Abstract
Each day, approximately 27,000 people become ill with tuberculosis (TB), and 4,000 die from this disease. Pulmonary TB is the main clinical form of TB, and affects the lungs with a considerably heterogeneous manifestation among patients. Immunomodulation by an interplay of host-, environment-, and pathogen-associated factors partially explains such heterogeneity. Microbial communities residing in the host's airways have immunomodulatory effects, but it is unclear if the inter-individual variability of these microbial communities is associated with the heterogeneity of pulmonary TB. Here, we investigated this possibility by characterizing the microbial composition in the sputum of 334 TB patients from Tanzania, and by assessing its association with three aspects of disease manifestations: sputum mycobacterial load, severe clinical findings, and chest x-ray (CXR) findings. Compositional data analysis of taxonomic profiles based on 16S-rRNA gene amplicon sequencing and on whole metagenome shotgun sequencing, and graph-based inference of microbial associations revealed that the airway microbiome of TB patients was shaped by inverse relationships between Streptococcus and two anaerobes: Selenomonas and Fusobacterium. Specifically, the strength of these microbial associations was negatively correlated with Faith's phylogenetic diversity (PD) and with the accumulation of transient genera. Furthermore, low body mass index (BMI) determined the association between abnormal CXRs and community diversity and composition. These associations were mediated by increased abundance of Selenomonas and Fusobacterium, relative to the abundance of Streptococcus, in underweight patients with lung parenchymal infiltrates and in comparison to those with normal chest x-rays. And last, the detection of herpesviruses and anelloviruses in sputum microbial assemblage was linked to co-infection with HIV. Given the anaerobic metabolism of Selenomonas and Fusobacterium, and the hypoxic environment of lung infiltrates, our results suggest that in underweight TB patients, lung tissue remodeling toward anaerobic conditions favors the growth of Selenomonas and Fusobacterium at the expense of Streptococcus. These new insights into the interplay among particular members of the airway microbiome, BMI, and lung parenchymal lesions in TB patients, add a new dimension to the long-known association between low BMI and pulmonary TB. Our results also drive attention to the airways virome in the context of HIV-TB coinfection.
Highlights
Pulmonary TB is the main clinical form of TB; an airborne infectious disease caused by members of the Mycobacterium tuberculosis (MTB) complex, and the leading cause of death from a single infection
This study presents a comprehensive investigation of the hypothesis that inter-individual variability of the airway microbiome in TB patients is associated with differences in TB-disease manifestations; aiming at identifying biomarkers associated with TB-disease severity in a noninvasively collected respiratory sample, the expectorated sputum
We included 334 (53%) sputa to investigate the potential relationship between sputum microbial composition and three aspects of TB-disease manifestations, at time of diagnosis, which include: (i) high mycobacterial load in sputum, (ii) severe clinical findings, and (iii) chest X-ray findings
Summary
Pulmonary TB is the main clinical form of TB; an airborne infectious disease caused by members of the Mycobacterium tuberculosis (MTB) complex, and the leading cause of death from a single infection. Worldwide during 2018, TB claimed the lives of 1.5 million people and caused 10 million new cases (WHO, 2019) who further spread the disease via coughing or sneezing MTB-carrying droplets. These droplets originate in lung lesions that formed after inhaled MTB bacilli reached the alveoli at the end of the lower airways, subverted local immunity, replicated inside infected alveolar macrophages, and triggered inflammatory responses with concomitant lung damage. Lung lesions might be asymptomatic (latent TB) or might progress to more extended lung tissue damage with formation of consolidations and/or cavities and accompanied of signs and symptoms (active TB). Latent and active TB are opposite ends in a more complex spectrum of infection outcomes and disease manifestations (Lin and Flynn, 2018)
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