A functional immune response is crucial to prevent and limit infections with Streptococcus pneumoniae.
Dendritic cells (DCs) play a central role in orchestrating the adaptive and innate immune responses by communicating with other cell types via antigen presentation and secretion of cytokines.
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In this study, we set out to understand how pneumococci activate human monocyte-derived DCs to produce interleukin-12 (IL-12) p70, an important cytokine during pneumococcal infections. We show that IL-12p70 production requires uptake of bacteria as well as the presence of the adaptor molecule TRIF, which is known to transfer signals of Toll-like receptor 3 (TLR3) or TLR4 from the endosome into the cell.
While TLR4 is redundant for IL-12p70 production in DCs, we found that TLR3 is required to induce full IL-12p70 secretion. Influenza A virus (IAV) infection of DCs did not induce IL-12p70 but markedly upregulated TLR3 expression that during coinfection with S. pneumoniae significantly enhanced IL-12p70 secretion. Finally, we show that pneumococcal RNA can act as a bacterial stimulus for TLR3 and that it is a key signal to induce IL-12p70 production during challenge of DCs with pneumococci.
OBJECTIVE
Streptococcus pneumoniae, a common colonizer of the nose, is the causative agent of severe and deadly diseases. A well-orchestrated immune response is vital to prevent and limit these diseases. Dendritic cells (DCs) reside in the mucosal linings of the lungs and sample antigens. They are activated by pathogens to present antigens and secrete cytokines. While many studies focus on murine models, we focused our work on human monocyte-derived DCs. We found that pneumococcal RNA is an important stimulus in DCs to activate the endosomal receptor TLR3, a receptor previously not identified to sense pneumococci, and its adaptor molecule TRIF.
This leads to secretion of the cytokine interleukin-12 (IL-12). Severe pneumococcal pneumonia occurs closely after influenza A virus (IAV) infection. We show that IAV infection upregulates TLR3 in DCs, which sensitizes the cells to endosomal pneumococcal RNA. This new insight contributes to unlock the interplay between pneumococci, IAV, and humans.
Calcium mobilization treatment acts as a joint signal for interleukin-12 induction mediated by TLR (<em> il </ em> – <em> 12p70 </ em>) secretion by dendritic cells originating from murine bone marrow.
We strive to determine whether the pharmacological calcium mumigation agent can act in collaboration with receptor signals such as toll (TLR) to induce high-level IL-12 production from dendritic cells originating from murine bone marrow. We found that calcium mobilization was induced without IL-12, but dramatically increased the secretion of IL-12P70 caused by TLR ligands. Increased production of IL-12 induced by calcium ionophore plus single TLR ligands, but not through double ligands of TLR, inhibited by Cyclosporine Calcineurin A antagonists, suggesting different mechanisms from IL-12 induction.
Dendritic cells activated with calciabionofore plus TLR9 ODN1826 ligands can cause Th1 polarization in Murine Naïve T cells at the same level or superior to dendritic cells that are activated with the most efficient TLR ligand pairs; ODN1826 plus lipopolysaccharide bacteria. Parallel analysis of 38 soluble products related to inflammation shows increased calciumophores limited to a set of small factors. This data shows the previously unscrupulous activation signal for IL-12 production by dendritic cells.
Receptors such as toll road 3 / trif depend on <em> il </ em> 12p70 </ em> secretion mediated by Streptococcus pneumoniae RNA and priming by influenza coinfected viruses in human dendritic cells.
Functional immune responses are very important to prevent and limit infection with streptococcus pneumoniae. Dendritic cells (DCS) play a central role in regulating adaptive and innate immune responses by communicating with other types of cells through antigen presentations and cytokine secretions. In this study, we departed to understand how Pneumococci activated DC which was derived from the human monocy to produce interleukin-12 (IL-12) P70, an important cytokine during pneumococcal infection. We show that the production of IL-12P70 requires absorption of bacteria and the existence of adapter molecular trifs, which are known to transfer receptor signals such as toll (TLR3) or TLR4 from endosome into cells.
While the TLR4 is excessive for the production of IL-12P70 in DCS, we find that TLR3 is needed to induce full-12p70 secretion. Influenza A Virus (IAV) DCS infection does not induce IL-12P70 but significantly reveals the expression of TLR3 which during co-infection with S. pneumoniae significantly increases the secretion of IL-12P70 significantly. Finally, we showed that RNA pneumococci can act as a bacterial stimulus for TLR3 and that it is a key signal to induce IL-12P70 production during the DCS challenge with pneumococci.
Objective
Streptococcus pneumoniae, common nose invaders, is an agent of causing severe and deadly disease. The immune response that is well organized is very important to prevent and limit this disease. Dendritic cells (DCS) are in the lung mucous layer and sample antigen. They are activated by pathogens to serve antigens and remove cytokines. While many studies focus on murine models, we focus our work on DCS monocyte-human derivatives. We found that the Pneumococcal RNA was an important stimulus in DC to activate TLR3 endosom receptors, previous receptors were not identified to feel pneumococci, and the adapter molecules trif.
This leads to the secretion of the interleukin-12 cytokine (IL-12). Severe pneumococcal pneumonia occurred tightly after influenza virus (IAV) infection. We show that IAV infection confirms TLR3 in DCS, which is sensitive to cells against endosomal pneumococcal RNA. This new insight contributes to opening interactions between Pneumococci, IAV, and humans.
