Despite these known direct and indirect mechanisms of Mtb interference with T cell acknowledgement of infected cells, questions remain: (a) Do these evasion mechanisms impact non-CD4+ T cells? (b) During which stages of Mtb contamination and disease do they impact the immune response? (c) Which of these different T cell evasion mechanisms dominates, and at what stage of Mtb pathogenesis in vivo? Antibodies and B cells in LTBI Antibodies may contribute to long-term Mtb control in LTBI (reviewed in refs. understanding of LTBI, ranging from the earliest events of exposure and contamination to success or failure of Mtb control. Introduction (Mtb), a bacterium transmitted through ENO2 respiratory droplets, is one of the most successful human pathogens. With approximately 10 million cases and 1.45 million associated deaths per year, tuberculosis (TB), which is caused by uncontrolled Mtb infection, is the worlds most lethal infectious disease next to COVID-19 (1). Failure of TB control programs and the lack of a highly efficacious vaccine against TB have refocused attention on the earliest events in TB pathogenesis the acquisition and control of Mtb bacilli in the human lung. Because of its ability to infect and survive in macrophages (examined in ref. 2), Mtb can persist and cause, in most individuals, a clinically inapparent contamination referred to as latent TB contamination (LTBI) (examined in ref. 3). However, TB and LTBI are not binary classifications but rather terms comprising a heterogeneous spectrum (examined in ref. 4). Our failure to detect prolonged/latent Mtb bacilli makes it impossible to determine who among those presumed infected and asymptomatic have cleared the bacilli (5), remain latently infected, or will progress to uncontrolled contamination/TB (Table 1). Instead, we rely on a detectable cellular immune response to Mtb antigens in the form of a positive tuberculin skin test (TST) and/or blood-based IFN- release assay (IGRA) as surrogates for presumed LTBI (3, 6C8). Therefore, LTBI is an operational and not a pathogenetic definition. Table 1 Major human defense mechanisms in Mtb exposure and contamination Open in a separate window Since a quarter of the worlds populace is estimated to have LTBI, there is a large reservoir from which TB can emerge to gas its worldwide pandemic (9). Understanding all of the immune components that result in LTBI or resistance to it, and in the continued control or possibly clearance of Mtb, is critical for insights into protective immunity to Mtb and for determining who is at risk of developing TB (10). Genetic studies show that Mtb may have coevolved with humans for more than 6000 years, which likely contributed to its success in intracellular survival and escape from innate and adaptive immune mechanisms (10C13). The bacterial pathogenesis, development, and strain diversity of Mtb have been extensively examined elsewhere (10C14). Based on human and nonhuman primate (NHP) studies, we here focus on new concepts and point out major knowledge gaps in efforts to understand the complexity of immune responses in LTBI. Models for human LTBI Animal models have provided insight into essential mechanisms of TB pathogenesis, but few reflect the heterogeneity of human responses to Mtb, particularly during the early Caffeic acid events of control and containment in the airways (refs. 15, 16, and Caffeic acid examined in refs. 17C19). NHPs, especially macaques, have been priceless models Caffeic acid for Mtb contamination of the lung. They display the full spectrum of host responses and clinical manifestations that most closely resemble those in humans (examined in refs. 20, 21). Macaques differ in their susceptibility to Mtb around 90% of rhesus and 60% of cynomolgus macaques develop TB after low-dose airway contamination (20C22). Both macaque models are being used to study TB pathogenesis and TB vaccine responses, and provide important insights into T and B cellCmediated correlates and mechanisms of protection against Mtb and its progression to TB in the setting of immunosuppression (e.g., SIV contamination) and T and B cell depletion (examined in refs. 17C21; refs. 23C26). The cynomolgus model, owing to its higher rate of Mtb control, is usually more suitable for investigation of the earliest events in the lung leading to granuloma development, and LTBI or progression to TB (15C18, 20C22). With sophisticated imaging, systems immunology, and computational modeling methods (27), NHP models will continue to enhance our understanding of pathogenesis in human TB and LTBI. Human granuloma models allow for analyses of early host-pathogen interactions during Mtb contamination (examined in ref. 28). They bring together cells such as mononuclear phagocytes, lymphocytes, fibroblasts, and epithelial cells, and allow investigation of the impact of different human immune components on early granuloma.
