Sanna M Goyert | The City College of New York (original) (raw)
Papers by Sanna M Goyert
Journal of Immunology, 2009
Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cell... more Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule epidermal growth factor (EGF)-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Because endotoxin is elevated in polymicrobial sepsis, we hypothesized that down-regulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14 ؊/؊), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by i.p. injection of LPS. LPS was also neutralized by pretreating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity, and apoptosis were assessed 5 and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49 and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the down-regulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14 ؊/؊ and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14 ؊/؊ mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14 ؊/؊ mice. Thus, MFG-E8 production is down-regulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
Cancer Research, Apr 4, 2023
Compared with previous standards of care, the use of immune checkpoint inhibitors (ICI) has broug... more Compared with previous standards of care, the use of immune checkpoint inhibitors (ICI) has brought significant improvements in survival and quality of life for lung cancer patients. However, only a small proportion of these patients respond durably. People with different ancestries differ probabilistically in genetic factors, environmental exposures, and socio-economic conditions. Whether patients of different ancestry benefit equally from ICIs remains unclear. We studied the impact of genomic ancestry, tumor genomics, and social determinants of health (SDH) factors and factors that are impacted from SDH including recorded race/ethnicity, inferred low-income status from patient zip codes, exposure to smoking, and BMI on ICI response, defined by cancer progression-free survival (PFS, minimum 6 months FU), for non-small cell lung cancer (NSCLC) patients with MSK-IMPACT targeted panel sequencing. This FDA approved assay includes matched tumor-white blood cell sequencing to distinguish germline from somatic variants and has been applied to 1,802 NSCLC patients who received ICI treatment, including 81 and 117 patients with at least 80% of African (AFR) and East Asian (EAS) ancestry, respectively. Moreover, 173 samples were derived from admixed patients with more than one major ancestry. We first used a natural language processing (NLP) model to obtain PFS from free-text clinical notes. A multivariable cox proportional hazard model was then used to associate PFS with ancestry, race, smoking status, ICI drug regimen, PD-L1 status, disease stage, tumor mutational burden (TMB), inferred income, and BMI. Neither genetic ancestry nor self-reported race/ethnicity was associated with the PFS. Moreover, ICI drug regimen types, low-income status, and BMI were not associated with PFS in our cohort. TMB-high was associated with longer PFS across all ancestries, although TMB was lower in patients with EAS ancestry (Median 7.9 vs. 5.3 mut/Mb, p<0.001). These results suggest that the benefits of ICI extend across ancestry, race, and income lines in a single institution, arguing for more equitable patient access to these medications. We also show that TMB is a generalizable biomarker for ICI outcome across ancestries. However, more diverse patient populations are needed to understand whether there is ancestry-specificity in other ICI outcome biomarkers. Citation Format: Christopher J. Fong, Michele Waters, Karl Pichotta, Justin Jee, Devika R. Jutagir, David Ma, Tomin Perea-Chamblee, Susie Kim, Kanika Arora, Brooke Mastrogiacomo, Thinh Tran, Steven Maron, Mirella Altoe, Anisha Luthra, Joseph Kholodenko, Arfath Patha, Doori Rose, Michael F. Berger, Gregory J. Riely, Nikolaus Schultz, Sanna Goyert, Adam Schoenfeld, Francesca Gany, Jian Carrot-Zhang. Understanding genomic and social determinants of cancer immunotherapy outcome across ancestry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4260.
Journal of Leukocyte Biology, Nov 1, 2001
This paper reviews the Seventh Human Leucocyte Differentiation Antigen (HLDA7) workshop. Due to t... more This paper reviews the Seventh Human Leucocyte Differentiation Antigen (HLDA7) workshop. Due to the limitations of "blind" antibody screening, which had been evident at the previous meeting in 1996, participants at HLDA7 adopted a more selective approach to the choice of antibodies by identifying new CD specificities. This resulted in the addition of more than 80 new CD specificities. Plans for the eighth and subsequent workshops are also previewed.
Journal of Immunology, Jun 1, 1998
Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate mono... more Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages.
The Journal of Immunology
The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages,... more The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages, and its LPS-mimetic effects are blocked by LPS analogue antagonists. Since CD14 is central to the recognition of LPS by macrophages, we sought to examine a role for CD14 in the response to Taxol vs LPS. A comparison of responses of macrophages from wild-type mice with those from mice lacking CD14 due to a targeted disruption of the CD14 gene (CD14-deficient knockout (CD14KO)) revealed that like LPS, Taxol induces both CD14-dependent and -independent pathways of gene activation, although the CD14 dependency of Taxol stimulation is much less striking than that observed with LPS. The macrophage interaction with low concentrations of LPS (< or = 10 ng/ml) is largely CD14 dependent, as evidenced by the lack of induction of TNF-alpha, IL-1beta, and interferon-inducible protein-10 (IP-10) genes by CD14KO macrophages cultured in the absence of soluble CD14 (i.e., in autologous CD14KO -/- mou...
Immunologist, Dec 1, 2000
The process of categorizing the antigenic molecules and epitopes associated with human white cell... more The process of categorizing the antigenic molecules and epitopes associated with human white cells, via the collaborative study of monoclonal antibodies, dates back to the early 1980s, when the ®rst HLDA (Human Leucocyte Differentiation Antigen) Workshop was held in Paris. This initial meeting listed only 15 agreed molecular entities, but it created an internationally agreed basis for the nomenclature of leucocyte molecules (the CD scheme), and also provided a forum for reporting studies on their function and practical relevance. A further six HLDA meetings have been held since the ®rst Paris meeting. The most recent of these (`HLDA7') took place last year in Harrogate, UK and the proceedings of the meeting will be published later this year (Leucocyte Typing VII, Oxford University Press).
Leucocyte Typing, 1984
In vitro translation and immunoprecipitation were used to identify messenger RNAs (mRNAs) coding ... more In vitro translation and immunoprecipitation were used to identify messenger RNAs (mRNAs) coding for lymphocyte surface antigens. The mRNAs were extracted from human lymphoblastoid cell lines of B-cell or T-cell origin. Messenger RNA was also extracted from fibroblastoid lines as non-lymphoid control. Translation products were reacted with a xenoantiserum raised against human lymphoid surface antigens. Products immunoprecipitated with antiserum were analyzed by SDS-polyacrylamide gel electrophoresis and fluorography.
The Journal of Immunology
Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to ... more Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to bacterial LPS/endotoxin. Activation of monocytes and neutrophils by the binding of LPS to the membrane receptor, CD14, plays a key role in this response. Furthermore, a soluble form of the CD14 receptor enhances the endothelial cell response to LPS. We show here that despite the agonist effects of soluble CD14 on the endothelial cell response to LPS, recombinant soluble CD14 is able to protect mice from LPS-induced lethality. This protection appears to be associated with the inhibition of TNF-alpha release. These results suggest that the soluble CD14 receptor may represent a new form of therapy for endotoxic shock in humans.
International Immunology, 2010
unique to B. pseudomallei and not found in B. thailandensis. Hence, our data suggest that the abi... more unique to B. pseudomallei and not found in B. thailandensis. Hence, our data suggest that the ability of B. pseudomallei to synthesize lipid A species with long chain FA C 14:0 (2-OH) and Ara4N-modified phosphate groups is key to the bacterium's escape from innate immune recognition. This study was funded by D30 grant from DSTA, Singapore.
This article cites 54 articles, 30 of which can be accessed free
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1988
CD14 is a myeloid differentiation Ag expressed primarily on peripheral blood monocytes and macrop... more CD14 is a myeloid differentiation Ag expressed primarily on peripheral blood monocytes and macrophages. Although its function is unknown, the CD14 gene maps to a region encoding several myeloid growth factors and receptors. Analysis of the CD14 protein sequence deduced from the cDNA shows that although the CD14 protein contains a characteristic leader peptide, it lacks a characteristic transmembrane region, suggesting that CD14 may be anchored to the membrane via glycosylphosphatidylinositol (PI). Treatment of monocytes as well as a CD14-expressing neuroglioma cell line with PI-phospholipase C removed CD14 from the cell surface. Furthermore, monocytes from a patient with paroxysmal nocturnal hemoglobinuria, a disease characterized by lack of expression of other PI-linked proteins, failed to express CD14. Interestingly, the CD14-expressing neuroglioma cell line, which had been transfected with a single CD14 cDNA, released a soluble form of CD14 into the supernatant. Soluble forms of ...
The Journal of Immunology, 2005
Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia bur... more Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia burgdorferi. In vitro evidence suggests that binding of spirochetal lipoproteins to CD14, a pattern recognition receptor expressed on monocytes/macrophages and polymorphonuclear cells, is a critical requirement for cellular activation and the subsequent release of proinflammatory cytokines that most likely contribute to symptomatology and clinical manifestations. To test the validity of this notion, we assessed the impact of CD14 deficiency on Lyme disease in C3H/HeN mice. Contrary to an anticipated diminution in pathology, CD14 ؊/؊ mice exhibited more severe and persistent inflammation than did CD14 ؉/؉ mice. This disparity reflects altered gene regulation within immune cells that may engender the higher bacterial burden and serum cytokine levels observed in CD14 ؊/؊ mice. Comparing their in vitro stimulatory activity, live spirochetes, but not lysed organisms, were a potent CD14-independent stimulus of cytokine production, triggering an exaggerated response by CD14 ؊/؊ macrophages. Collectively, our in vivo and in vitro findings support the provocative notion that: 1) pattern recognition by CD14 is entirely dispensable for elaboration of an inflammatory response to B. burgdorferi, and 2) CD14-independent signaling pathways are inherently more destructive than CD14dependent pathways. Continued study of CD14-independent signaling pathways may provide mechanistic insight into the inflammatory processes that underlie development of chronic inflammation.
Medical Microbiology and Immunology, 1999
The CD14 myelomonocytic differentiation antigen plays a major role in acute Gram-negative infecti... more The CD14 myelomonocytic differentiation antigen plays a major role in acute Gram-negative infections with Escherichia coli; however, its role in chronic infections has not yet been analyzed. To address this question, we studied the role of CD14 in a chronic abscess-forming peritonitis, induced by Bacteroides fragilis. B. fragilis (3×10 8 CFU/ml) were resuspended in a liquid nutrient agar and injected into the peritoneal cavity of CD14-deficient (CD14-/-) and normal C57BL/6J (CD14+/+) mice, respectively. After 3 days there was a severe phlegmonous intraabdominal inflammation in both groups. After 7 days an abscess-forming peritonitis developed and by 14 days the infectious foci were compartimentalized. These observations were indistinguishable between CD14-/-and CD14+/+ mice. Although no differences were seen in abscess formation, CD14-/-mice were able to clear B. fragilis more efficiently from the blood than CD14+/+ mice. After 3, 7, and 14 days blood cultures were B. fragilis positive in 11% (1/9), 20% (2/10), and 0% (0/9) in CD14-/compared with 90% (9/10), 78% (7/9), and 20% (2/10) in CD14+/+ mice, respectively (P < 0.05). Furthermore, although the infection resulted in hepatocellular necrosis and severe hepatitis in both groups, at day 14 the liver cell damage was more severe in CD14+/+ than in CD14-/-mice (P < 0.05). These results show that the chronic abscess formation induced by B. fragilis capsular polysaccharides is CD14 independent; however, bacterial clearance and/or dissemination and liver cell damage are at least partially influenced by CD14-dependent mechanisms.
Infection and Immunity, 2007
Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that uti... more Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14−/− and CD14+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14−/− mice were resistant to the lethal effects of the K1-negative isolates. This resistance...
<b>Copyright information:</b>Taken from "CD14 mediates the innate immune respons... more <b>Copyright information:</b>Taken from "CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls"Arthritis Research & Therapy 2004;6(3):R273-R281.Published online 27 Apr 2004PMCID:PMC416450.Copyright © 2004 Li et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Spleen macrophages were stimulated for 30 min with PG-PS at a concentration of 20 μg/ml. The left column shows immunostaining of the p65 (RelA) subunit of NF-κB, and the right column shows counterstaining of nuclei with Hoechst 33342. The rows show the following: top – unstimulated cells from wild-type mice; middle – PG-PS stimulated cells from wild-type mice; and bottom row – PG-PS-stimulated cells from CD14 knockout mice. Representative data from three independent experiments are shown.
This article cites 72 articles, 54 of which you can access for free at:
<b>Copyright information:</b>Taken from "CD14 mediates the innate immune respons... more <b>Copyright information:</b>Taken from "CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls"Arthritis Research & Therapy 2004;6(3):R273-R281.Published online 27 Apr 2004PMCID:PMC416450.Copyright © 2004 Li et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Peritoneal macrophages were stimulated for 4 hours with the indicated concentrations of PG-PS. Concentrations of TNF-α and IL-6 were determined in supernatants by ELISA. Each determination was done in duplicates. TNF-α production by peritoneal macrophages. Data represent means ± standard error of the mean from three independent experiments. IL-6 production by peritoneal macrophages. Data represent mean ± SEM from two independent experiments.
Journal of Immunology, 2009
Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cell... more Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule epidermal growth factor (EGF)-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Because endotoxin is elevated in polymicrobial sepsis, we hypothesized that down-regulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14 ؊/؊), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by i.p. injection of LPS. LPS was also neutralized by pretreating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity, and apoptosis were assessed 5 and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49 and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the down-regulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14 ؊/؊ and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14 ؊/؊ mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14 ؊/؊ mice. Thus, MFG-E8 production is down-regulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
Cancer Research, Apr 4, 2023
Compared with previous standards of care, the use of immune checkpoint inhibitors (ICI) has broug... more Compared with previous standards of care, the use of immune checkpoint inhibitors (ICI) has brought significant improvements in survival and quality of life for lung cancer patients. However, only a small proportion of these patients respond durably. People with different ancestries differ probabilistically in genetic factors, environmental exposures, and socio-economic conditions. Whether patients of different ancestry benefit equally from ICIs remains unclear. We studied the impact of genomic ancestry, tumor genomics, and social determinants of health (SDH) factors and factors that are impacted from SDH including recorded race/ethnicity, inferred low-income status from patient zip codes, exposure to smoking, and BMI on ICI response, defined by cancer progression-free survival (PFS, minimum 6 months FU), for non-small cell lung cancer (NSCLC) patients with MSK-IMPACT targeted panel sequencing. This FDA approved assay includes matched tumor-white blood cell sequencing to distinguish germline from somatic variants and has been applied to 1,802 NSCLC patients who received ICI treatment, including 81 and 117 patients with at least 80% of African (AFR) and East Asian (EAS) ancestry, respectively. Moreover, 173 samples were derived from admixed patients with more than one major ancestry. We first used a natural language processing (NLP) model to obtain PFS from free-text clinical notes. A multivariable cox proportional hazard model was then used to associate PFS with ancestry, race, smoking status, ICI drug regimen, PD-L1 status, disease stage, tumor mutational burden (TMB), inferred income, and BMI. Neither genetic ancestry nor self-reported race/ethnicity was associated with the PFS. Moreover, ICI drug regimen types, low-income status, and BMI were not associated with PFS in our cohort. TMB-high was associated with longer PFS across all ancestries, although TMB was lower in patients with EAS ancestry (Median 7.9 vs. 5.3 mut/Mb, p<0.001). These results suggest that the benefits of ICI extend across ancestry, race, and income lines in a single institution, arguing for more equitable patient access to these medications. We also show that TMB is a generalizable biomarker for ICI outcome across ancestries. However, more diverse patient populations are needed to understand whether there is ancestry-specificity in other ICI outcome biomarkers. Citation Format: Christopher J. Fong, Michele Waters, Karl Pichotta, Justin Jee, Devika R. Jutagir, David Ma, Tomin Perea-Chamblee, Susie Kim, Kanika Arora, Brooke Mastrogiacomo, Thinh Tran, Steven Maron, Mirella Altoe, Anisha Luthra, Joseph Kholodenko, Arfath Patha, Doori Rose, Michael F. Berger, Gregory J. Riely, Nikolaus Schultz, Sanna Goyert, Adam Schoenfeld, Francesca Gany, Jian Carrot-Zhang. Understanding genomic and social determinants of cancer immunotherapy outcome across ancestry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4260.
Journal of Leukocyte Biology, Nov 1, 2001
This paper reviews the Seventh Human Leucocyte Differentiation Antigen (HLDA7) workshop. Due to t... more This paper reviews the Seventh Human Leucocyte Differentiation Antigen (HLDA7) workshop. Due to the limitations of "blind" antibody screening, which had been evident at the previous meeting in 1996, participants at HLDA7 adopted a more selective approach to the choice of antibodies by identifying new CD specificities. This resulted in the addition of more than 80 new CD specificities. Plans for the eighth and subsequent workshops are also previewed.
Journal of Immunology, Jun 1, 1998
Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate mono... more Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages.
The Journal of Immunology
The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages,... more The antitumor agent, Taxol, shares with bacterial LPS the ability to activate murine macrophages, and its LPS-mimetic effects are blocked by LPS analogue antagonists. Since CD14 is central to the recognition of LPS by macrophages, we sought to examine a role for CD14 in the response to Taxol vs LPS. A comparison of responses of macrophages from wild-type mice with those from mice lacking CD14 due to a targeted disruption of the CD14 gene (CD14-deficient knockout (CD14KO)) revealed that like LPS, Taxol induces both CD14-dependent and -independent pathways of gene activation, although the CD14 dependency of Taxol stimulation is much less striking than that observed with LPS. The macrophage interaction with low concentrations of LPS (< or = 10 ng/ml) is largely CD14 dependent, as evidenced by the lack of induction of TNF-alpha, IL-1beta, and interferon-inducible protein-10 (IP-10) genes by CD14KO macrophages cultured in the absence of soluble CD14 (i.e., in autologous CD14KO -/- mou...
Immunologist, Dec 1, 2000
The process of categorizing the antigenic molecules and epitopes associated with human white cell... more The process of categorizing the antigenic molecules and epitopes associated with human white cells, via the collaborative study of monoclonal antibodies, dates back to the early 1980s, when the ®rst HLDA (Human Leucocyte Differentiation Antigen) Workshop was held in Paris. This initial meeting listed only 15 agreed molecular entities, but it created an internationally agreed basis for the nomenclature of leucocyte molecules (the CD scheme), and also provided a forum for reporting studies on their function and practical relevance. A further six HLDA meetings have been held since the ®rst Paris meeting. The most recent of these (`HLDA7') took place last year in Harrogate, UK and the proceedings of the meeting will be published later this year (Leucocyte Typing VII, Oxford University Press).
Leucocyte Typing, 1984
In vitro translation and immunoprecipitation were used to identify messenger RNAs (mRNAs) coding ... more In vitro translation and immunoprecipitation were used to identify messenger RNAs (mRNAs) coding for lymphocyte surface antigens. The mRNAs were extracted from human lymphoblastoid cell lines of B-cell or T-cell origin. Messenger RNA was also extracted from fibroblastoid lines as non-lymphoid control. Translation products were reacted with a xenoantiserum raised against human lymphoid surface antigens. Products immunoprecipitated with antiserum were analyzed by SDS-polyacrylamide gel electrophoresis and fluorography.
The Journal of Immunology
Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to ... more Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to bacterial LPS/endotoxin. Activation of monocytes and neutrophils by the binding of LPS to the membrane receptor, CD14, plays a key role in this response. Furthermore, a soluble form of the CD14 receptor enhances the endothelial cell response to LPS. We show here that despite the agonist effects of soluble CD14 on the endothelial cell response to LPS, recombinant soluble CD14 is able to protect mice from LPS-induced lethality. This protection appears to be associated with the inhibition of TNF-alpha release. These results suggest that the soluble CD14 receptor may represent a new form of therapy for endotoxic shock in humans.
International Immunology, 2010
unique to B. pseudomallei and not found in B. thailandensis. Hence, our data suggest that the abi... more unique to B. pseudomallei and not found in B. thailandensis. Hence, our data suggest that the ability of B. pseudomallei to synthesize lipid A species with long chain FA C 14:0 (2-OH) and Ara4N-modified phosphate groups is key to the bacterium's escape from innate immune recognition. This study was funded by D30 grant from DSTA, Singapore.
This article cites 54 articles, 30 of which can be accessed free
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1988
CD14 is a myeloid differentiation Ag expressed primarily on peripheral blood monocytes and macrop... more CD14 is a myeloid differentiation Ag expressed primarily on peripheral blood monocytes and macrophages. Although its function is unknown, the CD14 gene maps to a region encoding several myeloid growth factors and receptors. Analysis of the CD14 protein sequence deduced from the cDNA shows that although the CD14 protein contains a characteristic leader peptide, it lacks a characteristic transmembrane region, suggesting that CD14 may be anchored to the membrane via glycosylphosphatidylinositol (PI). Treatment of monocytes as well as a CD14-expressing neuroglioma cell line with PI-phospholipase C removed CD14 from the cell surface. Furthermore, monocytes from a patient with paroxysmal nocturnal hemoglobinuria, a disease characterized by lack of expression of other PI-linked proteins, failed to express CD14. Interestingly, the CD14-expressing neuroglioma cell line, which had been transfected with a single CD14 cDNA, released a soluble form of CD14 into the supernatant. Soluble forms of ...
The Journal of Immunology, 2005
Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia bur... more Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia burgdorferi. In vitro evidence suggests that binding of spirochetal lipoproteins to CD14, a pattern recognition receptor expressed on monocytes/macrophages and polymorphonuclear cells, is a critical requirement for cellular activation and the subsequent release of proinflammatory cytokines that most likely contribute to symptomatology and clinical manifestations. To test the validity of this notion, we assessed the impact of CD14 deficiency on Lyme disease in C3H/HeN mice. Contrary to an anticipated diminution in pathology, CD14 ؊/؊ mice exhibited more severe and persistent inflammation than did CD14 ؉/؉ mice. This disparity reflects altered gene regulation within immune cells that may engender the higher bacterial burden and serum cytokine levels observed in CD14 ؊/؊ mice. Comparing their in vitro stimulatory activity, live spirochetes, but not lysed organisms, were a potent CD14-independent stimulus of cytokine production, triggering an exaggerated response by CD14 ؊/؊ macrophages. Collectively, our in vivo and in vitro findings support the provocative notion that: 1) pattern recognition by CD14 is entirely dispensable for elaboration of an inflammatory response to B. burgdorferi, and 2) CD14-independent signaling pathways are inherently more destructive than CD14dependent pathways. Continued study of CD14-independent signaling pathways may provide mechanistic insight into the inflammatory processes that underlie development of chronic inflammation.
Medical Microbiology and Immunology, 1999
The CD14 myelomonocytic differentiation antigen plays a major role in acute Gram-negative infecti... more The CD14 myelomonocytic differentiation antigen plays a major role in acute Gram-negative infections with Escherichia coli; however, its role in chronic infections has not yet been analyzed. To address this question, we studied the role of CD14 in a chronic abscess-forming peritonitis, induced by Bacteroides fragilis. B. fragilis (3×10 8 CFU/ml) were resuspended in a liquid nutrient agar and injected into the peritoneal cavity of CD14-deficient (CD14-/-) and normal C57BL/6J (CD14+/+) mice, respectively. After 3 days there was a severe phlegmonous intraabdominal inflammation in both groups. After 7 days an abscess-forming peritonitis developed and by 14 days the infectious foci were compartimentalized. These observations were indistinguishable between CD14-/-and CD14+/+ mice. Although no differences were seen in abscess formation, CD14-/-mice were able to clear B. fragilis more efficiently from the blood than CD14+/+ mice. After 3, 7, and 14 days blood cultures were B. fragilis positive in 11% (1/9), 20% (2/10), and 0% (0/9) in CD14-/compared with 90% (9/10), 78% (7/9), and 20% (2/10) in CD14+/+ mice, respectively (P < 0.05). Furthermore, although the infection resulted in hepatocellular necrosis and severe hepatitis in both groups, at day 14 the liver cell damage was more severe in CD14+/+ than in CD14-/-mice (P < 0.05). These results show that the chronic abscess formation induced by B. fragilis capsular polysaccharides is CD14 independent; however, bacterial clearance and/or dissemination and liver cell damage are at least partially influenced by CD14-dependent mechanisms.
Infection and Immunity, 2007
Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that uti... more Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14−/− and CD14+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14−/− mice were resistant to the lethal effects of the K1-negative isolates. This resistance...
<b>Copyright information:</b>Taken from "CD14 mediates the innate immune respons... more <b>Copyright information:</b>Taken from "CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls"Arthritis Research & Therapy 2004;6(3):R273-R281.Published online 27 Apr 2004PMCID:PMC416450.Copyright © 2004 Li et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Spleen macrophages were stimulated for 30 min with PG-PS at a concentration of 20 μg/ml. The left column shows immunostaining of the p65 (RelA) subunit of NF-κB, and the right column shows counterstaining of nuclei with Hoechst 33342. The rows show the following: top – unstimulated cells from wild-type mice; middle – PG-PS stimulated cells from wild-type mice; and bottom row – PG-PS-stimulated cells from CD14 knockout mice. Representative data from three independent experiments are shown.
This article cites 72 articles, 54 of which you can access for free at:
<b>Copyright information:</b>Taken from "CD14 mediates the innate immune respons... more <b>Copyright information:</b>Taken from "CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls"Arthritis Research & Therapy 2004;6(3):R273-R281.Published online 27 Apr 2004PMCID:PMC416450.Copyright © 2004 Li et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Peritoneal macrophages were stimulated for 4 hours with the indicated concentrations of PG-PS. Concentrations of TNF-α and IL-6 were determined in supernatants by ELISA. Each determination was done in duplicates. TNF-α production by peritoneal macrophages. Data represent means ± standard error of the mean from three independent experiments. IL-6 production by peritoneal macrophages. Data represent mean ± SEM from two independent experiments.