The microbiome at the pulmonary alveolar niche and its role in Mycobacterium tuberculosis infection

Abstract

Advances in next generation sequencing (NGS) technology have provided the tools to comprehensively and accurately characterize the microbial community in the respiratory tract in health and disease. The presence of commensal and pathogenic bacteria has been found to have important effects on the lung immune system. Until relatively recently, the lung has received less attention compared to other body sites in terms of microbiome characterization, and its study carries special technological difficulties related to obtaining reliable samples as compared to other body niches. Additionally, the complexity of the alveolar immune system, and its interactions with the lung microbiome, are only just beginning to be understood. Amidst this complexity sits Mycobacterium tuberculosis (Mtb), one of humanity's oldest nemeses and a significant public health concern, with millions of individuals infected with Mtb worldwide. The intricate interactions between Mtb, the lung microbiome, and the alveolar immune system are beginning to be understood, and it is increasingly apparent that improved treatment of Mtb will only come through deep understanding of the interplay between these three forces. In this review, we summarize our current understanding of the lung microbiome, alveolar immunity, and the interaction of each with Mtb.

Keywords: Alveolar macrophages; Innate immune; Lung microbiome; Mycobacterium tuberculosis; Phagosome; Pulmonary alveoli.

Figure 1

A. The interaction of the microbiome with Mycobacterium tuberculosis (Mtb) is characterized by complexity and the influence of external forces. Within the lung, the resident microbiota (Firmicutes, Bacteroidetes, Proteobacteria, etc) may cooperate or compete with Mtb. Existing organisms or newly-acquired organisms may also produce co-infections and additional pathology atop of existing pulmonary tuberculosis (TB). In addition, Mtb and the resident microbiota can interact with the respiratory epithelium and adjacent alveolar immune cells, and these interactions can influence the alveolar immune response (Fig 1B). Throughout this process, the microbiome of the Oropharyngeal/Nasopharyngeal spaces may contaminate, colonize, or migrate to the lung, contributing new organisms, including potential pathogens. To study the lung microbiome, sampling is performed using three primary techniques: induced sputum, broncho-alveolar lavage, and tissue sampling. Induced sputum is simple to obtain but always contaminated by upper respiratory tract and oro/nasopharyngeal microorganisms. Broncho-alveolar lavage (BAL) is less likely to be contaminated by upper respiratory flora but requires an invasive bronchoscopic procedure. Direct extraction from lung tissue has minimal risk of contamination but is only rarely feasible (i.e. lung transplantation). B. A thin lining of epithelial type I and type II cells surrounds the pulmonary alveolus. Alveolar Epithelial Cell (AEC) Type I cover most of the alveolar surface, allowing efficient gas exchange between the capillaries and the alveolar space. AEC Type II cells produce and secrete pulmonary surfactant as well as cytokines, opsonins and antimicrobial peptides. Alveolar macrophages (AMs) reside in the luminal side of the alveolus and constitute the first line of immune cell defense in the alveolar environment. AMs also serve to limit inflammation and minimize lung injury to preserve alveolar function. AM activation is tightly regulated, through processes that involve a complex balance between activating signals like TLR-dependent inflammatory responses and repressing signals through IL-10 and TGF-beta which limit the progression of inflammation. The function of AM as antigen presenting cell is limited, and they serve more as immunoregulatory macrophages. Negative regulation of inflammation is also achieved by cell-to-cell interaction with AEC. Mtb infection of AECs and AMs occurs after the bacteria reach the alveoli. Mtb is able to inhibit phagosome maturation, and when a lack of robust oxidative response is present in the host cell, the bacteria is allowed to persist in the phagosome of these cells. Other innate immune cells, including dendritic cells (DCs) are involved in transporting Mtb to draining lymph nodes.