scholarly journals Modulation of Adherence, Invasion, and Tumor Necrosis Factor Alpha Secretion during the Early Stages of Infection by Streptococcus pneumoniae ClpL

2007 ◽  
Vol 75 (6) ◽  
pp. 2996-3005 ◽  
Author(s):  
Le Nhat Tu ◽  
Hye-Yoon Jeong ◽  
Hyog-Young Kwon ◽  
Abiodun D. Ogunniyi ◽  
James C. Paton ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Actin Polymerization ◽  
Cytochalasin D ◽  
Host Cells ◽  
Raw 264.7 ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Heat shock proteins (HSPs) play a pivotal role as chaperones in the folding of native and denatured proteins and can help pathogens penetrate host defenses. However, the underlying mechanism(s) of modulation of virulence by HSPs has not been fully determined. In this study, the role of the chaperone ClpL in the pathogenicity of Streptococcus pneumoniae was assessed. A clpL mutant adhered to and invaded nasopharyngeal or lung cells much more efficiently than the wild type adhered to and invaded these cells in vitro, as well as in vivo, although it produced the same amount of capsular polysaccharide. However, the level of secretion of tumor necrosis factor alpha (TNF-α) from macrophages infected with the clpL mutant was significantly lower than the level of secretion elicited by the wild type during the early stages of infection. Interestingly, treatment of the human lung epithelial carcinoma A549 and murine macrophage RAW 264.7 cell lines with cytochalasin D, an inhibitor of actin polymerization, increased adherence of the mutant to the host cells. In contrast, cytochalasin D treatment of RAW 264.7 cells decreased TNF-α secretion after infection with either the wild type or the mutant. However, pretreatment of cell lines with the actin polymerization activator jasplakinolide reversed these phenotypes. These findings indicate, for the first time, that the ClpL chaperone represses adherence of S. pneumoniae to host cells and induces secretion of TNF-α via a mechanism dependent upon actin polymerization during the initial infection stage.

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

2004 ◽  
Vol 24 (10) ◽  
pp. 4438-4447 ◽  
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.

scholarly journals Nfa34810 Facilitates Nocardia farcinica Invasion of Host Cells and Stimulates Tumor Necrosis Factor Alpha Secretion through Activation of the NF-κB and Mitogen-Activated Protein Kinase Pathways via Toll-Like Receptor 4

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Xingzhao Ji ◽  
Xiujuan Zhang ◽  
Heqiao Li ◽  
Lina Sun ◽  
Xuexin Hou ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The mechanism underlying the pathogenesis of Nocardia is not fully known. The Nfa34810 protein of Nocardia farcinica has been predicted to be a virulence factor. However, relatively little is known regarding the interaction of Nfa34810 with host cells, specifically invasion and innate immune activation. In this study, we aimed to determine the role of recombinant Nfa34810 during infection. We demonstrated that Nfa34810 is an immunodominant protein located in the cell wall. Nfa34810 protein was able to facilitate the uptake and internalization of latex beads coated with Nfa34810 protein into HeLa cells. Furthermore, the deletion of the nfa34810 gene in N. farcinica attenuated the ability of the bacteria to infect both HeLa and A549 cells. Moreover, stimulation with Nfa34810 triggered macrophages to produce tumor necrosis factor alpha (TNF-α), and it also activated mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways by inducing the phosphorylation of ERK1/2, p38, JNK, p65, and AKT in macrophages. Specific inhibitors of ERK1/2, JNK, and NF-κB significantly reduced the expression of TNF-α, which demonstrated that Nfa34810-mediated TNF-α production was dependent upon the activation of these kinases. We further found that neutralizing antibodies against Toll-like receptor 4 (TLR4) significantly inhibited TNF-α secretion. Taken together, our results indicated that Nfa34810 is a virulence factor of N. farcinica and plays an important role during infection. Nfa34810-induced production of TNF-α in macrophages also involves ERK, JNK, and NF-κB via the TLR4 pathway.

scholarly journals Tumor Necrosis Factor Alpha-Deficient, but Not Interleukin-6-Deficient, Mice Resist Peripheral Infection with Scrapie

2000 ◽  
Vol 74 (7) ◽  
pp. 3338-3344 ◽  
Author(s):  
Neil A. Mabbott ◽  
Alun Williams ◽  
Christine F. Farquhar ◽  
Manolis Pasparakis ◽  
Giorgos Kollias ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Lymphoid Tissues ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Scrapie Strain ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT In most peripheral infections of rodents and sheep with scrapie, infectivity is found first in lymphoid tissues and later in the central nervous system (CNS). Cells within the germinal centers (GCs) of the spleen and lymph nodes are important sites of extraneural replication, from which infection is likely to spread to the CNS along peripheral nerves. Here, using immunodeficient mice, we investigate the identity of the cells in the spleen that are important for disease propagation. Despite possessing functional T and B lymphocytes, tumor necrosis factor alpha-deficient (TNF-α−/−) mice lack GCs and follicular dendritic cell (FDC) networks in lymphoid tissues. In contrast, lymphoid tissues of interleukin-6-deficient (IL-6−/−) mice possess FDC networks but have impaired GCs. When the CNSs of TNF-α−/−, IL-6−/−, and wild-type mice were directly challenged with the ME7 scrapie strain, 100% of the mice were susceptible, developing disease after closely similar incubation periods. However, when challenged peripherally (intraperitoneally), most TNF-α−/− mice failed to develop scrapie up to 503 days postinjection. All wild-type and IL-6−/− mice succumbed to disease approximately 300 days after the peripheral challenge. High levels of scrapie infection and the disease-specific isomer of the prion protein, PrPSc, were detectable in spleens from challenged wild-type and IL-6−/− mice but not from TNF-α−/−mice. Histopathological analysis of spleen tissue demonstrated heavy PrP accumulations in direct association with FDCs in challenged wild-type and IL-6−/− mice. No PrPScaccumulation was detected in spleens from TNF-α−/−mice. We conclude that, for the ME7 scrapie strain, mature FDCs are critical for replication in lymphoid tissues and that in their absence, neuroinvasion following peripheral challenge is impaired.

scholarly journals THP-1 Cell Apoptosis in Response to Mycobacterial Infection

2003 ◽  
Vol 71 (1) ◽  
pp. 254-259 ◽  
Author(s):  
Carrie J. Riendeau ◽  
Hardy Kornfeld
Keyword(s):  
Alveolar Macrophages ◽  
Mycobacterial Infection ◽  
Host Cells ◽  
Tnf Receptor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Retroviral Transduction ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT We previously reported that Mycobacterium tuberculosis infection primes human alveolar macrophages (HAM) for tumor necrosis factor alpha (TNF-α)-mediated apoptosis and that macrophage apoptosis is associated with killing internalized bacilli. Virulent mycobacterial strains elicit much less apoptosis than attenuated strains, implying that apoptosis is a defense against intracellular infection. The present study evaluated the potential for phorbol myristate acetate-differentiated THP-1 cells to mimic this response of primary macrophages. Consistent with the behavior of alveolar macrophages, attenuated M. tuberculosis H37Ra and Mycobacterium bovis BCG strongly induce THP-1 apoptosis, which requires endogenous TNF. THP-1 apoptosis is associated with reduced viability of infecting BCG. In contrast, virulent wild-type M. tuberculosis H37Rv and M. bovis do not increase THP-1 apoptosis over baseline. BCG induced early activation of caspase 10 and 9, followed by caspase 3. In contrast, wild-type M. bovis infection failed to activate any caspases in THP-1 cells. BCG-induced THP-1 apoptosis is blocked by retroviral transduction with vectors expressing crmA but not bcl-2. We conclude that differentiated THP-1 cells faithfully model the apoptosis response of HAM. Analysis of the THP-1 cell response to infection with virulent mycobacteria suggests that TNF death signals are blocked proximal to initiator caspase activation, at the level of TNF receptor 1 or its associated intracytoplasmic adaptor complex. Interference with TNF death signaling may be a virulence mechanism that allows M. tuberculosis to circumvent innate defenses leading to apoptosis of infected host cells.

scholarly journals Immunopathologic Effects of Tumor Necrosis Factor Alpha in Murine Mycobacterial Infection Are Dose Dependent

2000 ◽  
Vol 68 (12) ◽  
pp. 6954-6961 ◽  
Author(s):  
Linda-Gail Bekker ◽  
Andre L. Moreira ◽  
Amy Bergtold ◽  
Sherry Freeman ◽  
Bernard Ryffel ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mycobacterial Infection ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Granulomatous Response

ABSTRACT In experimental mycobacterial infection, tumor necrosis factor alpha (TNF-α) is required for control of bacillary growth and the protective granulomatous response, but may cause immunopathology. To directly examine the positive and detrimental effects of this cytokine, a murine model was used in which different amounts of TNF-α were delivered to the site of infection. Mice with a disruption in the TNF-α gene (TNF-KO) or wild-type mice were infected with low or high doses of recombinant Mycobacterium bovis BCG that secreted murine TNF-α (BCG-TNF). Infection of TNF-KO mice with BCG containing the vector (BCG-vector) at a low dose led to increased bacillary load in all organs and an extensive granulomatous response in the lungs and spleen. The mice succumbed to the infection by ∼40 days. However, when TNF-KO mice were infected with low doses of BCG-TNF, bacillary growth was controlled, granulomas were small and well differentiated, the spleen was not enlarged, and the mice survived. Infection with high inocula of BCG-TNF resulted in bacterial clearance, but was accompanied by severe inflammation in the lungs and spleen and earlier death compared to the results from the mice infected with high inocula of BCG-vector. Wild-type mice controlled infection with either recombinant strain, but showed decreased survival following high-dose BCG-TNF infection. The effects of TNF-α required signaling through an intact receptor, since the differential effects were not observed when TNF-α receptor-deficient mice were infected. The results suggest that the relative amount of TNF-α at the site of infection determines whether the cytokine is protective or destructive.

scholarly journals Tumor Necrosis Factor Alpha Is a Key Mediator in the Regulation of Experimental Trypanosoma brucei Infections

1999 ◽  
Vol 67 (6) ◽  
pp. 3128-3132 ◽  
Author(s):  
Stefan Magez ◽  
Magdalena Radwanska ◽  
Alain Beschin ◽  
Kenji Sekikawa ◽  
Patrick De Baetselier
Keyword(s):  
Tumor Necrosis Factor ◽  
Trypanosoma Brucei ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Immunoglobulin M ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT In order to evaluate during experimental Trypanosoma brucei infections the potential role of tumor necrosis factor alpha (TNF-α) in the host-parasite interrelationship, C57BL/6 TNF-α knockout mice (TNF-α−/−) as well as C57BL/6 wild-type mice were infected with pleomorphic T. bruceiAnTat 1.1 E parasites. In the TNF-α−/− mice, the peak levels of parasitemia were strongly increased compared to the peak levels recorded in wild-type mice. The increased parasite burden did not reflect differences in clearance efficacy or in production ofT. brucei-specific immunoglobulin M (IgM) and IgG antibodies. Trypanosome-mediated immunopathological features, such as lymph node-associated immunosuppression and lipopolysaccharide hypersensitivity, were found to be greatly reduced in infected TNF-α−/− mice. These results demonstrate that, during trypanosome infections, TNF-α is a key mediator involved in both parasitemia control and infection-associated pathology.

scholarly journals Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System

2008 ◽  
Vol 82 (18) ◽  
pp. 8956-8964 ◽  
Author(s):  
Bimmi Shrestha ◽  
Bo Zhang ◽  
Whitney E. Purtha ◽  
Robyn S. Klein ◽  
Michael S. Diamond
Keyword(s):  
West Nile Virus ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Antiviral Effect ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans, especially in immunocompromised individuals. Previous studies have shown essential protective roles for antiviral cytokines (e.g., alpha interferon [IFN-α] and IFN-γ) against WNV in mice. However, studies using cell culture offer conflicting answers regarding whether tumor necrosis factor alpha (TNF-α) has an anti-WNV function. To test the biological significance of TNF-α against WNV in vivo, experiments were performed with TNF receptor-1 (TNF-R1)-deficient and TNF-α-depleted C57BL/6 mice. TNF-R1−/− mice had enhanced mortality and decreased survival time after WNV infection compared to congenic wild-type mice. Consistent with this, administration of a neutralizing anti-TNF-α monoclonal antibody also decreased survival after WNV infection. Relatively small differences in viral burdens in peripheral tissues of TNF-R1−/− mice were observed, and this occurrence correlated with a modest antiviral effect of TNF-α on primary macrophages but not dendritic cells. In contrast, the viral titers detected in the central nervous systems of TNF-R1−/− mice were significantly increased compared to those of wild-type mice, although TNF-α did not have a direct antiviral effect in primary neuron cultures. Whereas no defect in priming of adaptive B- and T-cell responses in TNF-R1−/− mice was observed, there were significant reductions in accumulations of CD8+ T cells and macrophages in the brain. Our data are most consistent with a model in which interaction of TNF-α with TNF-R1 protects against WNV infection by regulating migration of protective inflammatory cells into the brain during acute infection.

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

2011 ◽  
Vol 79 (7) ◽  
pp. 2928-2935 ◽  
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.

scholarly journals Role of YopP in Suppression of Tumor Necrosis Factor Alpha Release by Macrophages during YersiniaInfection

1998 ◽  
Vol 66 (5) ◽  
pp. 1878-1884 ◽  
Author(s):  
Anne Boland ◽  
Guy R. Cornelis
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Type Strain ◽  
Tumor Necrosis ◽  
Wild Type Strain ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The Yersinia plasmid-encoded Yop virulon enables extracellular adhering bacteria to deliver toxic effector proteins inside their target cells. It includes a type III secretion system (Ysc), at least two translocator proteins (YopB, YopD), and a set of intracellular Yop effectors (YopE, YopH, YopO, YopM, and YopP). Infection of macrophages with a wild-type strain leads to low levels of tumor necrosis factor alpha (TNF-α) release compared to infection with plasmid-cured strains, suggesting that the virulence plasmid encodes a factor impairing the normal TNF-α response of infected macrophages. This effect is correlated with the inhibition of the macrophage mitogen-activated protein kinase (MAPK) activities. To identify the Yop protein responsible for the suppression of TNF-α release, we infected J774A.1 and PU5-1.8 macrophages with a battery of knockout Yersinia enterocolitica mutants and we quantified the TNF-α released. Mutants affected in secretion (yscN), in translocation (yopB and yopD), or in synthesis of all the known Yop effectors (yopH,yopO, yopP, yopE, andyopM polymutants) were unable to block the TNF-α response of the macrophages. In contrast, single yopE,yopH, yopO, and yopM mutants behaved like the wild-type strain. A yopP mutant elicited elevated TNF-α release, and complementation of the yopPmutant or the yop effector polymutant strain withyopP alone led to a drop in TNF-α release. In addition, YopP was also responsible for the inhibition of the extracellular signal-regulated kinase2 (ERK2) and p38 MAPK activities. These results show that YopP is the Yop effector responsible for theYersinia-induced suppression of TNF-α release by infected macrophages.

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