Harnessing Innate Immunity to Treat Mycobacterium tuberculosis Infections: Heat-Killed Caulobacter crescentus as a Novel Biotherapeutic (original) (raw)
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Host Innate Immune Response to Mycobacterium tuberculosis
Journal of Clinical Immunology, 2007
This review focuses on recent progress in our understanding of Mycobacterium tuberculosis survival in macrophages, the interaction of M. tuberculosis with Toll-like receptors (TLRs) and the establishment of the link between innate and adaptive immunity, and TLRs and interferon-γ-mediated antimicrobial pathways in macrophages. We also propose a paradigm that TLR2 signaling regulates the magnitude of the host Th1 response leading to either M. tuberculosis persistence and latent infection or replication and disease.
Mycobacterium tuberculosis Subverts Innate Immunity to Evade Specific Effectors
The Journal of Immunology, 2006
The macrophage is the niche of the intracellular pathogen Mycobacterium tuberculosis. Induction of macrophage apoptosis by CD4 ؉ or CD8 ؉ T cells is accompanied by reduced bacterial counts, potentially defining a host defense mechanism. We have already established that M. tuberculosis-infected primary human macrophages have a reduced susceptibility to Fas ligand (FasL)induced apoptosis. To study the mechanisms by which M. tuberculosis prevents apoptotic signaling, we have generated a cell culture system based on PMA-and IFN-␥-differentiated THP-1 cells recapitulating the properties of primary macrophages. In these cells, nucleotide-binding oligomerization domain 2 or TLR2 agonists and mycobacterial infection protected macrophages from apoptosis and resulted in NF-B nuclear translocation associated with up-regulation of the antiapoptotic cellular FLIP.
Innate immunity to Mycobacterium tuberculosis
Clinical microbiology …, 2002
The different manifestations of infection with Mycobacterium tuberculosis reflect the balance between the bacillus and host defense mechanisms. Traditionally, protective immunity to tuberculosis has been ascribed to T-cell-mediated immunity, with CD4 + T cells playing a crucial role. ...
Frontiers in Microbiology, 2016
T cells play a cardinal role in imparting protection against Mycobacterium tuberculosis (Mtb). However, ample time is required before T-cells are able to evoke efficient effector responses in the lung, where the mycobacterium inflicts disease. This delay in T cells priming, which is termed as lag phase, provides sufficient time for Mtb to replicate and establish itself within the host. In contrast, innate immunity efficiently curb the growth of Mtb during initial phase of infection through several mechanisms. Pathogen recognition by innate cells rapidly triggers a cascade of events, such as apoptosis, autophagy, inflammasome formation and nitric oxide production to kill intracellular pathogens. Furthermore, bactericidal mechanisms such as autophagy and apoptosis, augment the antigen processing and presentation, thereby contributing substantially to the induction of adaptive immunity. This manuscript highlights the role of innate immune mechanisms in restricting the survival of Mtb during lag phase. Finally, this article provides new insight for designing immuno-therapies by targeting innate immune mechanisms to achieve optimum immune response to cure TB.
Mycobacterium tuberculosis Rv2224c modulates innate immune responses
Proceedings of The National Academy of Sciences, 2008
Tuberculosis remains a major global health problem that kills up to 2 million people annually. Central to the success of Mycobacterium tuberculosis (Mtb) as a pathogen is its ability to evade host immunity and to establish a chronic infection. Although its primary intracellular niche is within macrophages, the underlying molecular mechanisms are poorly understood. Here we show that Rv2224c, a cell envelope-associated predicted protease, is critical for Mtb virulence. Disruption of Rv2224c led to prolonged survival of infected mice and highly reduced lung pathology. Absence of Rv2224c enhanced host innate immune responses, compromised the intracellular survival of Mtb in macrophages, and increased its susceptibility to lysozyme. We provide insights into the molecular basis for Rv2224c function by showing that Rv2224c activity promotes processing and extracellular release of the Mtb protein, GroEL2. Inhibition of Rv2224c and its targets offers opportunities for therapeutic interventions and immune-modulatory strategies.
Innate Immune Response to Mycobacterium tuberculosis Beijing and Other Genotypes
PLoS ONE, 2010
Background: As a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evoluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes.
The Innate and Adaptive Immune Response during M. tuberculosis Infection
Journal of Molecular and Genetic Medicine, 2014
Mycobacterium tuberculosis, the causative agent of tuberculosis is a facultative intracellular pathogen that infects and resides in humans and is a leading infectious cause of death in many parts of the world with a worrying increase in transmission and resistance to drugs. Surfactant proteins A and D (SP-A and-D) play a role in many acute bacterial, viral, and fungal infections and in acute allergic responses. In vitro, human SPs bind Mycobacterium tuberculosis and alter human and rat macrophage-mediated functions. Here we report the roles of SPA and SP-D in M. tuberculosis infection following aerosol challenge of SPA -, SP-D-, and SP-A/-D-deficient mice. These studies surprisingly identified no gross defects in uptake or immune control of M. tuberculosis in SPA -, SP-D-, and SP-A/-Ddeficient mice. While both SPA and SP-D-deficient mice exhibited evidence of immunopathologic defects, the CD11b high CD11c high dendritic cell populations and the gamma interferon (IFN-γ)-dependent CD4+ T cell response to M. tuberculosis were unaltered in all genotypes tested. Together, these data indicate that SPA and SP-D are dispensable for immune control of M. tuberculosis in a low-dose, aerosol challenge, murine model of tuberculosis (TB). This pathogen is generally transmitted by inhalation of infectious aerosols into the lung with deposition in the terminal bronchioles and alveoli. Most affected persons stand an effective immune response that might controls this pathology but does not totally eradicate the primary tuberculosis infection and the reactivation of persistent M. tuberculosis later in life occur frequently in active tuberculosis cases. Many studies are still running up in order to better understand the interactions between M. tuberculosis and the immune environment of the lung. In this review, we describe initial interactions between the lung environment and M. tuberculosis and we summarize the normal surfactant turnover by alveolar macrophages and AEC II in to the uptake of M. tuberculosis in alveolar epithelial cells and macrophages during the innate immune response followed by the T cells initiation of the adaptive immunity in the lung.
Natural and trained innate immunity against Mycobacterium tuberculosis
Immunobiology, 2020
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Understanding the early host immune response against Mycobacterium tuberculosis
Central European Journal of Immunology, 2020
Generation of immune response is a crucial activity of host defense against any microbial attack. When facultative organism Mycobacterium tuberculosis (MTB) invades its host, various pathways are activated in the host to mount immune responses against invading pathogen for nullifying its actions. During this host-pathogen interaction, interplay of complex network of cytokines and chemokines, initiation of phagocytosis, and formation of granuloma play an important role in containing MTB infections at host side. Simultaneously, MTB also evolves a plethora of specialized mechanisms to evade the host's killing cascades on other side, and during this bilateral cross-talk, many mycobacterial products play crucial role in survival of MTB inside the host. Hence, a better understanding of these phenomena is necessary not only for getting clear picture of pathogenesis of MTB, but also for developing effective, preventive, and therapeutic modalities against the pathogen. With some suggestions on future work, an insight into diversity of immune response of host against MTB was provided in the present review.