Versatile myeloid cell subsets contribute to tuberculosis‐associated inflammation

Abstract

Tuberculosis (TB), a chronic bacterial infectious disease caused by IntroductionMycobacterium tuberculosis (Mtb) continues to kill more individuals on this globe than any other bacterial contagious agent [1]. A breakthrough in disease pathogenesis was achieved by Robert Koch (1843Koch ( -1910 in 1882, who precisely elucidated the etiology of the disease tuberculosis (TB) [2,3]. Since then, nearly 1 billion deaths have been caused by TB, a higher mortality than any other infectious disease or war in our history [4]. Many attempts have been made to better understand TB pathogenesis, with the aim to create appropriate intervention measures. Despite the availability of a TB vaccine, as well as drugs and diagnostics, TB has not been controlled satisfactorily. In 2013, 9 million new cases Correspondence: Prof. Stefan H.E. Kaufmann and Dr. Anca Dorhoi e-mail: kaufmann@mpiib-berlin.mpg.de, dorhoi@mpiib-berlin.mpg.de and 1.5 million deaths were reported [5]. Increasing incidences of drug-resistant TB with varying severity require novel approaches for diagnostics, drugs, and vaccines. Accordingly, better knowledge of the immune response in protection and pathology of Mtb infection is necessary.At the core of TB pathophysiology are the inflammatory myeloid cells [6]. The evolutionary success of virulent mycobacteria likely depends on cross-species-conserved mechanisms operative in infected cells [7,8], which allow bacillary replication and persistence by fine-tuning pro-and anti-inflammatory networks [9,10]. While inflammation-promoting events are essential at the individual level and drive primary disease progression, balanced inflammatory mechanisms appear indispensable for Mtb persistence within hosts with latent TB infection (LTBI) [11]. Uncovering Mtb's strategies to modulate inflammation at various stages of infection represents a cornerstone for the development of disease control measures. Host-directed therapy (HDT) is the most Immunol. 2015Immunol. . 45: 2191Immunol. -2202 recent approach toward TB treatment. HDT encompasses usage of host modulators, and as such, requires in-depth knowledge on cells involved in disease pathogenesis, particularly inflammation [12][13][14]. In this review, we will focus on the diversity of myeloid cells that drive and modulate inflammation in TB, and discuss how different mechanisms of action could be targeted for HDT. Mycobacterium tuberculosis and its major counterpart, the mononuclear phagocyteIn the most prevalent form of TB, the lung serves as source of transmission, port of entry, and site of disease manifestation. Mtb is spread by expectoration of active TB patients, who produce aerosols [15,16] [60]. Autophagy bypasses the block in phagosome maturation and delivers Mtb-containing phagosomes to lysosomal compartments termed autophagolysosomes [60]. More recently, the aryl hydrocarbon receptor (AhR) has been identified as a cytosolic sensor for the mycobacterial lipid, phthiocol [61]. AhR activation following Mtb infection elicits the prompt release of TNF-α, IL-6, and IL-1...

Neutrophils and the S100A9 protein critically regulate granuloma formation

“…9,31 The neutrophil S100A9 protein may be involved in the initial steps of granuloma formation, including the recruitment of peripheral blood neutrophils to the site of inflammation. The S100A9-mediated pathway leading to the transendothelial migration of neutrophils has recently been elucidated at the molecular level.…”

“…4,[8][9][10] Of these, neutrophils are the most common and prominently detected cell type in granulomas 9,10 ; however, due to their various functions, which are known to be executed in acute, rather than chronic inflammation, the contribution of neutrophils to the formation of granulomas has not yet been elucidated in detail. In the present study, we found that neutrophils expressing the marker protein, S100A9, accumulated in the central part of granulomas generated in vivo in the bacille Calmette-Guérin (BCG)-challenged guinea pig lung.…”

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

“…Mtb interacts with multiple cell types [12,13] and triggers complex tissue changes [14]. Versatility of Mtb regarding its subcellular niches and its facultative intracellular replication correlates with an intricate pathology picture.…”

“…The diversity of myeloid cell types and subtypes hosting bacilli is increasingly acknowledged [12]. However, vast information on subcellular locations of Mtb emerges from ex vivo studies with macrophages.…”

Bacterial Virulence Factors: Secreted for Survival

“…Mtb, an obligate aerobic intracellular pathogen, gains entry into its host through the respiratory route via aerosols generated by an infected individual. Once inside the pulmonary alveoli, the pathogen is entrapped by alveolar macrophages, neutrophils, dendritic cells (DCs) or even epithelial cells [1,2]. Various ligands present on the mycobacterial cell surface such as phosphatidylinositol mannoside (PIM), HSP70, 19 kDa lipoprotein, lipoarabinomannan (LAM) are recognised by phagocytic receptors and/or specific pattern recognition receptors (PRRs) present at the cell membrane of macrophages or DCs [3].…”