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Restoring and maintaining the function of endothelial cells is critical for acute respiratory distress syndrome (ARDS). Guanylate binding protein 1(GBP1) is proved to elevated in ARDS patients, but its role and mechanism remains unclear. The objective of this study is to investigate the internal mechanism of GBP1 in lung injury. Our study showed that when the LPS and IFN-γ induced human Pulmonary Microvascular Endothelial Cells (HPMECs) injury model was established, cell viability was significantly reduced, and the levels of GBP1 levels and inflammatory factors were significantly increased. When transfection with si-GBP1, low expression of GBP1 promoted cell proliferation and migration, and decreased the expression of downstream inflammatory factors. Furthermore, the inhibition of GBP1 significantly reduced the occurrence of cell pyroptosis and the expression of NLRP3 and STAT1. Our study indicated that GBP1 alleviates endothelial pyroptosis and inflammation through STAT1 / NLRP3/GSDMD signaling pathway, and GBP1 may be a new target in the treatment of lung injury in the future. • GBP1 was increased in Inflammation induced HPMECs. • GBP1 is the key to regulate the proliferation and migration of HPMECs. • GBP1 regulate the inflammatory response of HPMECs. • GBP1 may regulate the pyroptosis of HPMECs through regulating STAT1 and NLRP3. [ABSTRACT FROM AUTHOR]

The combination of inflammatory factors resulting from an influenza A virus infection is one of the main causes of death in host animals. Studies have shown that guinea pig guanosine monophosphate binding protein 1 (guanylate-binding protein 1, gGBP1) can downregulate cytokine production induced by the influenza virus. Therefore, exploring the innate immune defense mechanism of GBP1 in the process of H5N1 influenza virus infection has important implications for understanding the pathogenic mechanism, disease prevention, and the control of influenza A virus infections. We found that, in addition to inhibiting the early replication of influenza virus, gGBP1 also inhibited the production of CCL2 and CXCL10 cytokines induced by the influenza virus as well as the proliferation of mononuclear macrophages induced by these cytokines. These findings further confirmed that gGBP1 inhibited the production of cytokines through its GTPase activity and cell proliferation through its C-terminal α-helix structure. This study revealed the effect of gGBP1 on the production of cellular inflammatory factors during influenza virus infection and determined the key amino acid residues that assist in the inhibitory processes mediated by gGBP1. [ABSTRACT FROM AUTHOR]

Brucellosis is a zoonotic disease that affects wild and domestic animals. It is caused by members of the bacterial genus Brucella. Guanylate-binding protein 1 (GBP1) is associated with microbial infections. However, the role of GBP1 during Brucella infection remains unclear. This investigation aimed to identify the association of GBP1 with brucellosis. Results showed that Brucella infection induced GBP1 upregulation in RAW 264.7 murine macrophages. Small interfering GBP1 targeting RNAs were utilized to explore how GBP1 regulates the survival of Brucella intracellularly. Results revealed that GBP1 knockdown promoted Brucella 's survival ability, activated Nod-like receptor (NLR) containing a pyrin domain 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammatory corpuscles, and induced pro-inflammatory cytokines IFN-γ and IL-1β. Furthermore, Brucella stimulated the expression of GBP1 in bone marrow-derived macrophages (BMDMs) and mice. During the inhibition of GBP1 in BMDMs, the intracellular growth of Brucella increased. In comparison, GBP1 downregulation enhanced the accumulation of Brucella -induced reactive oxygen species (ROS) in macrophages. Overall, the data indicate a significant role of GBP1 in regulating brucellosis and suggest the function underlying its suppressive effect on the survival and growth of Brucella intracellularly. • B. melitensis infection increased GBP1 expression in RAW 264.7 murine macrophages. • Knocking down the expression of GBP1 promotes Brucella infection RAW 264.7 murine macrophages. • Knocking down the expression of GBP1 induces the production of inflammatory cytokine in Brucella -infected macrophages. • Knocking down the expression of GBP1 promotes B. abortus persistence in bone marrow-derived macrophages. • Brucella infection increased GBP1 expression in vivo. [ABSTRACT FROM AUTHOR]

Highlights • Four markers associated with disease resistance were analyzed in several pig populations. • Two GBP1 SNPs were not in complete linkage disequilibrium in most pig breeds. • MUC4, FUT1 and GBP1 SNPs did not affect any production traits in Italian Large White pigs. • SNP allele frequencies did not substantially change over 20 years of selection in Italian Large White boars. • Marker-assisted selection based on these SNPs should not affect genetic gain for production traits. Abstract Infectious diseases have large economic impacts on the pig breeding industry worldwide. A few genetic markers associated to disease resistance have been recently identified and used in marker-assisted selection (MAS) in a few pig populations, as part of disease control programs. Neonatal Diarrhea (ND), Post-weaning Diarrhea (PWD), caused by enterotoxigenic E. coli , and Porcine Reproductive and Respiratory Syndrome, caused by PRRS virus (PRRSV), are diseases with high priority for the pig industry. Since interactions or antagonism between growth, innate immunity and disease resistance traits could exist, this work investigated if four disease resistance gene markers [mucin 4 (MUC4), rs338992994 associated with resistance to ND; fucosyltransferase 1 (FUT1), rs335979375 associated with resistance to PWD; and guanylate binding protein 1 (GBP1), rs340943904 and rs80800372 (also known as WUR10000125) associated with resistance to PRRS] could affect seven production traits (average daily gain, back fat thickness, lean meat cuts, feed gain ratio, ham weight, visible intermuscular fat and ham weight loss at first salting) and 15 haematological parameters in about 550 performance tested Italian Large White pigs. We also monitored allele frequencies of the same markers on Italian Large White boars sampled under the national selection breeding program over a 20 years-period. Moreover, we evaluated allele frequencies of these polymorphisms in four Italian local pig breeds (Apulo-Calabrese, Casertana, Cinta Senese and Nero Siciliano). The frequency of the resistance-associated alleles for the four polymorphisms was usually higher in all local pig breeds, indirectly supporting a higher rusticity of autochthonous breeds, compared to commercial populations. The two GBP1 polymorphisms were not in complete linkage disequilibrium in all breeds, except in Apulo-Calabrese. No significant allele frequency change for the investigated markers occurred over 20 years in the Italian Large White boar population in three of these markers. Only FUT1 showed a modest but significant change of allele frequencies over this period. Association analyses carried out in Italian Large White pigs for production traits, meat quality or haematological parameters under investigation showed no significant effect of any genotyped polymorphisms. Our results indicate that implementing MAS programs in Italian Large White pigs with polymorphisms associated with disease resistance have no direct effects on production traits. The selection program running for this heavy pig breed might not negatively impact disease resistance derived by the investigated major genes. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome (PRRS) is the most economically important disease to the swine industry, and effective prevention strategy for this disease is still required. Guanylate-binding protein 1 (GBP1) and myxovirus resistance protein 1 (Mx1) are two important proteins belonging to the GTPase superfamily that have been previously described to show antiviral effects. CD163 is considered the most important receptor for PRRSV attachment and internalization. Therefore, the aim of the present study was to evaluate the effects of these genes on host resistance against PRRSV infection in conjunction with the host immune response following PRRSV challenge. The results showed that pigs with AG genotype for the GBP1 exon2 exhibited a significantly higher average daily weight gain (ADWG) and lower average viremia than AA or GG genotype. Furthermore, pigs harbouring the AG genotype for the GBP1 gene presented greater CD4 + CD25 + and CD8 + CD25 + T cell populations at 4 and 18 days post challenge (dpc), respectively, as compared with other genotypes whereas pigs with CC genotype for the CD163 gene displayed significantly higher nucleocapsid-specific antibody titers at 11 dpc. However, pigs with a single 11-bp deletion or insertion in the Mx1 gene did not show significant differences in either weight gain or viremia. Based on these results, we concluded that GBP1 is most significantly associated with resistance against PRRSV infection and efficient T cell activation in pigs. [ABSTRACT FROM AUTHOR]

Abstract: The interferon-induced guanylate-binding protein 1 gene (GBP1) plays an important role in host defense against viral, bacterial and protozoan infections. To explore novel genetic variants in this gene, we re-sequenced a 587-bp fragment spanning the exon 2 of the GBP1 gene in a sample panel consisting of 34 wild boars and 59 local domestic pigs from three geographic regions (China, Iberian Peninsula, and Central Europe) and 12 individuals of three commercial breeds (Pietrain, Landrace, and Large White). In a final 543-bp sequence fragment, there were 14 single nucleotide polymorphisms (SNPs), of which five were coding (three novel mutations). A total of 19 haplotypes were reconstructed and most haplotypes were shared by two or more sample groups. Those shared haplotypes revealed a clear signature of genetic introgression from Chinese domestic pigs into European domestic pigs. In addition, there were six haplotypes with frequencies below 1%, but none of them were present in the three commercial breeds (Pietrain, Landrace, and Large White). Although a limited number of individuals and breeds were analyzed, the absence of rare alleles (or haplotypes) in the commercial breeds is an indication that a significant proportion of genetic diversity in domestic species is not present in commercial breeds. This study demonstrated the potential to find sufficient genetic variation for population genetic analyses of demography versus selection, in functional candidate genes of domestic pigs and wild boars worldwide. [Copyright &y& Elsevier]

Alveolar macrophage apoptosis induced by Mycobacterium tuberculosis (Mtb) plays a significant role in mediating the pathogenesis of tuberculosis. There is growing evidence that guanylate-binding proteins (GBPs) are associated with different pathological processes such as microbial infection. However, it remains unclear whether GBPs can regulate the apoptosis of macrophages induced by Mtb. In this study, we investigated the potential effect of GBP1 on RAW 264.7 cell apoptosis during Bacillus Calmette-Guerin (BCG) infection. The results demonstrated that BCG could induce macrophage apoptosis and GBP1 upregulation. In addition, we explored the role of GBP1 in regulating BCG-induced RAW 264.7 cell apoptosis using small interfering RNAs targeting GBP1. The results showed that knockdown of GBP1 could attenuate BCG-induced apoptosis in RAW 264.7 cells. Moreover, we found that GBP1 knockdown decreased the levels of cleaved-Caspase 3 and cleaved-PARP-1, while decreased those of cleaved-Caspase 9, BAX, Cytochrome C and APAF1. These findings imply that GBP1 knockdown can prevent BCG-induced apoptosis through an endogenous apoptosis pathway. In addition, the mitochondrial membrane potential of macrophages was significantly increased after BCG infection, and GBP1 knockdown could alleviate this phenomenon. Furthermore, downregulation of GBP1 also attenuated BCG-induced accumulation of reactive oxygen species in macrophages. Mechanistically, GBP1 suppressed the phosphorylation of the target molecules in p38/JNK pathway, thus regulating the apoptosis of BGC-infected macrophages. Collectively, these findings reveal a significant role of GBP1 in mediating cell apoptosis in macrophages infected with BCG, and the molecular mechanism underlying its suppressive effect on BCG-induced apoptosis. • BCG induces macrophage apoptosis. • BCG induces GBP1 upregulation. • Knockdown of GBP1 reduces BCG-induced cell apoptosis. • Knockdown of GBP1 suppresses the p38/JNK signal transduction pathway. [ABSTRACT FROM AUTHOR]

Abstract: Experimental evidence indicated that interferon-inducible guanylate-binding proteins (GBPs) are similar with genes in the myxovirus (Mx) resistance protein subfamily of the large GTPases protein family and play important roles in the resistance to intracellular pathogens. As more diseases exert significant influence on pig industry, it is anticipated that more candidate disease-resistance genes could be found in future strategies aimed at improving genetic resistance to infectious diseases. In this study, we cloned cDNA sequences and analyzed the genomic structure of porcine GBP1 (poGBP1) and GBP2 (poGBP2). The two genes were mapped to SSC4q21-q23 and SSC4q24 by the SCHP panel respectively, further IMpRH panel analysis showed both genes were most closely linked to the marker SWR153. The deduced amino acid sequences of these two genes share the same three classical GTP-binding motifs at the amino terminus and are less conserved at the carboxyl termini except for a CaaX motif, compared with human and mouse counterparts. The reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that poGBP1 and poGBP2 were both widely expressed in many tissues, and transient transfection indicated that poGBP1 and poGBP2 proteins were both located in cytoplasms within Pig Kidney Epithelial cells (PK15). Quantitative real-time PCR (Q-RT-PCR) analyses showed poGBP1 and poGBP2 had very similar expression patterns in PK15 cells at different time points after poly I:C stimulation, suggesting that ISRE (interferon-stimulated response element) plays a crucial role in the transcriptional regulation of these two genes. Four single nucleotide polymorphisms (SNPs) and three SNPs were detected in the cDNA sequences of poGBP1 and poGBP2, respectively. Association analyses revealed that the poGBP1 Eco81I and poGBP2 SspI polymorphisms both had significant associations (p <0.05) with red blood cell count (RBC), haemoglobin concentration (HGB) and hematocrit (HCT) of 17-day-old pigs. [Copyright &y& Elsevier]