| 1. |
- Arko-Mensah, John, et al.
(author)
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Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice
- 2009
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In: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 15:8, s. 777-786
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Journal article (peer-reviewed)abstract
- Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.
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| 2. |
- Chuquimia, Olga D., 1977-, et al.
(author)
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The Role of Alveolar Epithelial Cells in Initiating and Shaping Pulmonary Immune Responses : Communication between Innate and Adaptive Immune Systems
- 2012
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2, s. e32125-
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Journal article (peer-reviewed)abstract
- Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guerin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.
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| 3. |
- Martínez-Pérez, Amparo, et al.
(author)
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Changes in the Immune Phenotype and Gene Expression Profile Driven by a Novel Tuberculosis Nanovaccine : Short and Long-Term Post-immunization
- 2021
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Journal article (peer-reviewed)abstract
- Deciphering protection mechanisms against Mycobacterium tuberculosis (Mtb) remains a critical challenge for the development of new vaccines and therapies. We analyze the phenotypic and transcriptomic profile in lung of a novel tuberculosis (TB) nanoparticle-based boosting mucosal vaccine Nano-FP1, which combined to BCG priming conferred enhanced protection in mice challenged with low-dose Mtb. We analyzed the vaccine profile and efficacy at short (2 weeks), medium (7 weeks) and long term (11 weeks) post-vaccination, and compared it to ineffective Nano-FP2 vaccine. We observed several changes in the mouse lung environment by both nanovaccines, which are lost shortly after boosting. Additional boosting at long-term (14 weeks) recovered partially cell populations and transcriptomic profile, but not enough to enhance protection to infection. An increase in both total and resident memory CD4 and CD8 T cells, but no pro-inflammatory cytokine levels, were correlated with better protection. A unique gene expression pattern with differentially expressed genes revealed potential pathways associated to the immune defense against Mtb. Our findings provide an insight into the critical immune responses that need to be considered when assessing the effectiveness of a novel TB vaccine.
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| 4. |
- Palma, Carla, et al.
(author)
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Mycobacterium tuberculosis PstS1 amplifies IFN-gamma and induces IL-17/IL-22 responses by unrelated memory CD4(+) T cells via dendritic cell activation
- 2013
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 43:9, s. 2386-2397
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Journal article (peer-reviewed)abstract
- The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN- and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few MtbAgs interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN- and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1 and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis.
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| 8. |
- Rahman, Muhammad Jubayer, et al.
(author)
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Immunization with mycobacterial antigens: a role for innate immunity in antigen presentation
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Other publication (other academic/artistic)abstract
- We have found that toll-like receptor (TLR) 2 was important in the control of mycobacterial infection in the lungs. However, it is unclear how the TLR2-mediated innate immunity contributes to the development of acquired immune responses upon immunization with mycobacterial antigens. In the present study, we addressed this issue by immunizing TLR2 knockout (TLR2-/-) and wild-type (WT) mice with mycobacterial 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand) antigens. We compared both humoral and cellular immune responses in the two mouse strains. Interferon gamma (IFN-g) responses were measured in the culture supernatants after in vitro restimulation of spleen cells with antigen alone, antigen-pulsed bone marrow derived macrophages (BMMAg) or BCG-infected BMM (BMMBCG). We found that the magnitude of antigen-specific antibody responses in serum was comparable in the two mouse strains. With regard to the two antigens, immunization with 19kDa induces more Th1 type immune responses compared to the immunization with Ag85A. We observed differences in the response of the two strains upon restimulation with antigen alone or with BMMAg regarding 19kDa. Recall IFN-g responses to 19kDa were significantly lower in the TLR2-/- mice compared to the WT mice. Interestingly, IFN-g responses to BMMBCG were similar in both strains probably due to the fact that BCG targets other cell surface molecules. The expression of CD86 in the BMMBCG was found to be TLR2-independent whereas in the BMMAg it was TLR2-dependent. Altogether, results from this study indicate that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigens (TLR2 dependent or independent) used for immunization. We discuss the relevance of innate immunity for the induction of acquired immune responses.
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| 9. |
- Rahman, Muhammad J, et al.
(author)
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Impact of Toll-like receptor 2 deficiency on immune responses to mycobacterial antigens
- 2011
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In: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 79:11, s. 4649-4656
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Journal article (peer-reviewed)abstract
- In the present study, we addressed the question of whether Toll-like receptor 2 (TLR2)-mediated innate immunity can contribute to the development of acquired immune responses. We immunized TLR2(-/-) and wild-type (WT) mice three times subcutaneously with the mycobacterial antigen (Ag19kDa) (a TLR2 ligand) or Ag85A (not a TLR2 ligand). One week after the last immunization, sera and spleens were collected. To evaluate cellular responses, we measured gamma interferon (IFN-γ) after in vitro restimulation of spleen cells with antigen alone or antigen-pulsed bone marrow-derived macrophages (BMM(Ag)) or pulmonary macrophages (PuM(Ag)). Antibody responses were comparable in the two mouse strains, but we observed differences in the cellular responses. Recall responses to Ag85A were similar in the two strains, but responses to Ag19kDa given alone or presented by BMM or PuM were lower in TLR2(-/-) than in WT mice. The largest differences in cellular responses were observed when Ag19kDa was presented by PuM. To understand this, we analyzed phenotypic and functional differences between BMM and PuM upon stimulation with various ligands. Generally, PuM had a lower response to the TLR2 ligand Pam(3)Cys-Ser-(Lys)(4) trihydrochloride and to anti-CD40 than BMM, as measured by cytokine secretion and upregulation of costimulatory molecules. This might provide a partial explanation for the lower capacity of PuM when pulsed with Ag19kDa, also a TLR2 ligand. Altogether, our results revealed weaknesses in the T cell and antigen-presenting cell (APC) compartments of the Ag19kDa-immunized TLR2(-/-) mice but indicated that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigen used.
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| 10. |
- Rahman, Muhammad Jubayer, et al.
(author)
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Influence of maternal gestational treatment with mycobacterial antigens on postnatal immunity in an experimental murine model
- 2010
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:3, s. e9699-
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Journal article (peer-reviewed)abstract
- It has been proposed that the immune system could be primed as early as during the fetal life and this might have an impact on postnatal vaccination. Therefore, we addressed in murine models whether gestational treatment with mycobacterial antigens could induce better immune responses in the postnatal life. METHODS/FINDINGS: BALB/c mice were treated subcutaneously (s.c.) at the second week of gestation with antigen (Ag)85A or heparin-binding hemagglutinin (HBHA) in the absence of adjuvant. Following birth, offspring mice were immunized intranasally (i.n.) with the same antigens formulated with the adjuvant cholera toxin (CT) at week 1 and week 4. One week after the last immunization, we assessed antigen-specific recall interferon gamma (IFN-gamma) responses by in vitro restimulation of lung-derived lymphocytes. Protection against infection was assessed by challenge with high dose Mycobacterium bovis Bacille Calmette-Guérin (BCG) given i.n. We found that recall IFN-gamma responses were higher in the offspring born to the treated mother compared to the untreated-mother. More importantly, we observed that the offspring born to the treated mother controlled infection better than the offspring born to the untreated mother. Since the gestational treatment was done in absence of adjuvant, essentially there was no antibody production observed in the pregnant mice and therefore no influence of maternal antibodies was expected. We hypothesized that the effect of maternal treatment with antigen on the offspring occurred due to antigen transportation through placenta. To trace the antigens, we conjugated fluorescent nanocrystals with Ag85A (Qdot-ITK-Ag85A). After inoculation in the pregnant mice, Qdot-ITK-Ag85A conjugates were detected in the liver, spleen of pregnant females and in all the fetuses and placentas examined. CONCLUSION: The fetal immune system could be primed in utero by mycobacterial antigens transported through the placenta.
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