During tuberculosis (TB) infection, the granuloma provides the microenvironment in which antigen-specific T cells colocate with and activate infected macrophages to inhibit the growth of Mycobacterium tuberculosis. Although the granuloma is the site for mycobacterial killing, virulent mycobacteria have developed a variety of mechanisms to resist this macrophage-mediated killing. These surviving mycobacteria become dormant, however, if host cellular immunity or the signals maintaining granuloma structure wane, or if mycobacteria resume replication, leading to reactivation of TB. This balance of life and death applies not only to the mycobacterium but also to the host macrophages that may undergo apoptosis or necrosis, leading to the characteristic caseous necrosis within the granuloma, and the potential spread of TB infection. The immunological factors controlling the development and maintenance of the granuloma will be reviewed. Keywords: granuloma; tuberculosis; reactivation; cytokines; chemokinesThe formation and maintenance of granulomas are essential for the control of mycobacterial infections but, paradoxically, granulomas are also responsible for the typical immunopathology caused by these infections. There are over 70 species of Mycobacteria, but Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, are the major human pathogens. These slow-growing mycobacteria have adapted to survival within the macrophage, and this capacity for persistence of mycobacteria in the face of a potent cellular response underlies the chronic inflammatory reaction of the host. Mycobacterial infection of dendritic cells (DCs) stimulates CD4 and CD8 T cells, which on recruitment to the sites of infection activate infected macrophages. M. tuberculosis, however, blocks phago-lysosomal fusion and acidification of infected phagosomes, and also partially inhibits the activation of infected macrophages by interferon (IFN)-g, the major effector cytokine released by Th1-like CD4 T cells. As a result, some mycobacteria persist in the infected lung, leading to chronic antigenic stimulation and T-cell accumulation around macrophages. In the face of chronic cytokine stimulation, macrophages differentiate into epithelioid cells and fuse to form typical giant cells. Within the resulting granuloma, there is a balance between mycobacterial killing and survival. The local architecture results in the close apposition of lymphocytes and macrophages, and this is necessary for the activation of macrophages to kill M. tuberculosis. But the survival of some tuberculous bacilli leads to latent TB infection (LTBI), which is contained by the granulomatous process. Following acute M. tuberculosis infection, this process is adequate to control the infection in 95% of subjects, while the remainder progress to primary TB disease. There are currently two billion humans with LTBI, and reactivation of the infection occurs in 5-7% 1 of these subjects without, and in up to 50% with, human immunodeficiency virus...

Evidence showing that neutrophils play a protective role in the host response to infection by different intracellular parasites has been published in the past few years. We assessed this issue with regard to the infection of mice with Mycobacterium tuberculosis. We found a chronic recruitment of neutrophils to the infection foci, namely, to the peritoneal cavity after intraperitoneal infection and to the spleen and liver after intravenous inoculation of the mycobacteria. However, bacilli were never found associated with the recruited neutrophils but rather were found inside macrophages. The intravenous administration of the antineutrophil monoclonal antibody RB6-8C5 during the first week of infection led to selective and severe neutropenia associated with an enhancement of bacillary growth in the target organs of the mice infected by the intravenous route. The neutropenia-associated exacerbation of infection was most important in the liver, where a bacterial load 10-fold higher than that in nonneutropenic mice was found; the exacerbation in the liver occurred both during and after the neutropenic period. Early in infection by M. tuberculosis, neutropenic mice expressed lower levels of mRNAs for gamma interferon and inducible nitric oxide synthase in the liver compared to nondepleted mice. These results point to a protective role of neutrophils in the host defense mechanisms against M. tuberculosis, which occurs early in the infection and is not associated with the phagocytic activity of neutrophils but may be of an immunomodulatory nature.

SummaryThe generation of prolonged immunity to Mycobacterium tuberculosis requires not only an antigenspecific IFN-γ-producing T cell response, including both CD4 and CD8 T cells, but also the generation of protective granulomatous lesions, whereby the close apposition of activated T cells and macrophages acts to contain bacterial growth. The importance of the granulomatous lesion in controlling this immune response and in limiting both tissue damage and bacterial dissemination has been considered a secondary event but, as the present review illustrates, is no less important in surviving mycobacterial infection than an antigen-specific T-cell response. The formation of a protective granuloma involves the orchestrated production of a host of chemokines and cytokines, the upregulation of their receptors along with upregulation of addressins, selectins and integrins to coordinate the recruitment, migration and retention of cells to and within the granuloma. In the present review, the principal components of the protective response are outlined and the role of granuloma formation and maintenance in mediating prolonged containment of mycobacteria within the lung is addressed.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.