scholarly journals IL-4 and helminth infection downregulate MINCLE-dependent macrophage response to mycobacteria and Th17 adjuvanticity

2021 ◽  
Author(s):  
Roland Lang ◽  
Stefan Wirtz ◽  
David Voehringer ◽  
Matthew Lacorcia ◽  
Meltem Altunay ◽  
...  
Keyword(s):  
Helminth Infection ◽  
Mycobacterial Infection ◽  
Nippostrongylus Brasiliensis ◽  
Macrophage Infection ◽  
Th17 Response ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Plasmid Injection ◽  
Mycobacterial Cell Wall ◽  
The Impact

The myeloid C-type lectin receptor (CLR) MINCLE senses the mycobacterial cell wall component trehalose-6,6-dimycolate (TDM). Recently, we found that IL-4 down-regulates MINCLE expression in macrophages. IL-4 is a hallmark cytokine in helminth infections, which appear to increase the risk for mycobacterial infection and active tuberculosis. Here, we investigated functional consequences of IL-4 and helminth infection on MINCLE-driven macrophage activation and Th1/Th17 adjuvanticity. IL-4 inhibited MINCLE and cytokine induction after macrophage infection with Mycobacterium bovis Bacille Calmette-Guerin (BCG). Infection of mice with BCG upregulated MINCLE on myeloid cells, which was inhibited by IL-4 plasmid injection and by infection with the nematode Nippostrongylus brasiliensis in monocytes. To determine the impact of helminth infection on MINCLE dependent immune responses, we vaccinated mice with a recombinant protein together with the MINCLE ligand Trehalose-6,6-dibehenate (TDB) as adjuvant. Concurrent infection with N. brasiliensis or with Schistosoma mansoni promoted T cell-derived IL-4 production and suppressed Th1/Th17 differentiation in the spleen. In contrast, helminth infection did not reduce Th1/Th17 induction by TDB in draining peripheral lymph nodes, where IL-4 levels were unaltered. Upon use of the TLR4-dependent adjuvant G3D6A, N. brasiliensis infection impaired selectively the induction of splenic antigen-specific Th1 but not of Th17 cells. Thus, helminth infection attenuated the Th17 response to MINCLE-dependent immunization in an organ-specific manner. Taken together, our results demonstrate down-regulation of MINCLE expression on monocytes and macrophages by IL-4 as a possible mechanism of thwarted Th17 vaccination responses by underlying helminth infection.

scholarly journals Infection with the Helminth Nippostrongylus brasiliensis Does Not Interfere with Efficient Elimination of Mycobacterium bovis BCG from the Lungs of Mice

2002 ◽  
Vol 9 (3) ◽  
pp. 727-730 ◽  
Author(s):  
Klaus J. Erb ◽  
Claudia Trujillo ◽  
Mike Fugate ◽  
Heidrun Moll
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Helminth Infection ◽  
Nippostrongylus Brasiliensis ◽  
Th2 Response ◽  
Th2 Responses ◽  
The Impact ◽  
Th1 Immune Response

ABSTRACT Infection with Mycobacterium tuberculosis continues to be one of the major global health threats. Strong mycobacterium-specific Th1 immune responses correlate with protection, and decreased Th1 responses correlate with disease progression. In contrast, the impact of Th2 responses on the development of protective immune responses to mycobacteria remains unclear. To analyze whether ongoing Th2 responses present in the lung influence the development of a protective Th1 immune response to mycobacteria, we coinfected mice with the helminth Nippostrongylus brasiliensis and Mycobacterium bovis BCG. We found that the T cells from the lymph nodes of coinfected mice secreted significantly less gamma interferon than did the T cells from mice infected with M. bovis BCG after in vitro stimulation with purified protein from M. tuberculosis when 108 CFU of M. bovis BCG were used for the infection. This result indicates that the helminth infection reduced the Th1 immune response to the mycobacteria in the lung. However, mycobacterial clearance was not delayed in the coinfected animals. Importantly, the infection with BCG after the helminth infection did not reduce the helminth-induced Th2 response in the lung, ruling out the possibility that the lack of a reduction in bacterial clearance in the coinfected mice was due to a downmodulation of the helminth-induced Th2 response. Taken together, our results suggest that ongoing Th2 responses in the lung do not necessarily lead to increased susceptibility to mycobacterial infection.

scholarly journals DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria

2021 ◽  
Vol 4 (6) ◽  
pp. e202000810
Author(s):  
Barbara Killy ◽  
Barbara Bodendorfer ◽  
Jörg Mages ◽  
Kristina Ritter ◽  
Jonathan Schreiber ◽  
...  
Keyword(s):  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Transcriptional Responses ◽  
Macrophage Differentiation ◽  
Bacille Calmette Guerin ◽  
Lectin Receptor ◽  
Mycobacterial Cell Wall ◽  
The Impact

The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) activates macrophages through the C-type lectin receptor MINCLE. Regulation of innate immune cells relies on miRNAs, which may be exploited by mycobacteria to survive and replicate in macrophages. Here, we have used macrophages deficient in the microprocessor component DGCR8 to investigate the impact of miRNA on the response to TDM. Deletion of DGCR8 in bone marrow progenitors reduced macrophage yield, but did not block macrophage differentiation. DGCR8-deficient macrophages showed reduced constitutive and TDM-inducible miRNA expression. RNAseq analysis revealed that they accumulated primary miRNA transcripts and displayed a modest type I IFN signature at baseline. Stimulation with TDM in the absence of DGCR8 induced overshooting expression of IFNβ and IFN-induced genes, which was blocked by antibodies to type I IFN. In contrast, signaling and transcriptional responses to recombinant IFNβ were unaltered. Infection with live Mycobacterium bovis Bacille Calmette–Guerin replicated the enhanced IFN response. Together, our results reveal an essential role for DGCR8 in curbing IFNβ expression macrophage reprogramming by mycobacteria.

scholarly journals Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

2015 ◽  
Vol 83 (3) ◽  
pp. 1217-1223 ◽  
Author(s):  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
William C. Gause ◽  
Padmini Salgame
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Regulatory Cells ◽  
Helminth Infection ◽  
Treg Cells ◽  
Helminth Species ◽  
Nippostrongylus Brasiliensis ◽  
T Regulatory Cell ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type

Previously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.

scholarly journals Modeling the Effects of Helminth Infection on the Transmission Dynamics of Mycobacterium tuberculosis under Optimal Control Strategies

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Aristide G. Lambura ◽  
Gasper G. Mwanga ◽  
Livingstone Luboobi ◽  
Dmitry Kuznetsov
Keyword(s):  
Optimal Control ◽  
Equilibrium Point ◽  
Drug Administration ◽  
Mass Drug Administration ◽  
Helminth Infection ◽  
Reproduction Number ◽  
Control Strategies ◽  
Active Tuberculosis ◽  
Control Measures ◽  
The Impact

A deterministic mathematical model for the transmission and control of cointeraction of helminths and tuberculosis is presented, to examine the impact of helminth on tuberculosis and the effect of control strategies. The equilibrium point is established, and the effective reproduction number is computed. The disease-free equilibrium point is confirmed to be asymptotically stable whenever the effective reproduction number is less than the unit. The analysis of the effective reproduction number indicates that an increase in the helminth cases increases the tuberculosis cases, suggesting that the control of helminth infection has a positive impact on controlling the dynamics of tuberculosis. The possibility of bifurcation is investigated using the Center Manifold Theorem. Sensitivity analysis is performed to determine the effect of every parameter on the spread of the two diseases. The model is extended to incorporate control measures, and Pontryagin’s Maximum Principle is applied to derive the necessary conditions for optimal control. The optimal control problem is solved numerically by the iterative scheme by considering vaccination of infants for Mtb, treatment of individuals with active tuberculosis, mass drug administration with regular antihelminthic drugs, and sanitation control strategies. The results show that a combination of educational campaign, treatment of individuals with active tuberculosis, mass drug administration, and sanitation is the most effective strategy to control helminth-Mtb coinfection. Thus, to effectively control the helminth-Mtb coinfection, we suggest to public health stakeholders to apply intervention strategies that are aimed at controlling helminth infection and the combination of vaccination of infants and treatment of individuals with active tuberculosis.

scholarly journals The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Jennifer L. Reedy ◽  
Paige E. Negoro ◽  
Marianela Feliu ◽  
Allison K. Lord ◽  
Nida S. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Wide Spectrum ◽  
Granulomatous Inflammation ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Exserohilum Rostratum

ABSTRACT Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

scholarly journals Quantitative Proteomics and Lipidomics Analysis of Endoplasmic Reticulum of Macrophage Infected with Mycobacterium tuberculosis

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Najmuddin Mohd Saquib ◽  
Shilpa Jamwal ◽  
Mukul Kumar Midha ◽  
Hirdya Narain Verma ◽  
Venkatasamy Manivel
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Molecular Basis ◽  
Quantitative Proteomics ◽  
Host Response ◽  
Mycobacterial Infection ◽  
Cholesterol Homeostasis ◽  
Functional Attributes ◽  
Rough Er ◽  
The Impact

Even though endoplasmic reticulum (ER) stress associated with mycobacterial infection has been well studied, the molecular basis of ER as a crucial organelle to determine the fate of Mtb is yet to be established. Here, we have studied the ability of Mtb to manipulate the ultrastructural architecture of macrophage ER and found that the ER-phenotypes associated with virulent (H37Rv) and avirulent (H37Ra) strains were different: a rough ER (RER) with the former against a smooth ER (SER) with the later. Further, the functional attributes of these changes were probed by MS-based quantitative proteomics (133 ER proteins) and lipidomics (8 phospholipids). Our omics approaches not only revealed the host pathogen cross-talk but also emphasized how precisely Mtb uses proteins and lipids in combination to give rise to characteristic ER-phenotypes. H37Ra-infected macrophages increased the cytosolic Ca2+ levels by attenuating the ATP2A2 protein and simultaneous induction of PC/PE expression to facilitate apoptosis. However, H37Rv inhibited apoptosis and further controlled the expression of EST-1 and AMRP proteins to disturb cholesterol homeostasis resulting in sustained infection. This approach offers the potential to decipher the specific roles of ER in understanding the cell biology of mycobacterial infection with special reference to the impact of host response.

scholarly journals Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

2011 ◽  
Vol 79 (6) ◽  
pp. 2285-2294 ◽  
Author(s):  
Chien-wen Su ◽  
Yue Cao ◽  
Jess Kaplan ◽  
Mei Zhang ◽  
Wanglin Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Barrier Function ◽  
Helminth Infection ◽  
Scid Mice ◽  
Ultrastructural Changes ◽  
Intestinal Helminth ◽  
Epithelial Barrier ◽  
Epithelial Permeability ◽  
Content Type ◽  
The Impact

ABSTRACTChronic infection with intestinal helminth parasites is a major public health problem, particularly in the developing world, and can have significant effects on host physiology and the immune response to other enteric infections and antigens. The mechanisms underlying these effects are not well understood. In the current study, we investigated the impact of infection with the murine nematode parasiteHeligmosomoides polygyrus, which resides in the duodenum, on epithelial barrier function in the colon. We found thatH. polygyrusinfection produced a significant increase in colonic epithelial permeability, as evidenced by detection of elevated serum levels of the tracer horseradish peroxidase following rectal administration. This loss of normal barrier function was associated with clear ultrastructural changes in the tight junctions of colonic epithelial cells and an alteration in the expression and distribution of the junctional protein E-cadherin. These parasite-induced abnormalities were not observed in SCID mice but did occur in SCID mice that were adoptively transferred with wild-type T cells, indicating a requirement for adaptive immunity. Furthermore, the helminth-induced increase in gut permeability was not seen in STAT6 knockout (KO) mice. Taken together, the results demonstrate that one of the mechanisms by which helminths exert their effects involves the lymphocyte- and STAT6-dependent breakdown of the intestinal epithelial barrier. This increase in epithelial permeability may facilitate the movement of lumenal contents across the mucosa, thus helping to explain how helminth infection can alter the immune response to enteric antigens.

scholarly journals Effect of Protein O-Mannosyltransferase (MSMEG_5447) on M. smegmatis and Its Survival in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Liqiu Jia ◽  
Shanshan Sha ◽  
Shufeng Yang ◽  
Ayaz Taj ◽  
Yufang Ma
Keyword(s):  
Gene Knockout ◽  
Initial Step ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Macrophage Infection ◽  
Host Interaction ◽  
Activation Of Transcription ◽  
Host Innate Immune Response

Protein O-mannosyltransferase (PMT) catalyzes an initial step of protein O-mannosylation of Mycobacterium tuberculosis (Mtb) and plays a crucial role for Mtb survival in the host. To better understand the role of PMT in the host innate immune response during mycobacterial infection, in this study, we utilized Mycobacterium smegmatis pmt (MSMEG_5447) gene knockout strain, ΔM5447, to infect THP-1 cells. Our results revealed that the lack of MSMEG_5447 not only impaired the growth of M. smegmatis in 7H9 medium but also reduced the resistance of M. smegmatis against lysozyme and acidic stress in vitro. Macrophage infection assay showed that ΔM5447 displayed attenuated growth in macrophages at 24 h post-infection. The production of TNF-α and IL-6 and the activation of transcription factor NF-κB were decreased in ΔM5447-infected macrophages, which were further confirmed by transcriptomic analysis. Moreover, ΔM5447 failed to inhibit phagosome–lysosome fusion in macrophages. These findings revealed that PMT played a role in modulating the innate immune responses of the host, which broaden our understanding for functions of protein O-mannosylation in mycobacterium–host interaction.

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