miotto, Paolo, Mistry, Nerges, Moore, David, Musser, Kimberlee A., Ngcamu, Dumisani, Ngoc Nhung, Hoang, Niemann, Stefan, Soli Nilgiriwala, Kayzad, Nimmo, Camus, O'Donnell, Max, Okozi, Nana, Siqueira Oliveira, Rosangela, Omar, Shaheed Vally, Paton, Nicholas, Peto, Timothy Ea, Watanabe Pinhata, Juliana Maira, Plesnik, Sara, Puyen, Zully, Rabodoarivelo, Marie, Rakotosamimanana, Niaina, Rancoita, Paola, Rathod, Priti, Robinson, Esther, Rodger, Gillian, Rodrigues, Camilla, Rodwell, Timothy, Roohi, Aysha, Santos-Lazaro, David, Shah, Sanchi, Kohl, Thomas Andreas, Smith, Grace, Solano, Walter, Spitaleri, Andrea, Supply, Philip, Steyn, Adrie, Surve, Utkarsha, Tahseen, Sabira, Thuong, Nguyen, Thwaites, Guy, Todt, Katharina, Trovato, Alberto, Utpatel, Christian, van Rie, Annelies, Vijay, Srinivasan, Walker, Timothy, Walker, A. Sarah, Warren, Robin M., Werngren, Jim, Wijkander, Maria, Wilkinson, Robert, Wilson, Daniel, Wintringer, Penelope, Xiao, Yu-Xin, Yang, Yang, Zhao, Yanlin, Yao, Shen-Yuan, Zhu, Baoli, Fowler, Philip, Iqbal, Zamin, Consortium, The CRyPTIC, University of Oxford, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Forschungszentrum Borstel - Research Center Borstel, IRCCS San Raffaele Scientific Institute [Milan, Italie], Casa de Oswaldo Cruz [Rio de Janeiro] (COC), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Instituto Adolfo Lutz [São Paulo, Brazil], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Africa Health Research Institute [Durban/Mtubatuba] (AHRI), University of Edinburgh, Yale School of Public Health (YSPH), Universidad Peruana de Ciencias Aplicadas (Lima) (UPC), Wadsworth Center, New York State Department of Health [Albany], Chinese Center for Disease Control and Prevention, Bill & Melinda Gates Foundation [Seattle], UK Health Security Agency [London] (UKHSA), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University College of London [London] (UCL), University of New South Wales [Sydney] (UNSW), Public Health Agency of Sweden, University of British Columbia [Vancouver], Public Health Ontario - Santé publique Ontario, Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, National Institute for Communicable Diseases [Johannesburg] (NICD), Taipei Medical University, PD Hinduja Hospital & Research Institute, Mumbai, University of Cape Town, University of Surrey (UNIS), Imperial College London, Université de Montréal (UdeM), PRA Health sciences [Mumbai], London School of Hygiene and Tropical Medicine (LSHTM), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Columbia University Irving Medical Center (CUIMC), National University of Singapore (NUS), Socios En Salud [Lima, Peru], Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Foundation for Innovative New Diagnostics (FIND), University of California [San Diego] (UC San Diego), University of California (UC), Universidad Peruana Cayetano Heredia (UPCH), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), National TB control Program [Islamabad, Pakistan], University of Antwerp (UA), Stellenbosch University, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, The Francis Crick Institute [London], Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences [Beijing] (CAS), and Wellcome Trust (200205/Z/15/Z)Bill and Melinda Gates Foundation (OPP1133541)National Institute for Health Research Oxford Biomedical Research CentreNational Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial ResistanceWellcome Trust (203919/Z/16/Z)National Mega Project on Major Infectious Disease Prevention (2018ZX10103001)H2020 Marie Skłodowska-Curie Actions (EIPOD3)Unitaid (2019-32-FIND MDR)FAPESP (17/16082-7)FAPESP (2012/51756-5)National Natural Science Foundation of China (81991534)Beijing Municipal Science and Technology Commission (Z201100005520041)Wellcome Trust International Intermediate Fellowship (206724/Z/17/Z)Wellcome TrustSouth African Medical Research Councilthe Rhodes Trust and Stanford Medical Scientist Training Program (T32 GM007365)National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections at Imperial College LondonFonds de Recherche en Santé du QuébecWellcome Trust (203583/Z/16/Z)Research Foundation Flanders (G0F8316N)Wellcome Trust (98316)Wellcome Trust (214321/Z/18/Z)Wellcome Trust (203135/Z/16/Z)National Research Foundation South Africa (64787)Wellcome Trust (201470/Z/16/Z)National Institute of Allergy and Infectious Diseases (1R01AI146338)GOSH (1R01AI146338)GOSH/ICH Biomedical Research CentreOxford Medical Research Council Doctoral Training Partnership (NDM Prize Studentship)Nuffield Department of Clinical MedicineSir Henry Dale Fellowship (101237/Z/13/B)The Robertson FoundationNIHRWellcome Trust (214560/Z/18/Z)Rhodes TrustWellcome Trust (FC0010218)UK Research and Innovation (FC0010218)Cancer Research UK (FC0010218)National Institutes of HealthCenters for Disease Control and PreventionUSAIDBill and Melinda Gates FoundationWellcome Trust (203141/Z/16/Z)NIHR Oxford Biomedical Research Centre (BRC BRC-1215-20008)Deutsches Zentrum für InfektionsforschungPublic Health ScotlandCenters for Disease Control and Prevention (U60OE000103)Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI-117312)

Subjects
General Immunology and Microbiology, General Neuroscience, Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, Microbial Sensitivity Tests, Mycobacterium tuberculosis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, General Biochemistry, Genetics and Molecular Biology, Phenotype, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Resistance, Multiple, Bacterial, Mutation, Tuberculosis, Multidrug-Resistant, Humans, Rifampin, General Agricultural and Biological Sciences
Abstract

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

Published
2022

41. Similar Antibody Responses Against Severe Acute Respiratory Syndrome Coronavirus 2 in Individuals Living Without and with Human Immunodeficiency Virus on Antiretroviral Therapy during the First South African Infection Wave

Author

Snyman, Jumari, Hwa, Shi Hsia, Krause, Robert, Muema, Daniel, Reddy, Tarylee, Ganga, Yashica, Karim, Farina, Leslie, Alasdair, Sigal, Alex, Ndung'U, Thumbi, Archary, Moherndran, Dullabh, Kaylesh J., Goulder, Philip, Harling, Guy, Harrichandparsad, Rohen, Herbst, Kobus, Jeena, Prakash, Khoza, Thandeka, Klein, Nigel, Kloverpris, Henrik, Madansein, Rajhmun, Marakalala, Mohlopheni, Mazibuko, Matilda, Moshabela, Mosa, Mthabela, Ntombifuthi, Naidoo, Kogie, Ndhlovu, Zaza, Nyamande, Kennedy, Padayatchi, Nesri, Patel, Vinod, Smit, Theresa, Steyn, Adrie, Wong, Emily, Snyman, Jumari, Hwa, Shi Hsia, Krause, Robert, Muema, Daniel, Reddy, Tarylee, Ganga, Yashica, Karim, Farina, Leslie, Alasdair, Sigal, Alex, Ndung'U, Thumbi, Archary, Moherndran, Dullabh, Kaylesh J., Goulder, Philip, Harling, Guy, Harrichandparsad, Rohen, Herbst, Kobus, Jeena, Prakash, Khoza, Thandeka, Klein, Nigel, Kloverpris, Henrik, Madansein, Rajhmun, Marakalala, Mohlopheni, Mazibuko, Matilda, Moshabela, Mosa, Mthabela, Ntombifuthi, Naidoo, Kogie, Ndhlovu, Zaza, Nyamande, Kennedy, Padayatchi, Nesri, Patel, Vinod, Smit, Theresa, Steyn, Adrie, and Wong, Emily

Abstract

Background: There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis in African populations with a high burden of infectious disease comorbidities such as human immunodeficiency virus (HIV). The kinetics, magnitude, and duration of virus-specific antibodies and B-cell responses in people living with HIV (PLWH) in sub-Saharan Africa have not been fully characterized. Methods: We longitudinally followed SARS-CoV-2-infected individuals in Durban, KwaZulu-Natal, South Africa, and characterized SARS-CoV-2 receptor-binding domain-specific immunoglobulin (Ig) M, IgG, and IgA weekly for 1 month and at 3 months post-diagnosis. Thirty of 72 (41.7%) were PLWH, 25/30 (83%) of whom were on antiretroviral therapy (ART) with full HIV suppression. Plasma neutralization was determined using a live virus neutralization assay, and antibody-secreting cell population frequencies were determined by flow cytometry. Results: Similar seroconversion rates, time to peak antibody titer, peak magnitude, and durability of anti-SARS-CoV-2 IgM, IgG, and IgA were observed in people not living with HIV and PLWH with complete HIV suppression on ART. In addition, similar potency in a live virus neutralization assay was observed in both groups. Loss of IgA was significantly associated with age (P =. 023) and a previous diagnosis of tuberculosis (P=.018). Conclusions: Similar antibody responses and neutralization potency in people not living with HIV and PLWH on stable ART in an African setting suggest that coronavirus disease 2019 (COVID-19) natural infections may confer comparable antibody immunity in these groups. This provides hope that COVID-19 vaccines will be effective in PLWH on stable ART.

Published
2022

43. Publisher Correction: Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis

Author

Ardain, Amanda, Domingo-Gonzalez, Racquel, Das, Shibali, Kazer, Samuel W., Howard, Nicole C., Singh, Alveera, Ahmed, Mushtaq, Nhamoyebonde, Shepherd, Rangel-Moreno, Javier, Ogongo, Paul, Lu, Lan, Ramsuran, Duran, de la Luz Garcia-Hernandez, Maria, Ulland, Tyler K., Darby, Matthew, Park, Eugene, Karim, Farina, Melocchi, Laura, Madansein, Rajhmun, Dullabh, Kaylesh Jay, Dunlap, Micah, Marin-Agudelo, Nancy, Ebihara, Takashi, Ndung’u, Thumbi, Kaushal, Deepak, Pym, Alexander S., Kolls, Jay K., Steyn, Adrie, Zúñiga, Joaquín, Horsnell, William, Yokoyama, Wayne M., Shalek, Alex K., Kløverpris, Henrik N., Colonna, Marco, Leslie, Alasdair, and Khader, Shabaana A.

Published
2019
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48. A Rapid Drug Resistance Genotyping Workflow for Mycobacterium tuberculosis, Using Targeted Isothermal Amplification and Nanopore Sequencing

Author

Gliddon, Harriet D., primary, Frampton, Dan, additional, Munsamy, Vanisha, additional, Heaney, Jude, additional, Pataillot-Meakin, Thomas, additional, Nastouli, Eleni, additional, Pym, Alexander S., additional, Steyn, Adrie J. C., additional, Pillay, Deenan, additional, and McKendry, Rachel A., additional

Published
2021
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49. Aggregated Mycobacterium tuberculosis Enhances the Inflammatory Response

Author

Rodel, Hylton E., primary, Ferreira, Isabella A. T. M., additional, Ziegler, Carly G. K., additional, Ganga, Yashica, additional, Bernstein, Mallory, additional, Hwa, Shi-Hsia, additional, Nargan, Kievershen, additional, Lustig, Gila, additional, Kaplan, Gilla, additional, Noursadeghi, Mahdad, additional, Shalek, Alex K., additional, Steyn, Adrie J. C., additional, and Sigal, Alex, additional

Published
2021
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