Alternative titles; symbols
HGNC Approved Gene Symbol: PTX3
Cytogenetic location: 3q25.32 Genomic coordinates (GRCh38): 3:157,436,850-157,443,633 (from NCBI)
Pentraxins are conserved acute-phase proteins with a cyclic pentameric structure. PTX3, the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against select pathogens. Signals for PTX3 production differ from and precede those of the short pentraxins, C-reactive protein (CRP; 123260) and serum amyloid P (APCS; 104770) (summary by Rovere et al. (2000) and Jaillon et al. (2013)).
Using differential hybridization to identify cDNAs induced in human umbilical vein endothelial cells by interleukin-1-beta (IL1B; 147720), Breviario et al. (1992) cloned PTX3. The predicted 381-amino acid PTX3 protein has homology to the pentraxin protein family (see 600750). Based on the Greek derivation, Breviario et al. (1992) suggested that this family be named pentaxin.
Using differential hybridization to screen for cDNAs induced in fibroblasts treated with tumor necrosis factor (TNF; 191160), Lee et al. (1990) identified a partial cDNA encoding PTX3, which they designated 'tumor necrosis factor-stimulated gene sequence-14' (TSG14).
Basile et al. (1997) suggested that PTX3 belongs to the family of 'long pentraxins,' which have C-terminal pentraxin domains and novel N-terminal domains.
Breviario et al. (1992) determined that the PTX3 gene contains 3 exons.
Basile et al. (1997) studied the PTX3 promoter and identified a 1,317-bp fragment, located 5-prime to the transcriptional start site, that conferred TNF- and IL1B-inducible transcriptional activity in transfected fibroblasts. They also identified a functional NF-kappa-B (164011, 164012) site in the promoter.
Breviario et al. (1992) mapped the PTX3 gene to chromosome 3q25 by somatic cell hybrid analysis and fluorescence in situ hybridization.
Bottazzi et al. (1997) showed binding of the N-glycosylated multimer-forming PTX3 to C1q (see 120550), but not to C1S (120580) or ligands of the classical liver pentraxins, CRP or SAP (APCS).
Rovere et al. (2000) showed that PTX3 bound to apoptotic cells, and to a lesser extent necrotic cells, in a dose-dependent and saturable manner. Binding was restricted to the phase in which nuclear antigens segregated to the cell membrane. In the presence of PTX3, dendritic cells failed to internalize dying cells. PTX3 did not inhibit uptake of soluble particles. Rovere et al. (2000) proposed that PTX3-mediated sequestration of cell remnants may contribute to the prevention of onset of autoimmunity.
Using FACS analysis, Garlanda et al. (2002) showed that PTX3 bound selected pathogens, including Aspergillus fumigatus, Pseudomonas aeruginosa, and Salmonella typhimurium. PTX3 bound to either viable or heat-inactivated conidia, but not the hyphae, of A. fumigatus, and Ptx3 facilitated conidia interaction with mononuclear phagocytes. Conidia rapidly induced PTX3 production in human and mouse monocytes and dendritic cells, but not in neutrophils, fibroblasts, or endothelial or epithelial cells. Infection of mice and humans with A. fumigatus induced high levels of PTX3 in plasma and bronchoalveolar lavage fluid. Significant levels of PTX3 were detected in plasma of neutropenic patients with systemic A. fumigatus infection, but only low levels were found in control subjects. Flow cytometric analysis showed binding of PTX3 to monocytes and dendritic cells, but not to T lymphocytes.
Bozza et al. (2006) showed that PTX3 bound both murine and human cytomegalovirus (CMV), inhibited viral infection in vitro, and activated IRF3 (603734). PTX3 treatment protected mice from murine CMV infection by reducing viral load and inflammatory pathology. PTX3 treatment also completely prevented viral reactivation after hematopoietic stem cell transplantation and invasive pulmonary aspergillosis (see 614079). Mice lacking Il12p70 (IL12A; 161560), Ifng (147570), Tlr2 (603028), Tlr3 (603029), or Tlr4 (603030) could not be protected by PTX3. Protection mediated by PTX3 was independent of Myd88 (602170) and Tlr9 (605474). Bozza et al. (2006) concluded that PTX3 is effective in preventing CMV infection and reactivation, as well as subsequent Aspergillus infection.
Jaillon et al. (2013) noted that newborns are highly susceptible to microbial infections, but that this susceptibility is mitigated by maternal milk. They found that serum PTX3 levels were lower in neonatal compared with adult humans and mice. Colostrum in the first 2 days after delivery contained higher levels of PTX3 than in healthy adult or maternal serum. Western blot analysis detected 86- and 45-kD proteins, corresponding to PTX3 dimers and monomers, in human colostrum, but not in milk formula of bovine origin. Human mammary gland and neutrophils in human milk constitutively expressed PTX3 mRNA and protein. In vitro, human milk potentiated PTX3 production induced by lipopolysaccharide (LPS). Jaillon et al. (2013) concluded that breastfeeding constitutes an important source of PTX3, which may have an important protective role against infections, as well as therapeutic potential.
Among 268 patients who underwent hematopoietic stem cell transplantation, Cunha et al. (2014) found a significant association between the development of invasive aspergillosis within 24 months after transplant and homozygosity for an h2/h2 haplotype in the PTX3 gene in the donor cells. The cumulative incidence of invasive aspergillosis in patients who donor cells were homozygous for h2/h2 was 37%, compared to h1/h1 (15%) or h1/h2 donors (14%), yielding an adjusted hazard ratio of 3.08 (p = 0.003). This association was confirmed in a replication study of patients who underwent hematopoietic bone marrow transplantation (adjusted odds ratio of 2.78, p = 0.03), but was not observed in a second independent study of patients with prolonged neutropenia. PTX3 levels in bronchoalveolar lavage fluid was significantly different according to donor haplotype: it was decreased in patients with h2/h2 donors compared to those with h1/h1 donors, both in the presence and absence of invasive aspergillosis. Western blot analysis, immunofluorescence studies, and PTX3 mRNA levels were decreased in lung tissue and in neutrophils from patients with h2/h2 donors compared to those with h1/h1 donors. Neutrophils from patients with h2/h2 donors showed an impaired ability to phagocytose conidia of aspergillus compared to patients with h1/h1 donors, and the addition of PTX3 restored this ability. The association was independent of HLA status, suggesting an independent contribution of PTX3 variants to the development and outcome of invasive aspergillosis. Finally, the absence of an association between genetic variants in the transplant recipients themselves and invasive aspergillosis suggested that epithelial PTX3 has a smaller role, if any, in the immune response to the fungus. Cunha et al. (2014) concluded that decreased expression of PTX3 in neutrophil precursors affects the antifungal function of these immune cells, resulting in increased susceptibility to invasive aspergillosis in patients undergoing hematopoietic stem cell transplantation. De Boer et al. (2014) were unable to confirm the association between invasive aspergillosis following hematopoietic stem cell transplantation and PTX3 polymorphisms in a study of 44 cases and 68 controls, casting doubt on the findings of Cunha et al. (2014). Cunha et al. (2014) defended their results, noted that genetic susceptibility to invasive aspergillosis is probably polygenic, and attributed failure to validate the association to possible population heterogeneity.
Garlanda et al. (2002) found that Ptx3-deficient mice were susceptible to invasive pulmonary aspergillosis. Whereas normal mice survived challenge with aspergillus, Ptx3-deficient mice, like C1q-deficient mice, rapidly succumbed to infection. The increased susceptibility of Ptx3-deficient mice correlated with marked increase in lung and brain colonization; numerous, mainly extracellular conidia were seen, rather than the few intracellular conidia found in control mice. The Ptx3-deficient mice also produced reduced levels of Ifng and Il12 (161561) and increased Il4 (147780) compared with controls, and this defect could be reversed by Ptx3 administration. Garlanda et al. (2002) concluded that PTX3 acts as a soluble pattern-recognition receptor that has a nonredundant role in resistance against the fungal pathogen A. fumigatus. They proposed that PTX3 may have therapeutic potential in bone marrow transplantation and similar immunodeficiency contexts.
Using an air pouch mouse model, Cotena et al. (2007) found that Ptx3 amplified the inflammatory response elicited by Klebsiella pneumoniae outer membrane protein (OmpA), but not by LPS. Production of inflammatory mediators, such as complement, but not lipid moieties, such as leukotrienes and prostaglandins, was increased. Inactivation of complement drastically reduced the effect of Ptx3. Cotena et al. (2007) concluded that PTX3 activates a complement-dependent pathway of amplification of the innate immune response to microbial ligands.
Jaillon et al. (2013) detected Ptx3 in neonatal mouse tissues within 15 minutes after orally administering mouse Ptx3 to neonatal mice. Serum and lung Ptx3 was detected in most Ptx3 -/- neonates breastfed by Ptx3 +/- mothers, but not by Ptx3 -/- mothers, within 8 days after birth; Ptx3 levels were higher in breastfed Ptx3 +/+ and Ptx3 +/- neonates. Oral administration of Ptx3 protected Ptx3 -/- neonates from Pseudomonas aeruginosa lung infection. Jaillon et al. (2013) concluded that PTX3 in colostrum/milk may prevent colonization of lung by P. aeruginosa and that PTX3 has therapeutic potential for neonates.
Basile, A., Sica, A., d'Aniello, E., Breviario, F., Garrido, G., Castellano, M., Mantovani, A., Introna, M. Characterization of the promoter for the human long pentraxin PTX3: role of NF-kappa-B in tumor necrosis factor-alpha and interleukin-1-beta regulation. J. Biol. Chem. 272: 8172-8178, 1997. [PubMed: 9079634] [Full Text: https://doi.org/10.1074/jbc.272.13.8172]
Bottazzi, B., Vouret-Craviari, V., Bastone, A., De Gioia, L., Matteucci, C., Peri, G., Spreafico, F., Pausa, M., D'Ettorre, C., Gianazza, E., Tagliabue, A., Salmona, M., Tedesco, F., Introna, M., Mantovani, A. Multimer formation and ligand recognition by the long pentraxin PTX3: similarities and differences with the short pentraxins C-reactive protein and serum amyloid P component. J. Biol. Chem. 272: 32817-32823, 1997. [PubMed: 9407058] [Full Text: https://doi.org/10.1074/jbc.272.52.32817]
Bozza, S., Bistoni, F., Gaziano, R., Pitzurra, L., Zelante, T., Bonifazi, P., Perruccio, K., Bellocchio, S., Neri, M., Iorio, A. M., Salvatori, G., De Santis, R., Calvitti, M., Doni, A., Garlanda, C., Mantovani, A., Romani, L. Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation. Blood 108: 3387-3396, 2006. [PubMed: 16840729] [Full Text: https://doi.org/10.1182/blood-2006-03-009266]
Breviario, F., d'Aniello, E. M., Golay, J., Peri, G., Bottazzi, B., Bairoch, A., Saccone, S., Marzella, R., Predazzi, V., Rocchi, M., Della Valle, G., Dejana, E., Mantovani, A., Introna, M. Interleukin-1-inducible genes in endothelial cells: cloning of a new gene related to C-reactive protein and serum amyloid P component. J. Biol. Chem. 267: 22190-22197, 1992. [PubMed: 1429570]
Cotena, A., Maina, V., Sironi, M., Bottazzi, B., Jeannin, P., Vecchi, A., Corvaia, N., Daha, M. R., Mantovani, A., Garlanda, C. Complement dependent amplification of the innate immune response to a cognate microbial ligand by the long pentraxin PTX3. J. Immun. 179: 6311-6317, 2007. [PubMed: 17947708] [Full Text: https://doi.org/10.4049/jimmunol.179.9.6311]
Cunha, C., Aversa, F., Lacerda, J. F., Busca, A., Kurzai, O., Grube, M., Loffler, J., Maertens, J. A., Bell, A. S., Inforzato, A., Barbati, E., Almeida, B., and 12 others. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. New Eng. J. Med. 370: 421-432, 2014. [PubMed: 24476432] [Full Text: https://doi.org/10.1056/NEJMoa1211161]
Cunha, C., Kurzai, O., Carvalho, A. Response to de Boer. (Letter) New Eng. J. Med. 370: 1666-1667, 2014. [PubMed: 24758632] [Full Text: https://doi.org/10.1056/NEJMc1402787]
de Boer, M. G. J., Halkes, C. J. M., van de Vosse, E. PTX3 deficiency and aspergillosis. (Letter) New Eng. J. Med. 370: 1665-1666, 2014. [PubMed: 24758633] [Full Text: https://doi.org/10.1056/NEJMc1402787]
Garlanda, C., Hirsch, E., Bozza, S., Salustri, A., De Acetis, M., Nota, R., Maccagno, A., Riva, F., Bottazzi, B., Peri, G., Doni, A., Vago, L., Botto, M., De Santis, R., Carminati, P., Siracusa, G., Altruda, F., Vecchi, A., Romani, L., Mantovani, A. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 420: 182-186, 2002. [PubMed: 12432394] [Full Text: https://doi.org/10.1038/nature01195]
Jaillon, S., Mancuso, G., Hamon, Y., Beauvillain, C., Cotici, V., Midiri, A., Bottazzi, B., Nebuloni, M., Garlanda, C., Fremaux, I., Gauchat, J.-F., Descamps, P., Beninati, C., Mantovani, A., Jeannin, P., Delneste, Y. Prototypic long pentraxin PTX3 is present in breast milk, spreads in tissues, and protects neonate mice from Pseudomonas aeruginosa lung infection. J. Immun. 191: 1873-1882, 2013. [PubMed: 23863905] [Full Text: https://doi.org/10.4049/jimmunol.1201642]
Lee, T. H., Lee, G. W., Ziff, E. B., Vilcek, J. Isolation and characterization of eight tumor necrosis factor-induced gene sequences from human fibroblasts. Molec. Cell. Biol. 10: 1982-1988, 1990. [PubMed: 2183014] [Full Text: https://doi.org/10.1128/mcb.10.5.1982-1988.1990]
Rovere, P., Peri, G., Fazzini, F., Bottazzi, B., Doni, A., Bondanza, A., Zimmermann, V. S., Garlanda, C., Fascio, U., Sabbadini, M. G., Rugarli, C., Mantovani, A., Manfredi, A. A. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood 96: 4300-4306, 2000. [PubMed: 11110705]