TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

The genetic basis of natural susceptibility to progressiveCryptococcus neoformansinfection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated withC. neoformanssusceptibility (Cnes1,Cnes2, andCnes3). To validate and characterize the role ofCnes2during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2mice 35 days afterC. neoformansinfection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+dendritic cells, and CD4+cells in B6.CBA-Cnes2than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2mice. Taken together, these findings demonstrate that theCnes2interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization followingC. neoformansinfection.

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Nocardia farcinica Activates Human Dendritic Cells and Induces Secretion of Interleukin-23 (IL-23) Rather than IL-12p70

Infection and Immunity ◽

10.1128/iai.00741-12 ◽

2012 ◽

Vol 80 (12) ◽

pp. 4195-4202 ◽

Cited By ~ 6

Author(s):

Martin Eisenblätter ◽

Ariane Buchal ◽

Hermine Gayum ◽

Edith Jasny ◽

Pablo Renner Viveros ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Characteristic Functions ◽

Interleukin 12 ◽

Adjuvant Effect ◽

Phagocytic Capacity ◽

Necrosis Factor Alpha ◽

Content Type ◽

Nocardia Farcinica

ABSTRACTStudying the interaction of dendritic cells (DCs) with bacteria controlled by T-cell-mediated immune responses may reveal novel adjuvants for the induction of cellular immunity. Murine studies and the observation that nocardias infect predominantly immunosuppressed patients have suggested that these bacteria may possess an adjuvant potential. Moreover, adjuvants on the basis of the nocardial cell wall have been applied in clinical studies. Since the handling of adjuvants by DCs may determine the type of immune responses induced by a vaccine, the present study aimed at investigating the interaction of immature human monocyte-derived DCs with live or inactivatedNocardia farcinicain vitroand determining the cellular phenotypic changes as well as alterations in characteristic functions, such as phagocytosis, induction of T-cell proliferation, and cytokine secretion. Human DCs ingestedN. farcinicaand eradicated the bacterium intracellularly. DCs exposed to inactivatedN. farcinicawere activated, i.e., they developed a mature phenotype, downregulated their phagocytic capacity, and stimulated allogeneic T cells in mixed leukocyte reactions. Soluble factors were not involved in this process. To elucidate the potential adjuvant effect ofN. farcinicaon the induction of T-cell-mediated immune responses, we characterized the cytokines produced by nocardia-exposed DCs and detected substantial amounts of tumor necrosis factor alpha (TNF-α) and interleukin-12 p40 (IL-12p40). However, nocardia-treated DCs secreted only small amounts of IL-12p70, which were significantly smaller than the amounts of IL-23. Thus,N. farcinicaactivates DCs, but adjuvants based on this bacterium may have only a limited capacity to induce Th1 immune responses.

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Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice

Infection and Immunity ◽

10.1128/iai.01389-10 ◽

2011 ◽

Vol 79 (8) ◽

pp. 3204-3215 ◽

Cited By ~ 8

Author(s):

Jagjit S. Yadav ◽

Suman Pradhan ◽

Renuka Kapoor ◽

Hansraj Bangar ◽

Benjamin B. Burzynski ◽

...

Keyword(s):

Survival Time ◽

Inbred Mice ◽

Bacterial Load ◽

Host Susceptibility ◽

Chromosome 17 ◽

Sex Bias ◽

Striking Difference ◽

Chromosome 11 ◽

Content Type ◽

Genome Wide

ABSTRACTMechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores ofBacillus anthracisAmes, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genome-wide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C×DF2 population revealed a significant QTL (designatedRpai1forresistance topulmonaryanthraxinfection, locus1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains.

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Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus—mediated interleukin-12

Journal of Neurosurgery ◽

10.3171/jns.2002.97.3.0611 ◽

2002 ◽

Vol 97 (3) ◽

pp. 611-618 ◽

Cited By ~ 39

Author(s):

Ryuya Yamanaka ◽

Susan A. Zullo ◽

Jay Ramsey ◽

Naoki Yajima ◽

Naoto Tsuchiya ◽

...

Keyword(s):

Dendritic Cells ◽

Brain Tumor ◽

Tumor Antigens ◽

Semliki Forest Virus ◽

Tumor Regression ◽

Interleukin 12 ◽

Content Type ◽

Retrovirus Vector ◽

Induced Apoptosis ◽

Fine Print

Object. The authors evaluated dendritic cell (DC)—based immunotherapy for malignant brain tumor to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from bone marrow and pulsed with phosphate-buffered saline, Semliki Forest virus (SFV)—LacZ, retrovirus vector GCsap—interleukin (IL)-12, and SFV—IL-12, respectively, to treat mice bearing brain tumors of the B16 cell line. The results indicated that therapeutic immunization with DCs pulsed with SFV—IL-12 prolonged the survival of mice with established tumors. Semliki Forest virus induced apoptosis in DCs, which in turn facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated IL-12 may be an excellent step in the development of new cancer vaccines. Intratumorally injected DCs that have been transiently transduced with IL-12 do not require pulsing of a source of tumor antigens to induce tumor regression.

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Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

Infection and Immunity ◽

10.1128/iai.00736-12 ◽

2013 ◽

Vol 81 (4) ◽

pp. 1064-1077 ◽

Cited By ~ 24

Author(s):

Adriana Pina ◽

Eliseu Frank de Araujo ◽

Maíra Felonato ◽

Flávio V. Loures ◽

Claudia Feriotti ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Responses ◽

Effector T Cells ◽

Interleukin 12 ◽

Content Type ◽

Cell Responses ◽

Plasmacytoid Dcs

ABSTRACTThe protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response toParacoccidioides brasiliensisinfection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified thatP. brasiliensisinfection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis.

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MyD88-Dependent Recruitment of Monocytes and Dendritic Cells Required for Protection from Pulmonary Burkholderia mallei Infection

Infection and Immunity ◽

10.1128/iai.05819-11 ◽

2011 ◽

Vol 80 (1) ◽

pp. 110-120 ◽

Cited By ~ 12

Author(s):

Andrew Goodyear ◽

Ryan Troyer ◽

Helle Bielefeldt-Ohmann ◽

Steven Dow

Keyword(s):

Dendritic Cells ◽

Nk Cell ◽

Interleukin 12 ◽

Burkholderia Mallei ◽

Wild Type ◽

Survival Times ◽

Content Type ◽

Monocyte Chemoattractant Protein 1 ◽

Inflammatory Monocytes ◽

Ifn Γ

ABSTRACTThe Gram-negative bacteriumBurkholderia malleicauses rapidly fatal illness in equines and humans when contracted by inhalation and also has the potential to be used as a bioweapon. However, little is known regarding the early innate immune responses and signaling mechanisms required to generate protection from pneumonicB. malleiinfection. We showed previously that monocyte chemoattractant protein 1 (MCP-1) was a critical chemokine required for protection from pneumonicB. malleiinfection. We have now extended those studies to identify key Toll-like receptor (TLR) signaling pathways, effector cells, and cytokines required for protection from respiratoryB. malleiinfection. We found that MyD88−/−mice were highly susceptible to pulmonary challenge withB. malleiand had significantly short survival times, increased bacterial burdens, and severe organ pathology compared to wild-type mice. Notably, MyD88−/−mice had significantly fewer monocytes and dendritic cells (DCs) in lung tissues and airways than infected wild-type mice despite markedly higher bacterial burdens. The MyD88−/−mice were also completely unable to produce gamma interferon (IFN-γ) at any time points following infection. In wild-type mice, NK cells were the primary cells producing IFN-γ in the lungs followingB. malleiinfection, while DCs and monocytes were the primary cellular sources of interleukin-12 (IL-12) production. Treatment with recombinant IFN-γ (rIFN-γ) was able to significantly restore protective immunity in MyD88−/−mice. Thus, we conclude that the MyD88-dependent recruitment of inflammatory monocytes and DCs to the lungs and the local production of IL-12, followed by NK cell production of IFN-γ, are the key initial cellular responses required for early protection fromB. malleiinfection.

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Platelets Enhance Dendritic Cell Responses againstStaphylococcus aureusthrough CD40-CD40L

Infection and Immunity ◽

10.1128/iai.00186-18 ◽

2018 ◽

Vol 86 (9) ◽

Cited By ~ 8

Author(s):

Sharmeen Nishat ◽

Leah M. Wuescher ◽

Randall G. Worth

Keyword(s):

Staphylococcus Aureus ◽

Dendritic Cells ◽

Dendritic Cell ◽

Critical Role ◽

Interleukin 12 ◽

Necrosis Factor Alpha ◽

Content Type ◽

Enhanced Production ◽

Bacterial Uptake ◽

Direct Killing

ABSTRACTStaphylococcus aureusis a major human pathogen that can cause mild to severe life-threatening infections in many tissues and organs. Platelets are known to participate in protection againstS. aureusby direct killing and by enhancing the activities of neutrophils and macrophages in clearingS. aureusinfection. Platelets have also been shown to induce monocyte differentiation into dendritic cells and to enhance activation of dendritic cells. Therefore, in the present study, we explored the role of platelets in enhancing bone marrow-derived dendritic cell (BMDC) function againstS. aureus. We observed a significant increase in dendritic cell phagocytosis and intracellular killing of a methicillin-resistantStaphylococcus aureus(MRSA) strain (USA300) by thrombin-activated platelets or their releasates. Enhancement of bacterial uptake and killing by DCs is mediated by platelet-derived CD40L. Coculture of USA300 and BMDCs in the presence of thrombin-activated platelet releasates invokes upregulation of the maturation marker CD80 on DCs and enhanced production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), and IL-6. Overall, these observations support our hypothesis that platelets play a critical role in the host defense againstS. aureusinfection. Platelets stimulate DCs, leading to direct killing ofS. aureusand enhanced DC maturation, potentially leading to adaptive immune responses againstS. aureus.

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Prophylactic and Therapeutic Vaccination Using Dendritic Cells Primed with Peptide 10 Derived from the 43-Kilodalton Glycoprotein of Paracoccidioides brasiliensis

Clinical and Vaccine Immunology ◽

10.1128/cvi.05414-11 ◽

2011 ◽

Vol 19 (1) ◽

pp. 23-29 ◽

Cited By ~ 33

Author(s):

A. Magalhães ◽

K. S. Ferreira ◽

S. R. Almeida ◽

J. D. Nosanchuk ◽

L. R. Travassos ◽

...

Keyword(s):

Dendritic Cells ◽

Protective Efficacy ◽

Paracoccidioides Brasiliensis ◽

Interleukin 12 ◽

Infection Model ◽

Content Type ◽

Model Combining ◽

Pulmonary Damage ◽

The Impact

ABSTRACTVaccination with peptide 10 (P10), derived from theParacoccidioides brasiliensisglycoprotein 43 (gp43), induces a Th1 response that protects mice in an intratrachealP. brasiliensisinfection model. Combining P10 with complete Freund's adjuvant (CFA) or other adjuvants further increases the peptide's antifungal effect. Since dendritic cells (DCs) are up to 1,000-fold more efficient at activating T cells than CFA, we examined the impact of P10-primed bone-marrow-derived DC vaccination in mice. Splenocytes from mice immunized with P10 were stimulatedin vitrowith P10 or P10-primed DCs. T cell proliferation was significantly increased in the presence of P10-primed DCs compared to the peptide. The protective efficacy of P10-primed DCs was studied in an intratrachealP. brasiliensismodel in BALB/c mice. Administration of P10-primed DCs prior to (via subcutaneous vaccination) or weeks after (via either subcutaneous or intravenous injection)P. brasiliensisinfection decreased pulmonary damage and significantly reduced fungal burdens. The protective response mediated by the injection of primed DCs was characterized mainly by an increased production of gamma interferon (IFN-γ) and interleukin 12 (IL-12) and a reduction in IL-10 and IL-4 compared to those of infected mice that received saline or unprimed DCs. Hence, our data demonstrate the potential of P10-primed DCs as a vaccine capable of both the rapid protection against the development of serious paracoccidioidomycosis or the treatment of establishedP. brasiliensisdisease.

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Interleukin-12-Producing CD103+CD11b−CD8+Dendritic Cells Are Responsible for Eliciting Gut Intraepithelial Lymphocyte Response against Encephalitozoon cuniculi

Infection and Immunity ◽

10.1128/iai.00820-15 ◽

2015 ◽

Vol 83 (12) ◽

pp. 4719-4730 ◽

Cited By ~ 6

Author(s):

Magali M. Moretto ◽

Danielle I. Harrow ◽

Teresa S. Hawley ◽

Imtiaz A. Khan

Keyword(s):

Dendritic Cells ◽

Natural Infection ◽

Organ Transplant ◽

Intraepithelial Lymphocyte ◽

Interleukin 12 ◽

Encephalitozoon Cuniculi ◽

Mesenteric Lymph Nodes ◽

Content Type ◽

Specific Subset

Microsporidia, which belong to the kingdomFungi, are important opportunistic pathogens in HIV-infected populations and organ transplant recipients that are often associated with a broad range of symptoms, such as diarrhea, nephritis, and encephalitis. Natural infection occurs via the oral route, and as a consequence, gut immunity plays an important role in restricting the dissemination of these pathogens. Studies from our laboratory have reported that the pathogens induce a rapid intraepithelial lymphocyte (IEL) response important for host protection. Although mucosal dendritic cells (DC) are likely involved in triggering an antigen-specific IEL response, the specific subset(s) responsible has yet to be identified. Toward this goal, we demonstrate a very important role for mucosal CD11b−CD8+DC in the initiation of an antigen-specific IELin vivo. Effectively, afterEncephalitozoon cuniculiinfection, CD11b−CD8+DC were activated in the lamina propria (LP) and acquired the ability to process retinoic acid (RA). However, this subset did not produce interleukin 12 (IL-12) but upregulated CD103, which is essential for migration to the mesenteric lymph nodes (MLN). Interestingly, CD103+CD11b−CD8+DC in the MLN, in addition to processing RA, also secreted IL-12 and were responsible for gut imprinting specificity on mucosal CD8 T cells. To the best of our knowledge, this is the first report describing the importance of MLN CD103+CD11b−CD8+DC isolated from infected animals in the generation of an IEL response against a live pathogen.

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CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

Infection and Immunity ◽

10.1128/iai.00962-09 ◽

2010 ◽

Vol 78 (5) ◽

pp. 2099-2107 ◽

Cited By ~ 9

Author(s):

Bryan L. Eppert ◽

Gregory T. Motz ◽

Brian W. Wortham ◽

Jennifer L. Flury ◽

Michael T. Borchers

Keyword(s):

Pseudomonas Aeruginosa ◽

T Cells ◽

Dendritic Cells ◽

Host Defense ◽

Pulmonary Infection ◽

Surface Expression ◽

T Cell Response ◽

Interleukin 12 ◽

Myeloid Dendritic Cells ◽

Proinflammatory Mediators

ABSTRACT CCR7 is a chemokine receptor expressed on the surfaces of T cells, B cells, and mature dendritic cells that controls cell migration in response to the cognate ligands CCL19 and CCL21. CCR7 is critical for the generation of an adaptive T cell response. However, the roles of CCR7 in the host defense against pulmonary infection and innate immunity are not well understood. We investigated the role of CCR7 in the host defense against acute pulmonary infection with Pseudomonas aeruginosa. We intranasally infected C57BL/6 mice with P. aeruginosa and characterized the expression of CCR7 ligands and the surface expression of CCR7 on pulmonary leukocytes. In response to infection, expression of CCL19 and expression of CCL21 were oppositely regulated, and myeloid dendritic cells upregulated CCR7 expression. We further examined the effects of CCR7 deficiency on the inflammatory response to P. aeruginosa infection. We infected Ccr7 −/− and wild-type mice with P. aeruginosa and characterized the accumulation of pulmonary leukocytes, production of proinflammatory mediators, neutrophil activation, and bacterial clearance. CCR7 deficiency led to an accumulation of myeloid dendritic cells and T cells in the lung in response to infection. CCR7 deficiency resulted in higher expression of CD80 and CD86 on dendritic cells; increased production of interleukin-12/23p40 (IL-12/23p40), gamma interferon (IFN-γ), and IL-1α; increased neutrophil respiratory burst; and, ultimately, increased clearance of acute P. aeruginosa infection. In conclusion, our results suggest that CCR7 deficiency results in a heightened proinflammatory environment in response to acute pulmonary P. aeruginosa infection and contributes to more efficient clearance.

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