scholarly journals Complement and Chlamydia psittaci: Early Complement-Dependent Events Are Important for DC Migration and Protection During Mouse Lung Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Martin Kohn ◽  
Christian Lanfermann ◽  
Robert Laudeley ◽  
Silke Glage ◽  
Claudia Rheinheimer ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lung Infection ◽  
Chlamydia Psittaci ◽  
Mouse Lung ◽  
Complement Factor ◽  
Experimental Conditions ◽  
Life Threatening ◽  
Complement Factor C3 ◽  
Anaphylatoxin C3a

The zoonotic intracellular bacterium Chlamydia psittaci causes life-threatening pneumonia in humans. During mouse lung infection, complement factor C3 and the anaphylatoxin C3a augment protection against C. psittaci by a so far unknown mechanism. To clarify how complement contributes to the early, innate and the late, specific immune response and resulting protection, this study addresses the amount of C3, the timing when its presence is required as well as the anaphylatoxin receptor(s) mediating its effects and the complement-dependent migration of dendritic cells. Challenge experiments with C. psittaci on various complement KO mice were combined with transient decomplementation by pharmacological treatment, as well as the analysis of in vivo dendritic cells migration. Our findings reveal that a plasma concentration of C3 close to wildtype levels was required to achieve full protection. The diminished levels of C3 of heterozygote C3+/− mice permitted already relative effective protection and improved survival as compared to C3−/− mice, but overall recovery of these animals was delayed. Complement was in particular required during the first days of infection. However, additionally, it seems to support protection at later stages. Migration of CD103+ dendritic cells from the infected lung to the draining lymph node—as prerequisite of antigen presentation—depended on C3 and C3aR and/or C5aR. Our results provide unique mechanistic insight in various aspects of complement-dependent immune responses under almost identical, rather physiological experimental conditions. Our study contributes to an improved understanding of the role of complement, and C3a in particular, in infections by intracellular bacteria.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals In Vivo Efficacies and Pharmacokinetics of DX-619, a Novel Des-Fluoro(6) Quinolone, against Streptococcus pneumoniae in a Mouse Lung Infection Model

2006 ◽  
Vol 50 (3) ◽  
pp. 1122-1122
Author(s):  
Yuichi Fukuda ◽  
Katsunori Yanagihara ◽  
Hideaki Ohno ◽  
Yasuhito Higashiyama ◽  
Yoshitsugu Miyazaki ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lung Infection ◽  
Mouse Lung ◽  
Infection Model

scholarly journals The Complement C3a Receptor Is Critical in Defense against Chlamydia psittaci in Mouse Lung Infection and Required for Antibody and Optimal T Cell Response

2013 ◽  
Vol 209 (8) ◽  
pp. 1269-1278 ◽  
Author(s):  
Pavel Dutow ◽  
Beate Fehlhaber ◽  
Jenny Bode ◽  
Robert Laudeley ◽  
Claudia Rheinheimer ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Lung Infection ◽  
T Cell Response ◽  
Chlamydia Psittaci ◽  
Mouse Lung

scholarly journals Francisella tularensis Enters Macrophages via a Novel Process Involving Pseudopod Loops

2005 ◽  
Vol 73 (9) ◽  
pp. 5892-5902 ◽  
Author(s):  
Daniel L. Clemens ◽  
Bai-Yu Lee ◽  
Marcus A. Horwitz
Keyword(s):  
Francisella Tularensis ◽  
Host Cells ◽  
Live Vaccine Strain ◽  
Complement Factor ◽  
Complement Receptors ◽  
Human Macrophages ◽  
Life Threatening ◽  
Infectious Pathogen ◽  
Complement Factor C3 ◽  
Uptake Mechanisms

ABSTRACT Intracellular bacterial pathogens employ a variety of strategies to invade their eukaryotic host cells. From an ultrastructural standpoint, the processes that bacteria employ to invade their host cells include conventional phagocytosis, coiling phagocytosis, and ruffling/triggered macropinocytosis. In this paper, we describe a novel process by which Francisella tularensis, the agent of tularemia, enters host macrophages. F. tularensis is a remarkably infectious facultative intracellular bacterial parasite—as few as 10 bacteria can cause life-threatening disease in humans. However, the ultrastructure of its uptake and the receptor mechanisms that mediate its uptake have not been reported previously. We have used fluorescence microscopy and electron microscopy to examine the adherence and uptake of a virulent recent clinical isolate of F. tularensis, subspecies tularensis, and the live vaccine strain (LVS), subspecies holarctica, by human macrophages. We show here that both strains of F. tularensis enter human macrophages by a novel process of engulfment within asymmetric, spacious pseudopod loops, a process that differs ultrastructurally from all previously described uptake mechanisms. We demonstrate also that adherence and uptake of F. tularensis by macrophages is strongly dependent upon complement receptors and upon serum with intact complement factor C3 and that uptake requires actin microfilaments. These findings have significant implications for understanding the intracellular biology and virulence of this extremely infectious pathogen.

scholarly journals Phosphorylation of complement factor C3 in vivo

1989 ◽  
Vol 261 (3) ◽  
pp. 1051-1054 ◽  
Author(s):  
S C Martin
Keyword(s):  
Complement System ◽  
Whole Blood ◽  
Complement Factor ◽  
S Protein ◽  
Atp Concentration ◽  
Central Protein ◽  
Complement Factor C3 ◽  
The Complement System

Complement factor C3, the central protein of the complement system, was found to be phosphorylated both in EDTA- and heparin-anticoagulated whole blood and in coagulating blood. Complement S protein (vitronectin) was also found to be phosphorylated under these conditions. Further, purified C3 was found to be a phosphoprotein in vivo, containing 0.15 mol of alkali-labile phosphate/mol of protein. The ATP concentration in plasma was measured and found to be about 2 microM.

scholarly journals Efficacy of Aerosol MP-376, a Levofloxacin Inhalation Solution, in Models of Mouse Lung Infection Due to Pseudomonas aeruginosa

2009 ◽  
Vol 53 (9) ◽  
pp. 3923-3928 ◽  
Author(s):  
Mojgan Sabet ◽  
Courtney E. Miller ◽  
Thomas G. Nolan ◽  
Kathy Senekeo-Effenberger ◽  
Michael N. Dudley ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Infection ◽  
Antimicrobial Agents ◽  
Bacterial Load ◽  
Lung Infection ◽  
In Vivo Studies ◽  
Mouse Lung ◽  
Bacterial Killing ◽  
High Concentrations

ABSTRACT Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.

scholarly journals Interleukin-12 Production Is Required for Chlamydial Antigen-Pulsed Dendritic Cells To Induce Protection against Live Chlamydia trachomatis Infection

1999 ◽  
Vol 67 (4) ◽  
pp. 1763-1769 ◽  
Author(s):  
Hang Lu ◽  
Guangming Zhong
Keyword(s):  
Dendritic Cells ◽  
Chlamydial Infection ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Mouse Lung ◽  
Infection Model ◽  
Mouse Bone Marrow ◽  
Th1 Cell ◽  
Dominant Response

ABSTRACT Immunization with dendritic cells pulsed ex vivo with antigens has been successfully used to elicit primary antigen-specific immune responses. We report that mouse bone marrow-derived dendritic cells pulsed with inactivated chlamydial organisms induced strong protection against live chlamydial infection in a mouse lung infection model. Either the dendritic cells or chlamydial organisms alone or macrophages similarly pulsed with chlamydial organisms failed to induce any significant protection. These observations suggest that dendritic cells can efficiently process and present chlamydial antigens to naive T cells in vivo. Mice immunized with the chlamydia-pulsed dendritic cells preferentially developed a Th1 cell-dominant response while mice immunized with the other immunogens did not, suggesting a correlation between a Th1 cell-dominant response and protection against chlamydial infection. We further found that dendritic cells produced a large amount of interleukin 12 (IL-12) upon ex vivo pulsing with inactivated chlamydial organisms, which may allow the dendritic cells to direct a Th1 cell-dominant response. Dendritic cells from mice deficient in the IL-12 p40 gene failed to produce IL-12 after a similar ex vivo pulse with chlamydial organisms, and more importantly, immunization with these dendritic cells failed to induce a Th1 cell-dominant response and did not induce strong protection against chlamydial infection. Thus, the ability of dendritic cells to efficiently process and present chlamydial antigens and to produce IL-12 upon chlamydial-organism stimulation are both required for the induction of protection against chlamydial infection. This information may be useful for the further design of effective chlamydial vaccines.

scholarly journals Survival of Chlamydia muridarum within Dendritic Cells

2007 ◽  
Vol 75 (8) ◽  
pp. 3707-3714 ◽  
Author(s):  
Jose Rey-Ladino ◽  
Xiaozhou Jiang ◽  
Brent R. Gabel ◽  
Caixia Shen ◽  
Robert C. Brunham
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Lung Infection ◽  
T Cell Memory ◽  
Mouse Lung ◽  
Term Survival ◽  
Chlamydia Muridarum ◽  
Antigen Presenting

ABSTRACT Immune responses to Chlamydia trachomatis underlay both immunity and immunopathology. Immunopathology in turn has been attributed to chronic persistent infection with persistence being defined as the presence of organisms in the absence of replication. We hypothesized that dendritic cells (DCs) play a central role in Chlamydia immunity and immunopathology by favoring the long-term survival of C. muridarum. This hypothesis was examined based on (i) direct staining of Chlamydia in infected DCs to evaluate the development of inclusions, (ii) titration of infected DCs on HeLa cells to determine cultivability, and (iii) transfer of Chlamydia-infected DCs to naive mice to evaluate infectivity. The results show that Chlamydia survived within DCs and developed both typical and atypical inclusions that persisted in a subpopulation of DCs for more than 9 days after infection. Since the cultivability of Chlamydia from DCs onto HeLa was lower than that estimated by the number of inclusions in DCs, this suggests that the organisms may be in state of persistence. Intranasal transfer of long-term infected DCs or DCs purified from the lungs of infected mice caused mouse lung infection, suggesting that in addition to persistent forms, infective Chlamydia organisms also developed within chronically infected DCs. Interestingly, after in vitro infection with Chlamydia, most DCs died. However, Chlamydia appeared to survive in a subpopulation of DCs that resisted infection-induced cell death. Surviving DCs efficiently presented Chlamydia antigens to Chlamydia-specific CD4+ T cells, suggesting that the bacteria are able to both direct their own survival and still allow DC antigen-presenting function. Together, these results raise the possibility that Chlamydia-infected DCs may be central to the maintenance of T-cell memory that underlies both immunity and immunopathology.

scholarly journals The murine cytomegalovirus MCK-2 facilitates in vivo infection transfer from dendritic cells to salivary gland acinar cells.

2021 ◽  
Author(s):  
Jiawei Ma ◽  
Kimberley Bruce ◽  
Philip G. Stevenson ◽  
Helen E. Farrell
Keyword(s):  
Dendritic Cells ◽  
Salivary Gland ◽  
Epithelial Cells ◽  
Salivary Glands ◽  
Immune Evasion ◽  
Acinar Cells ◽  
Lung Infection ◽  
Human Cmv

The cytomegaloviruses (CMVs) spread systemically via myeloid cells and demonstrate a broad tissue tropism. Human CMV (HCMV) UL128 encodes a component of the virion pentameric complex (PC) that is important for entry into epithelial cells and cell-cell spread in vitro . It possesses N-terminal amino acid sequences similar to C-C chemokines. While the species-specificity of HCMV precludes confirmation of UL128 function in vivo , UL128-like counterparts in experimental animals have demonstrated a role for salivary gland infection. How they achieve this has not been defined, although effects on monocyte tropism and immune evasion have been proposed. By tracking infected cells following lung infection, we show that although the UL128-like protein in mouse CMV (MCMV; designated MCK-2), facilitated entry into lung macrophages, it was dispensable for subsequent viremia mediated by CD11c + dendritic cells (DC) and extravasation to the salivary glands. Notably, MCK-2 was important for transfer of MCMV infection from DC to salivary gland acinar epithelial cells. Acinar cell infection of MCMVs deleted of MCK-2 was not rescued by T-cell depletion, arguing against an immune evasion mechanism for MCK-2 in the salivary glands. In contrast to lung infection, peritoneal MCMV inoculation yields a mixed monocyte/DC viremia. In this setting, MCK-2 again promoted DC-dependent infection of salivary gland acinar cells, but it was not required for monocyte-dependent spread to the lung. Thus, the action of MCK-2 in MCMV spread was specific to DC-acinar cell interaction. IMPORTANCE Cytomegaloviruses (CMVs) establish myeloid cell-associated viremias and persistent shedding from the salivary glands. In vitro studies with human CMV (HCMV) have implicated HCMV UL128 in epithelial tropism, but its role in vivo is unknown. Here we analysed how a murine CMV (CMV) protein with similar physical properties - designated MCK-2 - contributes to host colonization. We demonstrate that MCK-2 is dispensable for the initial systemic spread from primary infection sites, but within the salivary gland facilitates transfer of infection from dendritic cells (DC) to epithelial acinar cells. Virus transfer from extravasated monocytes to the lungs did not require MCK-2, indicating a tissue-specific effect. These results provide new information about how persistent viral tropism determinants operate in vivo .

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