Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection

ABSTRACTStaphylococcus aureusinfections are an important public health concern due to their increasing incidence and high rates of mortality. The success ofS. aureusas a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients.S. aureusprotein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate thatS. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-αin vitroandin vivo. The results obtained using a protein A-deficient mutant andtnfr1−/−mice strongly suggest that the increased levels of soluble TNFR1 present during experimentalS. aureusinfection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by whichS. aureussubverts the host immune response.

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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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REDUCTION OF TUMOR NECROSIS FACTOR-ALPHA AND INTERFERON-GAMMA CONCENTRATION ON TUBERCULOSIS WITH DIABETES MELLITUS AS A MARKER IN DECREASE IMMUNE SYSTEM

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i11.35424 ◽

2019 ◽

pp. 151-154

Author(s):

NELLY MARISSA ◽

NUR RAMADHAN ◽

SARI HANUM ◽

MARLINDA ◽

EKA FITRIA ◽

...

Keyword(s):

Diabetes Mellitus ◽

Immune Response ◽

Tumor Necrosis Factor ◽

Interferon Gamma ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Ifn Γ ◽

Necrosis Factor

Objective: This study aimed to determine the decreased immune response of tuberculosis (TB) with diabetes mellitus (DM) patients. Methods: A total of 105 TB patients who were undergoing treatment at health centers and hospitals in Banda Aceh and Aceh Besar were included in this study. Data collection was carried out by interviewed to obtained demographic and respondent categories based on the diagnosis. Measurements of height and weight were also conducted to obtain body mass index data. 5 mL peripheral blood was taken from each respondent group into a TB with DM (TB+DM) and TB without DM (TB-DM). The blood tested usage tumor necrosis factor-alpha (TNF-α) level using enzyme-linked immunosorbent assay and interferon-gamma (IFN-γ) using IFN-γ release assay. Results: The average concentration of both TNF-α and IFN-γ was higher in TB-DM group (TNF-a 5.2 pg/mL; IFN-g 1.5 IU/mL) than in TB+DM group (TNF-a 2.06 pg/mL; IFN-g 2.86 IU/mL). There were significant differences in TNF-α between the two groups but no significant differences in IFN-γ protein concentration. Conclusion: The immune response of TB patients with DM symptoms was markedly reduced by the decreased expression of TNF-α and IFN-γ.

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Brucella abortus Invasion of Osteocytes Modulates Connexin 43 and Integrin Expression and Induces Osteoclastogenesis via Receptor Activator of NF-κB Ligand and Tumor Necrosis Factor Alpha Secretion

Infection and Immunity ◽

10.1128/iai.01049-15 ◽

2015 ◽

Vol 84 (1) ◽

pp. 11-20 ◽

Cited By ~ 12

Author(s):

Ayelén Ivana Pesce Viglietti ◽

Paula Constanza Arriola Benitez ◽

María Virginia Gentilini ◽

Lis Noelia Velásquez ◽

Carlos Alberto Fossati ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Brucella Abortus ◽

Connexin 43 ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Receptor Activator ◽

Factor Alpha ◽

Necrosis Factor

Osteoarticular brucellosis is the most common localization of human active disease. Osteocytes are the most abundant cells of bone. They secrete factors that regulate the differentiation of both osteoblasts and osteoclasts during bone remodeling. The aim of this study is to determine ifBrucella abortusinfection modifies osteocyte function. Our results indicate thatB. abortusinfection induced matrix metalloproteinase 2 (MMP-2), receptor activator for NF-κB ligand (RANKL), proinflammatory cytokines, and keratinocyte chemoattractant (KC) secretion by osteocytes. In addition, supernatants fromB. abortus-infected osteocytes induced bone marrow-derived monocytes (BMM) to undergo osteoclastogenesis. Using neutralizing antibodies against tumor necrosis factor alpha (TNF-α) or osteoprotegerin (OPG), RANKL's decoy receptor, we determined that TNF-α and RANKL are involved in osteoclastogenesis induced by supernatants fromB. abortus-infected osteocytes. Connexin 43 (Cx43) and the integrins E11/gp38, integrin-α, integrin-β, and CD44 are involved in cell-cell interactions necessary for osteocyte survival.B. abortusinfection inhibited the expression of Cx43 but did not modify the expression of integrins. Yet the expression of both Cx43 and integrins was inhibited by supernatants fromB. abortus-infected macrophages.B. abortusinfection was not capable of inducing osteocyte apoptosis. However, supernatants fromB. abortus-infected macrophages induced osteocyte apoptosis in a dose-dependent manner. Taken together, our results indicate thatB. abortusinfection could alter osteocyte function, contributing to bone damage.

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Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production

Infection and Immunity ◽

10.1128/iai.00915-16 ◽

2017 ◽

Vol 85 (3) ◽

Cited By ~ 1

Author(s):

Alvaro Torres-Huerta ◽

Tomás Villaseñor ◽

Angel Flores-Alcantar ◽

Cristina Parada ◽

Estefanía Alemán-Navarro ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Transforming Growth Factor ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Mycobacterium tuberculosis is the causal agent of tuberculosis. Tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), and gamma interferon (IFN-γ) secreted by activated macrophages and lymphocytes are considered essential to contain Mycobacterium tuberculosis infection. The CD43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin Cpn60.2, facilitating mycobacterium-macrophage contact. We report here that Cpn60.2 induces both human THP-1 cells and mouse-derived bone marrow-derived macrophages (BMMs) to produce TNF-α and that this production is CD43 dependent. In addition, we present evidence that the signaling pathway leading to TNF-α production upon interaction with Cpn60.2 requires active Src family kinases, phospholipase C-γ (PLC-γ), phosphatidylinositol 3-kinase (PI3K), p38, and Jun N-terminal protein kinase (JNK), both in BMMs and in THP-1 cells. Our data highlight the role of CD43 and Cpn60.2 in TNF-α production and underscore an important role for CD43 in the host-mycobacterium interaction.

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Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces Soluble Tumor Necrosis Factor Receptor Production through Tumor Necrosis Factor Alpha-Converting Enzyme Activation

Infection and Immunity ◽

10.1128/iai.00060-12 ◽

2012 ◽

Vol 80 (11) ◽

pp. 3858-3868 ◽

Cited By ~ 4

Author(s):

Jillian M. Richmond ◽

Elizabeth R. Duffy ◽

Jinhee Lee ◽

Kavon Kaboli ◽

Daniel G. Remick ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACTPrimaryMycobacterium tuberculosisinfection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-α) is a host-protective cytokine duringM. tuberculosisinfection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs duringM. tuberculosisinfection. Using the murine model of aerosolM. tuberculosisinfection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation ofM. tuberculosiscell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-α-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples fromM. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by whichM. tuberculosisinfection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease.

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In VitroInfection of Bovine Monocytes with Mycoplasma bovis Delays Apoptosis and Suppresses Production of Gamma Interferon and Tumor Necrosis Factor Alpha but Not Interleukin-10

Infection and Immunity ◽

10.1128/iai.00961-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 62-71 ◽

Cited By ~ 35

Author(s):

Musa Mulongo ◽

Tracy Prysliak ◽

Erin Scruten ◽

Scott Napper ◽

Jose Perez-Casal

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 10 ◽

Mycoplasma Bovis ◽

Blood Monocytes ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACTMycoplasma bovisis one of the major causative pathogens of bovine respiratory complex disease (BRD), which is characterized by enzootic pneumonia, mastitis, pleuritis, and polyarthritis.M. bovisenters and colonizes bovine respiratory epithelial cells through inhalation of aerosol from contaminated air. The nature of the interaction betweenM. bovisand the bovine innate immune system is not well understood. We hypothesized thatM. bovisinvades blood monocytes and regulates cellular function to support its persistence and systemic dissemination. We used bovine-specific peptide kinome arrays to identify cellular signaling pathways that could be relevant toM. bovis-monocyte interactionsin vitro. We validated these pathways using functional, protein, and gene expression assays. Here, we show that infection of bovine blood monocytes withM. bovisdelays spontaneous or tumor necrosis factor alpha (TNF-α)/staurosporine-driven apoptosis, activates the NF-κB p65 subunit, and inhibits caspase-9 activity. We also report thatM. bovis-infected bovine monocytes do not produce gamma interferon (IFN-γ) and TNF-α, although the level of production of interleukin-10 (IL-10) is elevated. Our findings suggest thatM. bovistakes over the cellular machinery of bovine monocytes to prolong bacterial survival and to possibly facilitate subsequent systemic distribution.

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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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Role of Tumor Necrosis Factor Alpha in Helicobacter pylori Gastritis in Tumor Necrosis Factor Receptor 1-Deficient Mice

Infection and Immunity ◽

10.1128/iai.70.6.3149-3155.2002 ◽

2002 ◽

Vol 70 (6) ◽

pp. 3149-3155 ◽

Cited By ~ 26

Author(s):

Ulrike Thalmaier ◽

Norbert Lehn ◽

Klaus Pfeffer ◽

Manfred Stolte ◽

Michael Vieth ◽

...

Keyword(s):

Immune Response ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Necrosis Factor Alpha ◽

Humoral Immune ◽

Tnf Α ◽

Factor Alpha ◽

H Pylori ◽

Necrosis Factor

ABSTRACT Increased gastric production of interleukin 8 and tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of Helicobacter pylori-associated gastroduodenal disease. In the present study we used a mouse model to demonstrate whether loss of the tumor necrosis factor receptor 1 (TNF-R1) function leads to differences in gastric inflammation or the systemic immune response in H. pylori infection. Six different clinical isolates of H. pylori (three cytotoxin-positive and three cytotoxin-negative strains) were adapted to C57BL/6 mice. TNF-R1-deficient (TNF-R1−/−) mice (n = 19) and isogenetic controls (n = 24) were infected and sacrificed after 4 weeks of infection. Inflammation of the stomach and the humoral immune response to H. pylori were evaluated by histological, immunohistochemical, and serological methods. There was no detectable difference in the grade or activity of gastritis in TNF-R1−/− mice when they were compared with wild-type mice, but the number of lymphoid aggregates was slightly reduced in the gastric mucosa of TNF-R1−/− mice. Interestingly, total immunoglobulin G (IgG), as well as IgG1, IgG2b, and IgG3, H. pylori-specific antibody titers were significantly higher in wild-type mice. As revealed by immunoblot analysis, the difference in reactivity against H. pylori antigens was not based on a failure to recognize single H. pylori antigens in TNF-R1−/− mice. We therefore suggest that TNF-R1-mediated TNF-α signals might support a systemic humoral immune response against H. pylori and that the gastric inflammatory response to H. pylori infection seems to be independent of TNF-R1-mediated signals.

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A 20-Mer Peptide Derived from the Lectin Domain of SP-A2 Decreases Tumor Necrosis Factor Alpha Production during Mycoplasma pneumoniae Infection

Infection and Immunity ◽

10.1128/iai.00099-20 ◽

2020 ◽

Vol 88 (9) ◽

Author(s):

Usir S. Younis ◽

Hong Wei Chu ◽

Monica Kraft ◽

Julie G. Ledford

Keyword(s):

Amino Acid ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Content Type ◽

Lectin Domain ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Human surfactant protein-A2 (hSP-A2) is a component of pulmonary surfactant that plays an important role in the lung’s immune system by interacting with viruses, bacteria, and fungi to facilitate pathogen clearance and by downregulating inflammatory responses after an allergic challenge. Genetic variation in SP-A2 at position Gln223Lys is present in up to ∼30% of the population and has been associated with several lung diseases, such as asthma, pulmonary fibrosis, and lung cancer (M. M. Pettigrew, J. F. Gent, Y. Zhu, E. W. Triche, et al., BMC Med Genet 8:15, 2007, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-8-15; Y. Wang, P. J. Kuan, C. Zing, J. T. Cronkhite, et al., Am J Hum Genet 84:52–59, 2009, https://www.cell.com/ajhg/fulltext/S0002-9297(08)00595-8). Previous work performed by our group showed differences in levels of SP-A binding to non-live mycoplasma membrane fractions that were dependent on the presence of a lysine (K) or a glutamine (Q) at amino acid position 223 in the carbohydrate region of SP-A2. On the basis of these differences, we have derived 20-amino-acid peptides flanking this region of interest in order to test the ability of each to regulate various immune responses to live Mycoplasma pneumoniae in SP-A knockout mice and RAW 264.7 cells. In both models, the 20-mer containing 223Q significantly decreased both tumor necrosis factor alpha (TNF-α) mRNA levels and protein levels in comparison to the 20-mer containing 223K during M. pneumoniae infection. While neither of the 20-mer peptides (223Q and 223K) had an effect on p38 phosphorylation during M. pneumoniae infection, the 223Q-20mer peptide significantly reduced NF-κB p65 phosphorylation in both models. Taken together, our data suggest that small peptides derived from the lectin domain of SP-A2 that contain the major allelic variant (223Q) maintain activity in reducing TNF-α induction during M. pneumoniae infection.

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Influence of Vector-Encoded Cytokines on Anti-Salmonella Immunity: Divergent Effects of Interleukin-2 and Tumor Necrosis Factor Alpha

Infection and Immunity ◽

10.1128/iai.69.6.3980-3988.2001 ◽

2001 ◽

Vol 69 (6) ◽

pp. 3980-3988 ◽

Cited By ~ 26

Author(s):

Basel K. al-Ramadi ◽

Mariam H. Al-Dhaheri ◽

Nada Mustafa ◽

Mounir AbouHaidar ◽

Damu Xu ◽

...

Keyword(s):

Immune Response ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Interleukin 2 ◽

Fine Tuning ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Attenuated Salmonella strains are of interest as new vaccine candidates and as vectors of cloned genes of other organisms. Attenuated strains expressing specific cytokines were constructed as a means of manipulating the immune response in various disease settings. In the present study, interleukin-2 (IL-2)-expressing (GIDIL2) or tumor necrosis factor alpha (TNF-α)-expressing (GIDTNF) strains were compared with the parent strain (BRD509) for the effect of cytokines on anti-Salmonella immunity. Expression of IL-2 resulted in a rapid clearance of the organism soon after vaccination. The reduction in GIDIL2 CFU was 50- to 300-fold higher than that of BRD509 and correlated with a markedly decreased splenomegaly. Furthermore, no evidence for any significant activation, including upregulation of surface markers and production of nitric oxide (NO), was observed in spleens of GIDIL2-injected mice. In contrast, the host response to GIDTNF was marked by an early, strong, splenic cellular influx, but surprisingly, the degree of induced splenomegaly and NO secretion was only 50% of that observed in BRD509-treated mice. Despite this, bacterial colonization of the spleen in GIDTNF-immunized animals was either slightly decreased from or equivalent to that of the BRD509-treated group, suggesting the induction of additional antimicrobial mechanisms by TNF-α. In vivo protection studies demonstrated that, at limiting doses, GIDIL2 was inferior to GIDTNF and BRD509 in its capacity to protect against virulent challenge. At high doses, however, all three strains exhibited equal protective efficacy. These results demonstrate that the immune response against intracellular bacteria can be manipulated by pathogen-expressed cytokines and open the way for further fine tuning of immune responses not only to Salmonella strains themselves but also to the heterologous gene(s) carried by them.

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