CCR5 Is Involved in Interruption of Pregnancy in Mice Infected with Toxoplasma gondii during Early Pregnancy

ABSTRACT Toxoplasmosis can cause abortion in pregnant humans and other animals; however, the mechanism of abortion remains unknown. C-C chemokine receptor type 5 (CCR5) is essential for host defense against Toxoplasma gondii infection. To investigate the relationship between CCR5 and abortion in toxoplasmosis, we inoculated wild-type and CCR5-deficient (CCR5−/−) mice with T. gondii tachyzoites intraperitoneally on day 3 of pregnancy (embryonic day 3 [E3]). The pregnancy rate decreased as pregnancy progressed in infected wild-type mice. Histopathologically, no inflammatory lesions were observed in the fetoplacental tissues. Although wild-type mice showed a higher parasite burden at the implantation sites than did CCR5−/− mice at E6 (3 days postinfection [dpi]), T. gondii antigen was detected only in the uterine tissue and not in the fetoplacental tissues. At E8 (5 dpi), the embryos in infected wild-type mice showed poor development compared with those of infected CCR5−/− mice, and apoptosis was observed in poorly developed embryos. Compared to uninfected mice, infected wild-type mice showed increased CCR5 expression at the implantation site at E6 and E8. Furthermore, analyses of mRNA expression in the uterus of nonpregnant and pregnant mice suggested that a lack of the CCR5 gene and the downregulation of tumor necrosis factor alpha (TNF-α) and CCL3 expression at E6 (3 dpi) are important factors for the maintenance of pregnancy following T. gondii infection. These results suggested that CCR5 signaling is involved in embryo loss in T. gondii infection during early pregnancy and that apoptosis is associated with embryo loss rather than direct damage to the fetoplacental tissues.

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Differential Gamma Interferon- and Tumor Necrosis Factor Alpha-Driven Cytokine Response Distinguishes Acute Infection of a Metatherian Host with Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00173-17 ◽

2017 ◽

Vol 85 (6) ◽

Cited By ~ 7

Author(s):

Shannon L. Donahoe ◽

David N. Phalen ◽

Bronwyn M. McAllan ◽

Denis O'Meally ◽

Milton M. McAllister ◽

...

Keyword(s):

Immune Response ◽

Toxoplasma Gondii ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Neospora Caninum ◽

Necrosis Factor Alpha ◽

Content Type ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Toxoplasma gondii and Neospora caninum (both Apicomplexa) are closely related cyst-forming coccidian parasites that differ significantly in their host ranges and ability to cause disease. Unlike eutherian mammals, Australian marsupials (metatherian mammals) have long been thought to be highly susceptible to toxoplasmosis and neosporosis because of their historical isolation from the parasites. In this study, the carnivorous fat-tailed dunnart (Sminthopsis crassicaudata) was used as a disease model to investigate the immune response and susceptibility to infection of an Australian marsupial to T. gondii and N. caninum. The disease outcome was more severe in N. caninum-infected dunnarts than in T. gondii-infected dunnarts, as shown by the severity of clinical and histopathological features of disease and higher tissue parasite burdens in the tissues evaluated. Transcriptome sequencing (RNA-seq) of spleens from infected dunnarts and mitogen-stimulated dunnart splenocytes was used to define the cytokine repertoires. Changes in mRNA expression during the time course of infection were measured using quantitative reverse transcription-PCR (qRT-PCR) for key Th1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), Th2 (interleukin 4 [IL-4] and IL-6), and Th17 (IL-17A) cytokines. The results show qualitative differences in cytokine responses by the fat-tailed dunnart to infection with N. caninum and T. gondii. Dunnarts infected with T. gondii were capable of mounting a more effective Th1 immune response than those infected with N. caninum, indicating the role of the immune response in the outcome scenarios of parasite infection in this marsupial mammal.

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Tumor Necrosis Factor Alpha Production from CD8+T Cells Mediates Oviduct Pathological Sequelae following Primary Genital Chlamydia muridarum Infection

Infection and Immunity ◽

10.1128/iai.05022-11 ◽

2011 ◽

Vol 79 (7) ◽

pp. 2928-2935 ◽

Cited By ~ 89

Author(s):

Ashlesh K. Murthy ◽

Weidang Li ◽

Bharat K. R. Chaganty ◽

Sangamithra Kamalakaran ◽

M. Neal Guentzel ◽

...

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Content Type ◽

Chlamydia Muridarum ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACTThe immunopathogenesis ofChlamydia trachomatis-induced oviduct pathological sequelae is not well understood. Mice genetically deficient in perforin (perforin−/−mice) or tumor necrosis factor alpha (TNF-α) production (TNF-α−/−mice) displayed comparable vaginal chlamydial clearance rates but significantly reduced oviduct pathology (hydrosalpinx) compared to that of wild-type mice. Since both perforin and TNF-α are effector mechanisms of CD8+T cells, we evaluated the role of CD8+T cells during genitalChlamydia muridaruminfection and oviduct sequelae. Following vaginal chlamydial challenge, (i) mice deficient in TAP I (and therefore the major histocompatibility complex [MHC] I pathway and CD8+T cells), (ii) wild-type mice depleted of CD8+T cells, and (iii) mice genetically deficient in CD8 (CD8−/−mice) all displayed similar levels of vaginal chlamydial clearance but significantly reduced hydrosalpinx, compared to those of wild-type C57BL/6 mice, suggesting a role for CD8+T cells in chlamydial pathogenesis. Repletion of CD8−/−mice with wild-type or perforin−/−, but not TNF-α−/−, CD8+T cells at the time of challenge restored hydrosalpinx to levels observed in wild-type C57BL/6 mice, suggesting that TNF-α production from CD8+T cells is important for pathogenesis. Additionally, repletion of TNF-α−/−mice with TNF-α+/+CD8+T cells significantly enhanced the incidence of hydrosalpinx and oviduct dilatation compared to those of TNF-α−/−mice but not to the levels found in wild-type mice, suggesting that TNF-α production from CD8+T cells and non-CD8+cells cooperates to induce optimal oviduct pathology following genital chlamydial infection. These results provide compelling new evidence supporting the contribution of CD8+T cells and TNF-α production toChlamydia-induced reproductive tract sequelae.

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Toxoplasma gondii Cyclophilin 18-Mediated Production of Nitric Oxide Induces Bradyzoite Conversion in a CCR5-Dependent Manner

Infection and Immunity ◽

10.1128/iai.00361-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 3686-3695 ◽

Cited By ~ 30

Author(s):

Hany M. Ibrahim ◽

Hiroshi Bannai ◽

Xuenan Xuan ◽

Yoshifumi Nishikawa

Keyword(s):

Nitric Oxide ◽

Toxoplasma Gondii ◽

Inflammatory Responses ◽

Interleukin 12 ◽

Dependent Manner ◽

Independent Manner ◽

Necrosis Factor Alpha ◽

Parasite Multiplication ◽

Factor Alpha

ABSTRACT Toxoplasma gondii modulates pro- and anti-inflammatory responses to regulate parasite multiplication and host survival. Pressure from the immune response causes the conversion of tachyzoites into slowly dividing bradyzoites. The regulatory mechanisms involved in this switch are poorly understood. The aim of this study was to investigate the immunomodulatory role of T. gondii cyclophilin 18 (TgCyp18) in macrophages and the consequences of the cellular responses on the conversion machinery. Recombinant TgCyp18 induced the production of nitric oxide (NO), interleukin-12 (IL-12), and tumor necrosis factor alpha through its binding with cysteine-cysteine chemokine receptor 5 (CCR5) and the production of gamma interferon and IL-6 in a CCR5-independent manner. Interestingly, the treatment of macrophages with TgCyp18 resulted in the inhibition of parasite growth and an enhancement of the conversion into bradyzoites via NO in a CCR5-dependent manner. In conclusion, T. gondii possesses sophisticated mechanisms to manipulate host cell responses in a TgCyp18-mediated process.

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Fusobacterium nucleatum Infection of Colonic Cells Stimulates MUC2 Mucin and Tumor Necrosis Factor Alpha

Infection and Immunity ◽

10.1128/iai.05118-11 ◽

2011 ◽

Vol 79 (7) ◽

pp. 2597-2607 ◽

Cited By ~ 59

Author(s):

Poonam Dharmani ◽

Jaclyn Strauss ◽

Christian Ambrose ◽

Emma Allen-Vercoe ◽

Kris Chadee

Keyword(s):

Tumor Necrosis ◽

Bacterial Species ◽

Fusobacterium Nucleatum ◽

Mucin Secretion ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Colonic Cells ◽

Necrosis Factor

ABSTRACTThe etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial speciesFusobacterium nucleatumis a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasiveF. nucleatumisolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-α) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only liveF. nucleatuminduced mucin secretion and TNF-α expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasiveF. nucleatumisolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal thatF. nucleatummay represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis.

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The Host Antimicrobial Protein Calgranulin C Participates in the Control ofCampylobacter jejuniGrowth via Zinc Sequestration

Infection and Immunity ◽

10.1128/iai.00234-18 ◽

2018 ◽

Vol 86 (6) ◽

Cited By ~ 6

Author(s):

Janette M. Shank ◽

Brittni R. Kelley ◽

Joseph W. Jackson ◽

Jessica L. Tweedie ◽

Dana Franklin ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Serum Levels ◽

Interleukin 10 ◽

Poultry Meat ◽

Antimicrobial Protein ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Content Type ◽

Full Resolution ◽

Factor Alpha

ABSTRACTCampylobacter jejuniis a leading cause of bacterially derived gastroenteritis worldwide.Campylobacteris most commonly acquired through the consumption of undercooked poultry meat or through drinking contaminated water. Following ingestion,Campylobacteradheres to the intestinal epithelium and mucus layer, causing toxin-mediated inflammation and inhibition of fluid reabsorption. Currently, the human response to infection is relatively unknown, and animal hosts that model these responses are rare. As such, we examined patient fecal samples for the accumulation of the neutrophil protein calgranulin C during infection withCampylobacter jejuni. In response to infection, calgranulin C was significantly increased in the feces of humans. To determine whether calgranulin C accumulation occurs in an animal model, we examined disease in ferrets. Ferrets were effectively infected byC. jejuni, with peak fecal loads observed at day 3 postinfection and full resolution by day 12. Serum levels of interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α) significantly increased in response to infection, which resulted in leukocyte trafficking to the colon. As a result, calgranulin C increased in the feces of ferrets at the time whenC. jejuniloads decreased. Further, the addition of purified calgranulin C toC. jejunicultures was found to inhibit growth in a zinc-dependent manner. These results suggest that upon infection withC. jejuni, leukocytes trafficked to the intestine release calgranulin C as a mechanism for inhibitingC. jejunigrowth.

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Enterococcus faecalisDemonstrates Pathogenicity through Increased Attachment in anEx VivoPolymicrobial Pulpal Infection

Infection and Immunity ◽

10.1128/iai.00871-17 ◽

2018 ◽

Vol 86 (5) ◽

Cited By ~ 3

Author(s):

Wayne Nishio Ayre ◽

Genevieve Melling ◽

Camille Cuveillier ◽

Madhan Natarajan ◽

Jessica L. Roberts ◽

...

Keyword(s):

Inflammatory Response ◽

Host Response ◽

Ex Vivo ◽

Necrosis Factor Alpha ◽

Content Type ◽

Streptococcus Anginosus ◽

Cell Counts ◽

Tnf Α ◽

Factor Alpha ◽

Infection Types

ABSTRACTThis study investigated the host response to a polymicrobial pulpal infection consisting ofStreptococcus anginosusandEnterococcus faecalis, bacteria commonly implicated in dental abscesses and endodontic failure, using a validatedex vivorat tooth model. Tooth slices were inoculated with planktonic cultures ofS. anginosusorE. faecalisalone or in coculture atS. anginosus/E. faecalisratios of 50:50 and 90:10. Attachment was semiquantified by measuring the area covered by fluorescently labeled bacteria. Host response was established by viable histological cell counts, and inflammatory response was measured using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry. A significant reduction in cell viability was observed for single and polymicrobial infections, with no significant differences between infection types (∼2,000 cells/mm2for infected pulps compared to ∼4,000 cells/mm2for uninfected pulps).E. faecalisdemonstrated significantly higher levels of attachment (6.5%) thanS. anginosusalone (2.3%) and mixed-species infections (3.4% for 50:50 and 2.3% for 90:10), with a remarkable affinity for the pulpal vasculature. Infections withE. faecalisdemonstrated the greatest increase in tumor necrosis factor alpha (TNF-α) (47.1-fold forE. faecalis, 14.6-fold forS. anginosus, 60.1-fold for 50:50, and 25.0-fold for 90:10) and interleukin 1β (IL-1β) expression (54.8-fold forE. faecalis, 8.8-fold forS. anginosus, 54.5-fold for 50:50, and 39.9-fold for 90:10) compared to uninfected samples. Immunohistochemistry confirmed this, with the majority of inflammation localized to the pulpal vasculature and odontoblast regions. Interestingly,E. faecalissupernatant and heat-killedE. faecalistreatments were unable to induce the same inflammatory response, suggestingE. faecalispathogenicity in pulpitis is linked to its greater ability to attach to the pulpal vasculature.

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Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00027-20 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 1

Author(s):

Rachel S. Coombs ◽

Matthew L. Blank ◽

Elizabeth D. English ◽

Yaw Adomako-Ankomah ◽

Ifeanyi-Chukwu Samuel Urama ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Interferon Gamma ◽

Neospora Caninum ◽

Ectopic Expression ◽

Parasite Burden ◽

Interleukin 12 ◽

Content Type ◽

Ifn Γ ◽

And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

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Tumor Necrosis Factor Alpha-Induced Apoptosis Requires p73 and c-ABL Activation Downstream of RB Degradation

Molecular and Cellular Biology ◽

10.1128/mcb.24.10.4438-4447.2004 ◽

2004 ◽

Vol 24 (10) ◽

pp. 4438-4447 ◽

Cited By ~ 45

Author(s):

B. Nelson Chau ◽

Tung-Ti Chen ◽

Yisong Y. Wan ◽

James DeGregori ◽

Jean Y. J. Wang

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Abl Tyrosine Kinase ◽

Tnf Α ◽

Factor Alpha ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACT The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-α) to induce apoptosis. We show here the identification of two apoptotic effectors, i.e., c-ABL tyrosine kinase and p73, which are activated by TNF-α following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-α does not activate c-ABL. RB-MI also inhibits TNF-α-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-α in human cell lines and mouse fibroblasts. Thymocytes isolated from RbMI/MI , Abl −/−, or p73 −/− mice are resistant to TNF-α-induced apoptosis compared to their wild-type counterparts. This is in contrast to p53 −/− thymocytes, which exhibit a wild-type level of apoptosis in response to TNF-α. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-α, in addition to their role in promoting DNA damage-associated cell death.

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Keratins Modulate c-Flip/Extracellular Signal-Regulated Kinase 1 and 2 Antiapoptotic Signaling in Simple Epithelial Cells

Molecular and Cellular Biology ◽

10.1128/mcb.24.16.7072-7081.2004 ◽

2004 ◽

Vol 24 (16) ◽

pp. 7072-7081 ◽

Cited By ~ 50

Author(s):

Stéphane Gilbert ◽

Anne Loranger ◽

Normand Marceau

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Null Mouse ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Among the large family of intermediate filament proteins, the keratin 8 and 18 (K8/K18) pair constitutes a hallmark for all simple epithelial cells, such as hepatocytes and mammary cells. Functional studies with different cell models have suggested that K8/K18 are involved in simple epithelial cell resistance to several forms of stress that may lead to cell death. We have reported recently that K8/K18-deprived hepatocytes from K8-null mice are more sensitive to Fas-mediated apoptosis. Here we show that upon Fas, tumor necrosis factor alpha receptor, or tumor necrosis factor alpha-related apoptosis-inducing ligand receptor stimulation, an inhibition of extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation sensitizes wild-type but not K8-null mouse hepatocytes to apoptosis and that a much weaker ERK1/2 activation occurs in K8-null hepatocytes. In turn, this impaired ERK1/2 activation in K8-null hepatocytes is associated with a drastic reduction in c-Flip protein, an event that also holds in a K8-null mouse mammary cell line. c-Flip, along with Raf-1, is part of a K8/K18-immunoisolated complex from wild-type hepatocytes, and Fas stimulation leads to further c-Flip and Raf-1 recruitment in the complex. This points to a new regulatory role of simple epithelium keratins in the c-Flip/ERK1/2 antiapoptotic signaling pathway.

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Tumor Necrosis Factor Alpha Modulates the Dynamics of the Plasminogen-Mediated Early Interaction between Bifidobacterium animalis subsp.lactisand Human Enterocytes

Applied and Environmental Microbiology ◽

10.1128/aem.07883-11 ◽

2012 ◽

Vol 78 (7) ◽

pp. 2465-2469 ◽

Cited By ~ 5

Author(s):

Manuela Centanni ◽

Simone Bergmann ◽

Silvia Turroni ◽

Sven Hammerschmidt ◽

Gursharan Singh Chhatwal ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Content Type ◽

Bifidobacterium Animalis ◽

Factor Alpha ◽

Open Question ◽

Early Interaction ◽

Necrosis Factor

ABSTRACTThe capacity to intervene with the host plasminogen system has recently been considered an important component in the interaction process betweenBifidobacterium animalissubsp.lactisand the human host. However, its significance in the bifidobacterial microecology within the human gastrointestinal tract is still an open question. Here we demonstrate that human plasminogen favors theB. animalissubsp.lactisBI07 adhesion to HT29 cells. Prompting the HT29 cell capacity to activate plasminogen, tumor necrosis factor alpha (TNF-α) modulated the plasminogen-mediated bacterium-enterocyte interaction, reducing the bacterial adhesion to the enterocytes and enhancing migration to the luminal compartment.

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