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Complement Pathway Gene Activation and Rising Circulating Immune Complement pathway gene activation and rising PNAS PLUS circulating immune complexes characterize early disease in HIV-associated tuberculosis Hanif Esmaila,b,c,d,1, Rachel P. Laie, Maia Lesoskyb,c,f, Katalin A. Wilkinsonb,c,e, Christine M. Grahamg, Stuart Horswelle, Anna K. Coussensb,c,h, Clifton E. Barry IIIb,c,i,j,k, Anne O’Garrag,l, and Robert J. Wilkinsona,b,c,e,1 aDepartment of Medicine, Imperial College London, London W2 1PG, United Kingdom; bWellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa; cDepartment of Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa; dRadcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom; eThe Francis Crick Institute, London NW1 2AT, United Kingdom; fDivision of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa; gThe Francis Crick Institute, Laboratory of Immunoregulation and Infection, London NW1 2AT, United Kingdom; hDivision of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town 7925, Republic of South Africa; iFaculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, Republic of South Africa; jTuberculosis Research Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892; kDepartment of Clinical Laboratory Sciences, University of Cape Town, Cape Town 7925, Republic of South Africa; and lNational Heart and Lung Institute, Imperial College London, London W2 1PJ, United Kingdom Edited by Barry R. Bloom, Harvard T. H. Chan School of Public Health, Boston, MA, and approved December 13, 2017 (received for review July 2, 2017) The transition between latent and active tuberculosis (TB) occurs people in early subclinical stages of disease and interventions to before symptom onset. Better understanding of the early events prevent progression. This is of particular importance in those in subclinical disease will facilitate the development of diagnostics with HIV-1 coinfection where TB disease progression is more and interventions that improve TB control. This is particularly likely. However, studying the natural history of TB in this group relevant in the context of HIV-1 coinfection where progression of is further complicated by the imperative to provide preventive 18 TB is more likely. In a recent study using [ F]-fluoro-2-deoxy-D- therapy, so novel approaches are needed. glucose positron emission/computed tomography (FDG-PET/CT) In macaques the failure of the granuloma has been shown to be on 35 asymptomatic, HIV-1–infected adults, we identified 10 par- INFLAMMATION followed by cellular infiltration within bronchi (pneumonia) (4). In IMMUNOLOGY AND ticipants with radiographic evidence of subclinical disease, signif- human autopsy studies, pneumonic infiltration has also been ob- icantly more likely to progress than the 25 participants without. To served as the first pathological sign of pulmonary disease (5). Dis- gain insight into the biological events in early disease, we per- ease regression and self-healing of lesions is associated with fibrosis; formed blood-based whole genome transcriptomic analysis on however, it appears that disease risk following this is significantly these participants and 15 active patients with TB. We found tran- increased (6). Medical imaging is a key approach to detecting evi- γ scripts representing the classical complement pathway and Fc re- dence of early disease in asymptomatic persons, facilitated by a ceptor 1 overabundant from subclinical stages of disease. Levels of characteristic distribution of pathology. Chest radiography (CXR) circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript Significance abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available inthe2ybeforeTBdiseasepresentation.Transcriptsrepresenting Understanding events in early tuberculosis disease will facili- the classical complement pathway and Fcγ receptor 1 were also tate the development of novel tests to predict disease pro- differentially expressed in the 12 mo before disease presentation. gression and interventions to prevent it. Blood-based Our results indicate that levels of antibody/antigen complexes in- transcriptomic approaches consistently identify several path- crease early in disease, associated with increased gene expression of ways relevant to clinical disease. Here we show in asymp- C1q and Fcγ receptors that bind them. Understanding the role this tomatic people with HIV infection and early subclinical plays in disease progression may facilitate development of interven- tuberculosis defined by FDG-PET/CT that transcripts relating to γ tions that prevent this, leading to a more favorable outcome and the classical complement pathway and Fc receptor remain may also be important to diagnostic development. enriched, accompanied by rising levels of circulating antibody/ antigen immune complexes. We confirm that transcripts re- tuberculosis | HIV | complement | immune complex | incipient disease lating to these pathways also rise in the 12 mo prior to disease presentation in HIV-uninfected people. This supports observa- tions that antigen may be present in early disease despite be- onventionally, tuberculosis (TB) is divided into stages of ing paucibacillary and demonstrates that modulation of the Casymptomatic latent infection, during which bacillary repli- immune response could occur via immune complex formation. cation is effectively controlled in a healthy host, and active dis- ease in which this has failed, resulting in symptomatic Author contributions: H.E., C.E.B., A.O., and R.J.W. designed research; H.E., R.P.L., K.A.W., deterioration. Understanding the transition between these two C.M.G., and A.K.C. performed research; C.E.B., A.O., and R.J.W. contributed new reagents/ states is important, although until recently this has been over- analytic tools; H.E., R.P.L., M.L., S.H., A.K.C., A.O., and R.J.W. analyzed data; and H.E., A.O., looked (1). Active disease is usually defined by a combination of and R.J.W. wrote the paper. symptoms, pathology (radiographically or histologically identi- The authors declare no conflict of interest. fied), and culturable bacilli. These features do not appear si- This article is a PNAS Direct Submission. multaneously but develop over time and may be intermittently Published under the PNAS license. present, hence the active disease processes may begin months Data deposition: The data reported in this paper have been deposited in the Gene Ex- pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. before symptom onset, i.e., as subclinical active disease (2). In GSE69581). some of those who initially reactivate, disease progression may 1To whom correspondence may be addressed. Email: [email protected] or r.j. be arrested and regress particularly when disease extent is lim- [email protected]. ited (3). A greater understanding of the early events in disease is This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. critical for the development of novel approaches to both identify 1073/pnas.1711853115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1711853115 PNAS Early Edition | 1of10 Downloaded by guest on September 27, 2021 has long been used for this purpose; however, CXR has limitations with no evidence of subclinical TB. Participants were followed up for 18 in both sensitivity and reproducibility (7). [ F]-fluoro-2-deoxy-D- 6 mo; 27 of the 35 participants (6 subclinical and 21 latent) then had glucose positron emission/computed tomography (FDG-PET/CT) is repeat FDG-PET/CT. All 6 of the subclinical participants had im- a highly sensitive imaging modality, which combines cross-sectional provement in baseline abnormalities in lymph nodes and lung pa- anatomical detail from a CT scan with quantitation and localization renchyma in contrast to only 1/21 of those without evidence of of metabolic activity by quantifying uptake of FDG (a glucose an- subclinical TB. Three participants (2 in the subclinical group and 1 in alog) by PET scan. FDG uptake in tuberculosis is related to acti- the latent group) had been commenced on antiretroviral therapy vated macrophages and an inflammatory infiltrate at the site of during followup as CD4 count fell below 350/mm3, in accordance with disease (8). In a recent clinical study, we utilized FDG-PET/CT to local standard of care at the time of recruitment. identify evidence of early disease in asymptomatic people otherwise In addition, we recruited 15 participants with symptomatic, conventionally considered to have latent infection [QuantiFERON microbiologically confirmed pulmonary TB (referred to as “ac- Gold In-Tube (QFN-GIT) positive, sputum culture negative, CXR tive TB”) for blood sampling. There were no significant differ- no evidence of active disease] but at high risk of disease progression ences between those with active, subclinical, and latent TB with as HIV-1–infected, antiretroviral therapy (ART) naïve. Of regard to median age (P = 0.41), sex (P = 0.52), or median the 35 people scanned, 10 (28.6%) had evidence of subclinical CD4 count (P = 0.09). Conversely, median viral load (VL) and disease by FDG-PET/CT and they
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