Host response to intracellular infections Flashcards
Which type of CD4+ T helper cell is associated with efficient immunity against Mtb? Which cytokines associated with this type of T cell are important for control of Mtb infection? Which cells do these cytokines act on and what is their effect on these cells?
The CD4+ T helper cell that is associated with efficient immunity against Mtb is the classical T-helper subsets of Th1 cells which produces IFN-gamma, IL-2 and TNF-alpha. Additionally, the Th1 cells express the CD40 ligand on their surface with co-stimulates the macrophage during its activation due to their CD40 surface receptor.
These cytokines stimulates the macrophages for the phagocytosis degradation of the bacteria.
Which types of CD4+ T cells could potentially account for IFN-gamma-independent Mtb immunity? Which cytokines are secreted by these cells?
IFN-gamma is produced by CD4+ Th1 cells which induce phagocytosis of the bacteria by they now activated macrophages. Additional cytokines produced by these cells are: IL-2 and TNF-beta.
What is the effect of type I interferon on Mtb infection?
Type I interferons (IFN-alpha and IFN-beta) can inhibit the function of macrophages and the production of key cytokines (TNF-alpha) necessary for an effective immune response against Mtb (pro-bacteria); suppress Th1 responses; and cause a cytokine storm due to overexpression of the interferons (severe outcomes).
Which cytokines other than IFN-gamma are involved in protective immunity to Mtb?
IL-12: secreted by DCs for differentiation of the T cell into specific T effector cells (Th1 cell). It plays a central role in initiating and amplifying the Th1 immune response by promoting the differentiation and activation of Th1 cells. It stimulates the production of IFN-gamma by the Th1 cells.
TNF-alpha: produced by macrophages, T cells and other immune cells in response to Mtb infection. It plays a crucial role in the formation and maintenance of granulomas, which are organized structures that contain Mtb infection. It is also involved in activating macrophages and enhancing their antimicrobial activity against Mtb. IL-1: produced by macrophages and other immune cells in response to Mtb infections. It contributes to the inflammatory response and the recruitment of immune cells to the site of infection. It also enhances the antimicrobial activity of macrophages against Mtb.
IL-6: produced by various immune cells in response to Mtb infection. It plays a role in promoting inflammation and the acute phase response. It also contributes to the differentiation of T cells and the regulation of immune responses.
How does the granuloma contain infection with Mtb?
During infection when the bacteria enter the lungs, they get rapidly phagocytosed by tissue-resident macrophages. However, the bacteria are able to evade the immune-mediated killing and efficiently replicate within the populations of macrophages and other recruited immune cells (from the innate immune system). This causes an aggregation of these immune cell population where the Mtb are still hiding inside the infected macrophages.
Which cells are associated with Mtb granulomas and what are their functions?
Conventional macrophages - contains the Mtb and are located in the core of the granuloma; often undergone necrosis (lack of nutrients)
Epithelioid cells (differentiated macrophages) - surrounds the conventional macrophages as a protective/activated layer.
Giant cells - several macrophages that have fused together (multi-nucleated cells). These are found within the epithelioid macrophage-layer.
At the edge of the granuloma we find the other associated cells: Myeloid cells (Dendritic cells, Neutrophils, Eosinophils, Mast cells), Lymphocytes: (T cells, B cells, NK cells, and ILCs), and nonhematopoietic cells (fibroblasts, endothelial, epithelial cells). These are recruited due to the immune response, and thus still be activated by the antigen presenting cells (macrophages and dendritic cells). Thereby, looks like a local, chronic inflammation.
Which cells and molecules are most important for containing infection with L. monocytogenes? What are the functions of these cells/molecules?
CD4+ T cells: are activated by the MHC-II molecules, when the bacteria is present in the phagosome. They are needed in sterilizing immunity, and for the activation of macrophages (IFN-gamma), facilitating CD8+ T cell responses, promotion of granuloma formation, and regulation of inflammatory responses (TGF-beta, IL-10).
CD8+ cytotoxic T cells: gets activated by the MHC-I molecules that binds tightly to the infected macrophage. They have bactericidal capabilities; by a combination of cytokine production and cytolytic activity, and contains the effector molecules (perforins and granzymes) within granulomas that can transvers the membrane of the cell into the infected cell leading to granular exocytosis. They are also needed in sterilizing immunity. Kupffer cells (macrophages in the liver): contain Mtb within the cytosol, and transport the bacteria from the liver to the blood. NK cells: important in the early phases of the infection, where it produces the IFN-gamma, to enhance the recruitment of other immune cells. Neutrophils: important in the lesions involving the CNS during the infection. Can perform phagocytosis and express the CXCL1, CXCL2 and CXCR4 (chemokines; causing a chemotaxis) to enhance the recruitment of additional neutrophils from the bone marrow into circulation. Cytokines: acute inflammatory cytokines (TNF-alpha, IL-1, IL-6, and IL-12, IFN-gamma) mobilize and activate neutrophiles, monocytes and macrophages. Whereas, the anti-inflammatory cytokines (IL-10) limits immune-mediated injury an dampen the immune response to the pathogen. Perforins: help proliferate the membrane of the cells and transport granzymes into the cytoplasm.
Granzymes: activates caspases, resulting in activation of apoptosis and break down of the nucleus in the infected cells.
