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Identified virulence factors of Haemophilus: Adherence


Haemagglutinating pili  

Related genes: hifA; hifB; hifC; hifD; hifE;
Keywords: Adherence; Phase variation; Fimbrial structure;
Characteristics:
The first well studied adherence factors of H. influenzae, structural and functional homology to the Pap pili of UPEC and type 1 pili of Enterobacteriaceae, sometimes called fimbriae.
hif cluster is absent from the completely sequenced genome of H. influenzae Rd. It is cloned and sequenced from several independent type b and non-typable strains.
Expression of pili is a phase-variable phenomenon: the transcription of all pili genes is determined by reversible changes in the number of dinucleotide (TA) repeats located within the bidirectional promoter region between hifA and hifB.
Structure features:
Pilus shaft consists of repeating HifA subunits and appears to be double-stranded. The tip fibrillum contains the HifD and HifE subunits. Pili are assembled via the chaperone/usher pathway. HifB is the chaperone to facilitate assembly via donor strand exchange. HifC is the usher and is located in the outer membrane to facilitate the ordered incorporation of pilus subunits into the growing pilus.
Functions:
Promote adherence to respiratory mucus and human oropharyngeal epithelial cells.
Promote interaction with heparin-binding extracellular matrix proteins.
Mechanism:
Binding to the Anton antigen (An-Wj) common to buccal epithelial cells and erythrocytes. An-Wj is borne on CD44, a member of the cartilage link protein family that expressed on almost all tissues.
References:
Tang CM, et al., 2001. Pathogenesis of Haemophilus influenzae Infections. In Groisman EA (ed.), Principles of Bacterial pathogenesis. Academic Press. San Diego, Calif. pp. 675-716.
Gilsdorf JR, et al., 1997. Role of pili in Haemophilus influenzae adherence and colonization. Infect. Immun. 65(8):2997-3002.
Rao VK, et al., 1999. Molecular determinants of the pathogenesis of disease due to non-typable Haemophilus influenzae. FEMS Microbiol. Rev. 23(2):99-129.
Kubiet M, et al., 2000. Pilus-mediated adherence of Haemophilus influenzae to human respiratory mucins. Infect. Immun. 68(6):3362-3367.
Mu XQ, et al., 2002. Structure and function of Hib pili from Haemophilus influenzae type b. J. Bacteriol. 184(17):4868-4874.


Hap (Haemophilus adhesion and penetration)  

Related genes: hap;
Keywords: Adherence; Autotransporter; Serine protease; Nonfimbrial structure;
Characteristics:
Autotransporter, analogous to H. influenzae IgA1 protease.
Undergoes autoproteolysis, with extracellular release of the passenger domain.
Functions:
Promote adherence and invasion, adhesive activity is localized within the Hap passenger domain.
Mediates bacterial aggregation and microcolony formation.
Hap has serine protease activity.
References:
St Geme JW 3rd, et al., 1994. A Haemophilus influenzae IgA protease-like protein promotes intimate interaction with human epithelial cells. Mol. Microbiol. 14(2):217-233.
Hendrixson DR, et al., 1997. Structural determinants of processing and secretion of the Haemophilus influenzae hap protein. Mol. Microbiol. 26(3):505-518.
Fink DL, et al., 2001. The Hemophilus influenzae Hap autotransporter is a chymotrypsin clan serine protease and undergoes autoproteolysis via an intermolecular mechanism. J. Biol. Chem. 276(42):39492-39500.
St Geme JW 3rd, 2002. Molecular and cellular determinants of non-typeable Haemophilus influenzae adherence and invasion. Cell Microbiol. 4(4):191-200.
Fink DL, et al., 2002. The Haemophilus influenzae Hap autotransporter binds to fibronectin, laminin, and collagen IV. Infect. Immun. 70(9):4902-4907.
Fink DL, St Geme JW 3rd, 2003. Chromosomal expression of the Haemophilus influenzae Hap autotransporter allows fine-tuned regulation of adhesive potential via inhibition of intermolecular autoproteolysis. J. Bacteriol. 185(5):1608-1615.
Fink DL, et al., 2003. The Haemophilus influenzae Hap autotransporter mediates microcolony formation and adherence to epithelial cells and extracellular matrix via binding regions in the C-terminal end of the passenger domain. Cell Microbiol. 5(3):175-186.


Hia/Hsf  

Related genes: hia; hsf;
Keywords: Adherence; Autotransporter; Fimbrial structure;
Characteristics:
Nearly all nontypable Haemophilus influenzae strains that are HMW1/HMW2 deficient, contain a gene homologous to hia, and conversely, strains that express HMW1/HMW2-like proteins uniformly lack the intact hia gene.
The counterpart to hia is associated with expression of short, thin surface appendages referred to as fibrils and is called hsf. Hsf appears to be ubiquitous among typable H. influenzae, including both type b and non-type b strains.
The N-terminal and C-terminal regions of two proteins are highly homologus, whereas the central segment of hsf is a trimeric duplication of hia.
Structure features:
Autotransport protein, trimeric antotransporter subfamily.
N-terminal signal, cleavage site between amino acid 49 and 50, C-terminal 319 amino acids have translocator activity and phenylalanine residue is essential for targeting Hia to the outer membrane or perhaps for stablizing Hia in the outer member.
In contrast to Hap and other classic autotransporter proteins, the passenger domain remains uncleaved and completely cell associated in Hia.
PDB code: 2GR7 2GR8.
Functions:
High-affinity adhesive activity and mediates interaction with a broad array of respiratory epithelial cell types.
Receptor unknown.
References:
Barenkamp SJ, St Geme JW 3rd, 1996. Identification of a second family of high-molecular-weight adhesion proteins expressed by non-typable Haemophilus influenzae. Mol. Microbiol. 19(6):1215-1223.
St Geme JW 3rd, et al., 1996. Characterization of the genetic locus encoding Haemophilus influenzae type b surface fibrils. J. Bacteriol. 178(21):6281-6287.
St Geme JW 3rd, Cutter D, 2000. The Haemophilus influenzae Hia adhesin is an autotransporter protein that remains uncleaved at the C terminus and fully cell associated. J. Bacteriol. 182(21):6005-6013.
Laarmann S, et al., 2002. The Haemophilus influenzae Hia autotransporter harbours two adhesive pockets that reside in the passenger domain and recognize the same host cell receptor. Mol. Microbiol. 46(3):731-743.
Surana NK, et al., 2004. The Haemophilus influenzae Hia autotransporter contains an unusually short trimeric translocator domain. J. Biol. Chem. 279(15):14679-14685.
Yeo HJ, et al., 2004. Structural basis for host recognition by the Haemophilus influenzae Hia autotransporter. EMBO J. 23(6):1245-1256.
Meng G, et al., 2006. Structure of the outer membrane translocator domain of the Haemophilus influenzae Hia trimeric autotransporter. EMBO J. 25(11):2297-2304.


HMW1/HMW2 (high-molecular-weight proteins)  

Related genes: hmw1A; hmw1B; hmw1C; hmw2A; hmw2B; hmw2C;
Keywords: Adherence; Autotransporter; Nonfimbrial structure;
Characteristics:
Two HMWs are similar to each other and related to the filamentous hemagglutinin, a well-characterized adhesin from Bordetella pertussis.
To date, the hmw genes have only been detected in nontypable strains.
Structure features:
Autotransport protein.
Secretion of these adhesins HMW1A/HMW1B requires accessory proteins called HMW1B/HMW2B and HMW1C/HMW2C.
Functions:
The non-typable H. influenzae HMW1 and HMW2 adhesins are related proteins that mediate attachment to human epithelial cells, an essential step in the pathogenesis of disease.
Mechanism:
HMW1 mediates binding to human conjunctival cells through a glycoprotein receptor, which the target of HMW2 has not yet been defined.
References:
Bakaletz LO, Barenkamp SJ, 1994. Localization of high-molecular-weight adhesion proteins of nontypeable Haemophilus influenzae by immunoelectron microscopy. Infect. Immun. 62(10):4460-4468.
St Geme JW 3rd, et al., 1993. High-molecular-weight proteins of nontypable Haemophilus influenzae mediate attachment to human epithelial cells. Proc. Natl. Acad. Sci. USA. 90(7):2875-2879.
St Geme JW 3rd, Grass S, 1998. Secretion of the Haemophilus influenzae HMW1 and HMW2 adhesins involves a periplasmic intermediate and requires the HMWB and HMWC proteins. Mol. Microbiol. 27(3):617-630.
Dawid S, et al., 1999. Variation in expression of the Haemophilus influenzae HMW adhesins: a prokaryotic system reminiscent of eukaryotes. Proc. Natl. Acad. Sci. USA. 96(3):1077-1082.
Grass S, St Geme JW 3rd, 2000. Maturation and secretion of the non-typable Haemophilus influenzae HMW1 adhesin: roles of the N-terminal and C-terminal domains. Mol. Microbiol. 36(1):55-67.
Van Schilfgaarde M, et al., 2000. Characterization of adherence of nontypeable Haemophilus influenzae to human epithelial cells. Infect. Immun. 68(8):4658-4665.
St Geme JW 3rd, 2002. Molecular and cellular determinants of non-typeable Haemophilus influenzae adherence and invasion. Cell Microbiol. 4(4):191-200.
Grass S, et al., 2003. The Haemophilus influenzae HMW1 adhesin is glycosylated in a process that requires HMW1C and phosphoglucomutase, an enzyme involved in lipooligosaccharide biosynthesis. Mol. Microbiol. 48(3):737-751.
Winter LE, Barenkamp SJ, 2003. Human antibodies specific for the high-molecular-weight adhesion proteins of nontypeable Haemophilus influenzae mediate opsonophagocytic activity. Infect. Immun. 71(12):6884-6891.


OapA  

Related genes: oapA;
Keywords: Adherence; Nonfimbrial structure;
Characteristics:
A surface-associated lipoprotein that is responsible for the transparent colony phenotype of H. influenzae.
Functions:
Required for efficient colonization of the nasopharynx, may play a minor role in adherence.
References:
Weiser JN, et al., 1995. Identification and characterization of a cell envelope protein of Haemophilus influenzae contributing to phase variation in colony opacity and nasopharyngeal colonization. Mol. Microbiol. 17(3):555-564.
Prasadarao NV, et al., 1999. Opacity-associated protein A contributes to the binding of Haemophilus influenzae to chang epithelial cells. Infect. Immun. 67(8):4153-4160.


P5 protein  

Related genes: ompP5;
Keywords: Adherence; Fimbrial structure; Antigenic drift;
Characteristics:
Major outer membrane protein, shares homology with E. coli OmpA.
Antigenically variable from one train to another.
Functions:
Interacts with CEACAM1, a member of the carcinoembryonic antigen (CEA) family of cell adhesion molecules, a glycoprotein expressed by respiratory epithelial cell.
References:
Munson RS Jr, et al., 1993. Molecular cloning and sequence of the gene for outer membrane protein P5 of Haemophilus influenzae. Infect. Immun. 61(9):4017-4020.
Reddy MS, et al., 1996. Binding between outer membrane proteins of nontypeable Haemophilus influenzae and human nasopharyngeal mucin. Infect. Immun. 64(4):1477-1479.
Duim B, et al., 1997. Molecular variation in the major outer membrane protein P5 gene of nonencapsulated Haemophilus influenzae during chronic infections. Infect. Immun. 65(4):1351-1356.
Virji M, et al., 2000. Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae. Mol. Microbiol. 36(4):784-795.
Hill DJ, et al., 2001. The variable P5 proteins of typeable and non-typeable Haemophilus influenzae target human CEACAM1. Mol. Microbiol. 39(4):850-862.








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