Peptidoglycan Recognition Protein 1 Research Articles

The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells

ObjectivePancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant ‘stem-like’ cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending...

Peptidoglycan recognition protein-1 gene polymorphism and its association with mastitis in Murrah buffalo

A wide variety of environmental or contagious microorganisms implicated in mastitis, impede the economic growth of dairy sector. Identification of polymorphism in candidate gene of host’s immune system and to rule out mastitis resistant allelic form of candidate gene usually remains prime focal point of research. Bovine peptidoglycan recognition protein-1 (PGLYRP-1), exclusively present in the granules of polymorphonuclear leukocytes has direct microbicidal properties. The present study was carried out to find the association between PGLYRP-1 polymorphic alleles with mastitis. Milk samples for somatic cell count and blood samples for PCR-RFLP analysis of PGLYRP-1 gene were collected from 20 mastitis negative and 20 mastitis positive Murrah buffaloes. There was significant difference in somatic cell count of mastitis and mastitis free animals. All amplified PCR products of ~862 bp size of partial region of PGLYRP-1 gene were subjected to each restriction enzyme (HincII or TaqαΙ or ApaI). Polymorphism in the partial region of PGLYRP-1 gene had not been established using PCR-RFLP as uniformity in pattern of digested fragments was seen. Target sequence PGLYRP-1 gene of Murrah buffalo was cloned and sequenced. BLAST analysis revealed sequence identity of PGLYRP-1 of Murrah buffalo with Bos taurus (JN085441.1) sequence at NCBI was 96%, 96% with Bos indicus (JN085440.1) and 96% with Bos indicus X Bos taurus (EU746454.1). In phylogenetic tree, the target sequence of PGLYRP-1 gene of Bubalus bubalis are found more closely related to Bos taurus than to Bos indicus.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM’s ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.

Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.

Value of gingival crevicular fluid TREM-1, PGLYRP1, and IL-1β levels during menopause.

This study aimed to investigate the association of GCF TREM-1, PGLYRP1, and IL-1β levels with periodontal health in pre- and postmenopausal women. Triggering receptor expressed on myeloid cells 1 (TREM-1), activated through its ligand peptidoglycan recognition protein 1 (PGLYRP1), stimulates proinflammatory cytokine production, such as interleukin (IL)-1β, during periodontal inflammation. Postmenopausal changes may modulate these immune-inflammatory functions. No clinical study has yet investigated the effect of menopause on TREM-1, PGLYRP1, and IL-1β levels in gingival crevicular fluid (GCF). This cross-sectional study included 148 women (age range = 35-65 years), divided into postmenopausal women (PMW) (n = 76, mean age = 54 ± 5 years) and regularly menstruating premenopausal women (RMPW) (n = 72, mean age = 40 ± 4 years). Clinical periodontal parameters were recorded. TREM-1, PGLYRP1, and IL-1β levels were quantified with enzyme-linked immunosorbent assays. Pearson's Chi-squared test and Mann-Whitney-U test were used to compare categorical and numerical variables, respectively. Spearman's Rho correlation analysis was used to test the linear relationship between variables. Analyte level data were categorized based on the periodontal diagnosis and menopause status (2 × 2 nonparametric factorial ANOVA). No significant differences in TREM-1, PGLYRP1, and IL-1β levels between PMW and RMPW were observed (p > .05). Mean values of periodontal indexes including probing depth did not differ significantly between PMW and RMPW groups (p = .474). TREM-1 levels were significantly higher in both PMW and RMPW with periodontitis, compared to gingivitis or health (p = .0021). Menopause-related changes have no observable effect on GCF levels of TREM-1, PGLYRP1, and IL-1β. Higher GCF TREM-1 levels in women with periodontitis regardless of their menopausal status indicate that TREM-1 may be an indicator for periodontitis both in premenopausal and postmenopausal women.

Expressions of Peptidoglycan Recognition Protein 1, Neuron Towards Axon Guidance Factor-1 and miR-142-3p and Their Correlations in Patients with Rheumatoid Arthritis.

We aimed to explore the expressions of peptidoglycan recognition protein 1 (PGLYRP-1), neuron towards axon guidance factor-1 (Netrin-1) and miR-142-3p and their correlations in patients with rheumatoid arthritis. Sixty patients with rheumatoid arthritis treated from January 2022 to January 2023 were enrolled as a rheumatoid group, 30 patients with osteoarthritis were selected as an osteoarthritis group, and 30 healthy volunteers were recruited as a control group. The enzyme-linked immunosorbent assay, Western blotting and reverse transcriptase-polymerase chain reaction were employed to measure the expressions of PGLYRP-1, Netrin-1 and miR-142-3p, respectively. The correlations among PGLYRP-1, Netrin-1 and miR-142-3p expressions in patients with rheumatoid arthritis were analyzed. In patients with rheumatoid arthritis, PGLYRP-1 expression was negatively correlated with Netrin-1 expression (r=-0.570, P=0.001) but positively correlated with miR-142-3p expression (r=0.599, P=0.001), and a negative correlation was found between Netrin-1 and miR-142-3p expressions (r=-0.468, P=0.001). The combined detection of PGLYRP-1, Netrin-1 and miR-142-3p was more sensitive and less specific for predicting the prognosis of patients with rheumatoid arthritis than the measurement of a single marker (P<0.05). The combined measurement of PGLYRP-1, Netrin-1 and miR-142-3p has a predictive value for the prognosis of patients with rheumatoid arthritis.

Association of salivary TREM-1 and PGLYRP1 inflammatory markers with non-communicable diseases.

Triggering receptor expressed on myeloid cells 1 (TREM-1) and peptidoglycan recognition protein 1 (PGLYRP1) are elevated in biofluids in the presence of various inflammatory conditions. This cross-sectional study aimed to evaluate the effect of age, sex, smoking and different oral and systemic non-communicable diseases on the levels of TREM-1 and PGLYRP1 in saliva. In total, 445 individuals (mean age 48.7 ± 16.9 years, female:male 51%:49%) were included. All provided self-reported information on smoking and systemic diseases and whole stimulated saliva. Periodontal and cariological parameters were recorded. Salivary levels of TREM-1, PGLYRP1 and total protein were measured using commercially available assays. Salivary TREM-1 levels were significantly higher in stages III-IV periodontitis compared to other periodontal diagnoses (p < .05). Smoking, bleeding on probing (BOP), percentage of pockets ≥4 mm and the number of manifest caries were associated with TREM-1 (p < .05), while sex, BOP, number of manifest caries and muscle and joint diseases were associated with PGLYRP1 (p < .05). Salivary TREM-1 is associated with periodontitis and caries, while PGLYRP1 is associated with gingival inflammation and caries. Additionally, TREM-1 levels are modified by smoking, while PGLYRP1 is modified by sex and muscle and joint diseases. TREM-1 and PGLYRP1 in saliva could serve as potential biomarkers for detecting and monitoring non-communicable diseases.

A mechanistic analysis of bacterial recognition and serine protease cascade initiation in larval hemolymph of Manduca sexta

Serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid defense responses. Previous biochemical studies showed that in hemolymph of a caterpillar, Manduca sexta, recognition of fungi by β-1,3-glucan recognition proteins (βGRP1 and βGRP2) or recognition of bacteria by peptidoglycan recognition protein-1 (PGRP1) and microbe binding protein (MBP) results in autoactivation of hemolymph protease-14 precursor (proHP14). HP14 then activates downstream members of a protease cascade leading to the melanization immune response. ProHP14 has a complex domain architecture, with five low-density lipoprotein receptor class A repeats at its amino terminus, followed by a Sushi domain, a Sushi domain variant called Wonton, and a carboxyl-terminal serine protease catalytic domain. Its zymogen form is activated by specific proteolytic cleavage at the amino-terminal end of the protease domain. While a molecular mechanism for recognition and triggering the response to β-1,3-glucan has been delineated, it is unclear how bacterial recognition stimulates proHP14 activation. To fill this knowledge gap, we expressed the two domains of M. sexta MBP and found that the amino-terminal domain binds to diaminopimelic acid-peptidoglycan (DAP-PG). ProHP14 bound to both the carboxyl-terminal domain (MBP-C) and amino-terminal domain (MBP-N) of MBP. In the mixture of DAP-PG, MBP, and larval plasma, inclusion of an HP14 fragment composed of LDLa repeats 2–5 (LDLa2–5) or MBP-C significantly reduced prophenoloxidase activation, likely by competing with the interactions of the full-length proteins, and suggesting that molecular interactions involving these regions of proHP14 and MBP take part in proHP14 activation in response to peptidoglycan. Using a series of N-terminally truncated versions of proHP14, we found that autoactivation required LDLa2–5. The optimal ratio of PGRP1, MBP, and proHP14 is close to 3:2:1. In summary, proHP14 autoactivation by DAP-type peptidoglycan requires binding of DAP-PG by PGRP1 and the MBP N-terminal domain and association of the LDLa2–5 region of proHP14 with the MBP C-terminal domain. These interactions may concentrate the proHP14 zymogen at the bacterial cell wall surface and promote autoactivation.

Association of peptidoglycan recognition protein 1 to post-myocardial infarction and periodontal inflammation: A subgroup report from the PAROKRANK (Periodontal Disease and the Relation to Myocardial Infarction) study.

Peptidoglycan recognition protein 1 (PGLYRP1) is an antimicrobial and proinflammatory innate immunity protein activated during infections. We aimed to investigate whether PGYLRP1 and associated molecules of the immune response in saliva is a cumulative outcome result of both MI and periodontal inflammation. Two hundred patients with MI and another 200 matched non-MI controls were included. A full-mouthexamination was conducted to assess periodontal inflammation and collection of stimulated saliva was performed 6 to 10weeks after the first MI. PGLYRP1, triggering receptor expressed on myeloid cells 1(TREM-1), interleukin-1 beta (IL-1β) were analyzed by ELISA. Matrix metalloproteinase (MMP)-8 levels were determined by IFMA. Compared to controls, MI patients showed higher salivary PGLYRP1, but not TREM-1 levels. The difference in PGLYRP1 levels remained after adjustment for covariates. In MI patients, the PGLYRP1 levels positively correlated with BOP and PPD 4 to 5mm. Among non-MI subjects, the levels of PGLYRP1 correlated positively and significantly with BOP and total PPD. Salivary PGLYRP1 concentrations also showed strong positive correlations with levels of TREM-1, IL-1β and MMP-8. In multivariate linear regression analysis, in MI patients, BOP and former smokingstatus displayed an association with salivary PGLYRP1 concentration. MI patients showed higher salivary PGLYRP1 levels than healthy controls, also after adjusting for smoking, sex, age and periodontal health status. Salivary levels of PGLYRP1 may reflect the overall inflammatory burden to chronic bacterial exposure, possibly underpinning the observed associations between periodontitis and exposure with MI.

TNF upregulates peptidoglycan recognition protein 1 in esophageal cancer cells to clear the path to its signaling: Making the “enemy” a friend

TNF, CCN1, and peptidoglycan recognition protein 1 (PGLYRP1) are often found together in the inflammatory tissue. While TNF and CCN1 promote tissue regeneration, PGLYRP1 protects it from bacterial infection. In fibroblasts, CCN1 was reported to support TNF in apoptosis induction while PGLYRP1 was found to compete with TNF for binding to TNFR1. When PGLYRP1 binds to TNFR1 by itself, it silences the receptor, but if HSP70 joins them, it leads to cell death. In cancer cells, however, CCN1 was found to antagonize TNF signaling by increasing the extracellular pool of TNFR1. In this study, we assessed their relationship in the esophageal cancer cells and found a more complex liaison among them. At first, TNF highly upregulated PGLYRP1 expression but downregulated CCN1. Secondly, PGLYRP1 bound TNFR1 and HSP70 both intracellularly and extracellularly, but TNF only promoted their extracellular interaction. Lastly, the knockdown of PGLYRP1 impaired TNF signaling. Taken together, this study shows that CCN1 interrupts TNF signaling by increasing the extracellular TNFR1 species while TNF fights back by upregulating PGLYRP1 to absorb them.

A study on variability of bioactive proteins in camel (Camelus dromedarius) milk: Insulin, insulin‐like growth factors, lactoferrin, immunoglobulin G, peptidoglycan recognition protein‐1, lysozyme and lactoperoxidase

Milk samples were collected from 140 individual dromedary camels (Camelus dromedarius) to determine the variability in the concentrations of several bioactive whey proteins. The ranges were as follows: insulin (IN) (17.8–51.1 mIU/L), insulin‐like growth factor I (IGF1) (1.4–736.1 ng/mL), insulin‐like growth factor II (IGF2) (13.7–82.6 ng/mL), lactoferrin (639.4–2094.9 µg/mL), immunoglobulin G (IgG) (7.3–17.9 mg/mL), peptidoglycan recognition protein‐1 (PGRP‐1) (1.6–22.3 ng/mL), lysozyme (LZ) (23.3–71.4 µg/mL) and lactoperoxidase (LPO) (7.1–15.5 ng/mL). These data demonstrate wide variation in the concentrations of the studied proteins. Significant correlations (P &lt; 0.05) were observed between the concentrations of IN and LZ, IN and IgG, IN and PGRP‐1, LZ and PGRP‐1, IgG and LPO, and IgG and PGRP‐1.

SEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae.

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2-/-) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2-/- mice. Ephx2-/- mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2-/- macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2-/- macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.

A Short-Type Peptidoglycan Recognition Protein 1 (PGRP1) Is Involved in the Immune Response in Asian Corn Borer, Ostrinia furnacalis (Guenée).

The insect immune response is initiated by the recognition of invading microorganisms. Peptidoglycan recognition proteins (PGRPs) function primarily as pattern recognition receptors by specifically binding to peptidoglycans expressed on microbial surfaces. We cloned a full-length cDNA for a PGRP from the Asian corn borer Ostrinia furnacalis (Guenée) and designated it as PGRP1. PGRP1 mRNA was mainly detected in the fat bodies and hemocytes. Its transcript levels increased significantly upon bacterial and fungal challenges. Purified recombinant PGRP1 exhibited binding activity to the gram-positive Micrococcus luteus, gram-negative Escherichia coli, entomopathogenic fungi Beauveria bassiana, and yeast Pichia pastoris. The binding further induced their agglutination. Additionally, PGRP1 preferred to bind to Lys-type peptidoglycans rather than DAP-type peptidoglycans. The addition of recombinant PGRP1 to O. furnacalis plasma resulted in a significant increase in phenoloxidase activity. The injection of recombinant PGRP1 into larvae led to a significantly increased expression of several antimicrobial peptide genes. Taken together, our results suggest that O. furnacalis PGRP1 potentially recognizes the invading microbes and is involved in the immune response in O. furnacalis.

Peptidoglycan Recognition Protein 1 Attenuates Atherosclerosis by Suppressing Endothelial Cell Adhesion.

Peptidoglycan recognition protein 1 (PGLYRP1) has long been believed to play an important role in infectious and immune diseases. We hypothesized that it might be involved in the pathophysiology of atherosclerotic diseases, which are regarded as chronic inflammatory diseases. Serum PGLYRP1 concentrations were measured in 240 patients with coronary artery disease (CAD) and 209 age-matched and gender-matched individuals with normal coronary arteries using enzyme-linked immunosorbent assay. The expression of PGLYRP1 in atherosclerotic plaques was quantified using western blotting and immunostaining. ApoE-/- mice, fed a high-fat diet, were randomly given intraperitoneal injections of saline or recombinant PGLYRP1 protein for 12 weeks. The effects of PGLYRP1 on human umbilical vein endothelial cells were investigated by western blotting. Higher concentrations of PGLYRP1 were significantly associated with a higher risk of CAD. The odd ratio for upper quartile versus lower quartile was 2.24 (95% confidence interval: 1.21-4.13) after adjustment for sex, age, smoking, body mass index, lipid profile, blood pressure, fasting glucose, and estimated glomerular filtration rate. PGLYRP1 was highly expressed in murine atherosclerotic plaques. Recombinant PGLYRP1 protein alleviated the progress of atherosclerosis in vivo and reduced the expression of endothelial cells' adhesion molecules in vitro. In conclusion, our study suggested that PGLYRP1 is upregulated in patients with CAD and atherosclerotic plaques. PGLYRP1 may participate in the pathophysiological process of atherosclerosis.

Effects of colostrum feeding on the mRNA abundance of genes related to toll-like receptors, key antimicrobial defense molecules, and tight junctions in the small intestine of neonatal dairy calves

The objective of the present study was to elucidate the effect of feeding either colostrum or milk-based formula on the mRNA abundance of genes related to pathogen recognition [toll-like receptors (TLR1-10)], antimicrobial defense [β-defensin 1 (DEFB1) and peptidoglycan recognition protein 1 (PGLYRP1)], and tight junctions (claudin 1 = CLDN1, claudin 4 = CLDN4, and occludin = OCLN) in different sections of the small intestine of neonatal calves at d 4 of life. Holstein dairy calves were fed either colostrum (COL; n = 7) or milk-based formula (FOR; n = 7) with comparable nutrient composition but lower contents of several bioactives in the formula than in the respective colostrum group until d 4 of life. Following euthanasia on d 4 (2 h after feeding), tissue samples from the duodenum, jejunum (proximal, middle, and distal), and ileum were collected. The mRNA abundance of the target genes was quantified by quantitative PCR. The mRNA abundance of TLR1, TLR6, TLR9, and TLR10 were greater in COL than in FOR calves. However, the mRNA abundance of TLR2, TLR3, TLR4, TLR5, and TLR7 did not differ between groups. A group × gut region interaction was observed for the mRNA abundance of TLR8 with greater values in duodenum and proximal jejunum of COL than in FOR calves but in the more distal regions, in mid and distal jejunum, and ileum, this diet effect disappeared or was reversed. We observed greater mRNA abundance of TLR1 in the jejunum (middle and distal) and ileum, TLR2, TLR4, TLR6, and TLR9-10 in the distal jejunum and ileum, and of TLR3 in the distal jejunum, and TLR5, TLR7, and TLR8 in the ileum compared with the other gut regions. The mRNA abundance of PGLYRP1, DEFB1, and OCLN did not differ between groups. The mRNA abundance of CLDN1 was greater, but the CLDN4 mRNA tended to be lower in COL than in FOR calves. The mRNA abundance of PGLYRP1 was lower in the distal jejunum and DEFB1 mRNA in the middle jejunum compared with the other gut regions. The mRNA abundances of OCLN and CLDN4 were greater in the duodenum, and of CLDN1 in the middle and proximal jejunum compared with the other gut regions. Overall, the greater mRNA abundance of 5 different TLR, and CLDN1 in most intestinal sections of the COL calves may suggest that feeding colostrum improves immune responsiveness and epithelial barrier function in neonatal calves.

Measurement of Seminal plasma peptidoglycan recognition protein-1 (PGLYRP‐1) protein infertile males as a measure of leukocytospermia and bad seminal fluid parameters

Human peptidoglycan recognition protein-1 (PGLYRP‐1) protein molecule activation in the semen of infertile patients has been suggested to induce a negative impact on seminal fluid analysis. 176 infertile patients included in this study were tested for seminal fluid analysis, Endtz test, and PGLYRP‐1 in seminal plasma using enzyme-linked immunosorbent assay (ELISA) technology. PGLYRP‐1 is evident in the seminal plasma of infertile men and is statistically different according to the type of infertility. The concentration of PGLYRP-1 in the semen is directly proportional to the presence of leukocytes (Endtz test), which is reflected negatively on the quality of the semen. To the best of our knowledge, this study has not been done in Iraq or elsewhere. The presence of PGLYRP-1 protein in the semen may be evidence of leukocytospermia that may be related to bad quality for semen across infertile men with higher sensitivity than the Endtz test.

Circulating PGLYRP1 Levels as a Potential Biomarker for Coronary Artery Disease and Heart Failure.

Coronary artery disease (CAD) and associated comorbidities such as heart failure (HF) remain the leading cause of morbidity and mortality worldwide attributed to, at least partially, the lack of biomarkers for efficient disease diagnosis. Here, we evaluated the diagnostic potential of serum peptidoglycan recognition protein 1 (PGLYRP1), an important component of the innate immunity and inflammation system, for both CAD and HF. A machine-learning method (random forest) was used to evaluate the clinical utility of circulating PGLYRP1 for diagnosis of CAD and HF in a total of 370 individuals. Causal links of chronic serum PGLYRP1 elevation to both diseases were further explored in ApoE-/- mice. The serum levels of PGLYRP1 were significantly higher in individuals with either chronic CAD or acute coronary syndrome than those in those without coronary artery stenosis (the control group) and even more pronounced in CAD individuals with concomitant HF. Our random forest classifier revealed that this protein performed better than other recommended clinical indicators in distinguishing the CAD from the control individuals. In addition, this protein associates more with the biomarkers of HF including left ventricular ejection fraction than inflammation. Notably, our mice experiment indicated that long-term treatment with recombinant PGLYRP1 could significantly impair the cardiovascular system as reflected from both increased atherogenic lesions and reduced fractional shortening of the left ventricle. Our findings, therefore, supported the circulating levels of PGLYRP1 as a valuable biomarker for both CAD and HF.

Survey of Candidate Single-Nucleotide Polymorphisms in SLC11A1, TLR4, NOD2, PGLYRP1, and IFNγ in Ankole Longhorn Cattle in Central Region of Uganda to Determine Their Role in Mycobacterium avium Subspecies paratuberculosis Infection Outcome.

Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne's disease (JD) in a wide range of domestic and wild ruminants. Single-nucleotide polymorphisms (SNPs) in several genes including solute-like carrier 11A1 (SLC11A1), interferon gamma (IFNγ), Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain 2 gene (NOD2), and bovine peptidoglycan recognition protein 1 (PGLYRP1) have been implicated in influencing the infection outcome of MAP in cattle. We have carried out a survey in a population of Ankole cattle from three districts in the central region of Uganda including Isingiro, Lyantonde, and Rakai to determine the role played by several SNPs on the above genes in the infection outcome of local cattle in Uganda. Nine hundred fifty-five heads of cattle obtained from 93 herds were tested using ELISA. Thirty-five ELISA-positive cattle and 35 negative herd mates from a total of 955 cattle tested for MAP were genotyped using iPLEX MassARRAY genotyping systems to detect the presence of a total of 13 SNPS in five different genes (SLC11A1, IFNγ, TLR4, NOD2, and PGLYRP1). The cow-level prevalence of MAP infection in Ankole Longhorn cattle in the three districts was 3.98% (35/955), while the herd-level prevalence was 27.9% and within-herd prevalence was 12 ± 1.5% (95% CI = 9.1–14.8%). The genotypes and allele frequencies of the MAP-positive cattle were compared with those of their ELISA-negative herd mates to determine the significance of the polymorphisms. The results showed that SNPs rs109915208, rs110514940, and rs110905610 on SLC11A1, c.480G>A and c.625C>A on PGLYRP1, and c.2021C>T on TLR4 were monomorphic in both seropositive and seronegative cattle and therefore had no influence on the infection outcome. The remaining SNPs studied in the five genes [SLC11A1: rs109614179; TLR4: rs29017188 (c.226G>C), c.2021C>T; NOD2: rs110536091, rs111009394; PGLYRP1: c.102G>C, c.480G>A, c.625C>A; IFNγ: rs110853455] were polymorphic, but their allele and genotype frequencies did not show any significant difference between the seropositive and seronegative cattle. No significant difference was observed for any haplotype at the gene level.

Elevated serum TREM-1 is associated with periodontitis and disease activity in rheumatoid arthritis

The triggering receptor expressed on myeloid cells 1 (TREM-1) and peptidoglycan recognition protein 1 (PGLYRP1) are involved in the propagation of inflammatory responses. This study investigated whether serum levels of TREM-1 and PGLYRP1 correlate with periodontitis in rheumatoid arthritis (RA) patients. A total of 154 non-smoking participants with RA (n = 55, F/M: 41/14), Behçet´s disease (BD, n = 41, F/M: 30/11) and healthy controls (HC, n = 58, F/M: 40/18) were recruited. Serum and saliva were collected, the 28-joint disease activity score (DAS-28) was calculated and dental/periodontal measurements were recorded. Serum TREM-1 and PGLYRP1 levels were measured by ELISA and salivary bacterial DNA counts by quantitative polymerase chain reaction. TREM-1 and PGLYRP1 levels were higher in RA (166.3 ± 94.3; 155.5 ± 226.9 pg/ml) than BD (102.3 ± 42.8; 52.5 ± 26.3 pg/ml) and HCs (89.8 ± 55.7; 67.4 ± 37.3 pg/ml) (p < 0.05). In RA, periodontitis was associated with increased TREM-1 and PGLYRP1 levels (p < 0.05), yet in patients under methotrexate TREM-1 levels were lower. TREM-1 correlated with C-reactive protein (CRP) levels, DAS-28 and erythrocyte sedimentation rate, whereas PGLYRP1 positively correlated with CRP. RA patients displayed 3.5-fold higher salivary bacterial DNA counts than HCs. Increased serum TREM-1 levels correlated with PGLYRP1, CRP and DAS-28-ESR in RA patients with periodontitis.

A human secretome library screen reveals a role for Peptidoglycan Recognition Protein 1 in Lyme borreliosis.

Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host’s response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.