Variation in expression of HMW1 and HMW2 adhesins in invasive nontypeable Haemophilus influenzae isolates

Giufrè, Maria; Carattoli, Alessandra; Cardines, Rita; Mastrantonio, Paola; Cerquetti, Marina

doi:10.1186/1471-2180-8-83

Cited by 25 publications

(34 citation statements)

References 17 publications

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“…The hmwA binding regions ranged in size from 2652 to 3573 nucleotides (Table S2), which is consistent with previous studies (Buscher et al, 2004; Dawid et al, 2001; Giufre et al, 2008; St Geme et al, 1998; van Schilfgaarde et al, 2000). Sequence data were obtained for both hmwA 1679 and hmwA 1598 from 26/33 of the isolates chosen for sequence analysis and for the remaining seven isolates hmwA sequence was obtained for one of the two loci (Table S2).…”

Section: Resultssupporting

confidence: 90%

“…2) revealed a wide range of diversity in size and amino acid composition. The observed size and amino acid diversity of the binding region is consistent with other studies (Barenkamp and Bodor, 1990; Barenkamp and Leininger, 1992; Buscher et al, 2004; Cholon et al, 2008; Dawid et al, 2001; Ecevit et al, 2005; Giufre et al, 2008; Giufre et al, 2006; van Schilfgaarde et al, 2000). Five isolates, however, possessed identical or nearly identical hmwA sequences at both hmw loci suggestive of recent gene conversion events such as those described among outer membrane proteins of the gastric pathogen Helicobacter pylori (Solnick et al, 2004; Talarico et al, 2012).…”

Section: Discussionsupporting

confidence: 91%

“…HMW adhesins display a wide range of amino acid diversity both within and between isolates (Barenkamp and Leininger, 1992; Buscher et al, 2004; Dawid et al, 2001; Giufre et al, 2008). Rather than being evenly distributed throughout each mature HMW adhesin, the amino acid diversity is localized to the binding domain, the region of the adhesin that interacts with the host epithelium (Barenkamp and Leininger, 1992; Dawid et al, 2001; Ecevit et al, 2005; Giufre et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae

Davis

Patel

Hammond

et al. 2014

Infection, Genetics and Evolution

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Nontypeable Haemophilus influenzae (NTHi) are Gram-negative coccobacilli that colonize the human pharynx, their only known natural reservoir. Adherence to the host epithelium facilitates NTHi colonization and marks one of the first steps in NTHi pathogenesis. Epithelial cell attachment is mediated, in part, by a pair of high molecular weight (HMW) adhesins that are highly immunogenic, antigenically diverse, and display a wide range of amino acid diversity both within and between isolates. In this study, the prevalence of hmwA, which encodes the HMW adhesin, was determined for a collection of 170 NTHi isolates recovered from the middle ears of children with otitis media (OM isolates) or throats of healthy children (commensal isolates) from Finland, Israel, and the U. S. Overall, hmwA was detected in 61% of NTHi isolates and was significantly more prevalent (P = 0.004) among OM isolates than among commensal isolates; the prevalence ratio comparing hmwA prevalence among ear isolates with that of commensal isolates was 1.47 (95% CI (1.12, 1.92)). Ninety-five percent (98/103) of the hmwA-positive NTHi isolates possessed two hmw loci. To advance our understanding of hmwA binding sequence diversity, we determined the DNA sequence of the hmwA binding region of 33 isolates from this collection. The average amino acid identity across all hmwA sequences was 62%. Phylogenetic analyses of the hmwA binding revealed four distinct sequence clusters, and the majority of hmwA sequences (83%) belonged to one of two dominant sequence clusters. hmwA sequences did not cluster by chromosomal location, geographic region, or disease status.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae

Davis

Patel

Hammond

et al. 2014

Infection, Genetics and Evolution

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“…The latter is a conserved surface antigen and demonstrated partial efficacy in preventing H. influenzae-induced otitis media [11]. The high molecular weight proteins (HMW-1 and HMW-2) showed variation in expression and also elicited different immunogenic potential, depending on epitope immunogenicity [12]. Another predicted vaccine candidate is the H. influenzae adhesion protein (Hap; 110 kDa), which plays a significant role in adhesion to extracellular matrix proteins and epithelial cells [3].…”

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confidence: 99%

Protein E ofHaemophilus influenzaeIs a Ubiquitous Highly Conserved Adhesin

et al. 2010

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Protein E (PE) of nontypeable Haemophilus influenzae (NTHi) is involved in adhesion and activation of epithelial cells. A total of 186 clinical NTHi isolates, encapsulated H. influenzae, and culture collection strains were analyzed. PE was highly conserved in both NTHi and encapsulated H. influenzae (96.9%-100% identity without the signal peptide). PE also existed in other members of the genus Pasteurellaceae. The epithelial cell binding region (amino acids 84-108) was completely conserved. Phylogenetic analysis of the pe sequence separated Haemophilus species into 2 separate clusters. Importantly, PE was expressed in 98.4% of all NTHi (126 isolates) independently of the growth phase.

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“…1b). We chose to incorporate 17 sub-populations because that captures the range in repeat numbers, i.e., 12 to 28 repeats, commonly observed in population-level studies (van Schilfgaarde et al, 2000; Giufre et al, 2006; Dawid et al, 1999; Barenkamp, 1992; Ecevit et al, 2005; Giufre et al, 2008) each subpopulation was described by a single ordinary differential equation (ODE). We assume that changes in repeat number affect HMW-adhesin expression in a graded fashion, as repeats are gained the amount of surface-exposed HMW adhesin decreases in a stepwise fashion (Dawid et al, 1999).…”

Section: The Modelmentioning

confidence: 99%

Phase variation and host immunity against high molecular weight (HMW) adhesins shape population dynamics of nontypeable Haemophilus influenzae within human hosts

Davis

Marino

Marrs

et al. 2014

Journal of Theoretical Biology

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Nontypeable Haemophilus influenzae (NTHi) is a bacterium that resides within the human pharynx. Because NTHi is human-restricted, its long-term survival is dependent upon its ability to successfully colonize new hosts. Adherence to host epithelium, mediated by bacterial adhesins, is one of the first steps in NTHi colonization. NTHi express several adhesins, including the high molecular weight (HMW) adhesins that mediate attachment to the respiratory epithelium where they interact with the host immune system to elicit a strong humoral response. hmwA, which encodes the HMW adhesin, undergoes phase variation mediated by 7-base pair tandem repeats located within its promoter region. Repeat number affects both hmwA transcription and HMW-adhesin production such that as the number of repeats increases, adhesin production decreases. Cells expressing large amounts of HMW adhesins may be critical for the establishment and maintenance of NTHi colonization, but they might also incur greater fitness costs when faced with an adhesin-specific antibody-mediated immune response. We hypothesized that the occurrence of large deletion events within the hmwA repeat region allows NTHi cells to maintain adherence in the presence of antibody-mediated immunity. To study this, we developed a mathematical model, incorporating hmwA phase variation and antibody-mediated immunity, to explore the trade-off between bacterial adherence and immune evasion. The model predicts that antibody levels and avidity, catastrophic loss rates, and population carrying capacity all significantly affected numbers of adherent NTHi cells within a host. These results suggest that the occurrence of large, yet rare, deletion events allows for stable maintenance of a small population of adherent cells in spite of HMW adhesin specific antibody-mediated immunity. These adherent subpopulations may be important for sustaining colonization and/or maintaining transmission.

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Variation in expression of HMW1 and HMW2 adhesins in invasive nontypeable Haemophilus influenzae isolates

Cited by 25 publications

References 17 publications

Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae

Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae

Protein E ofHaemophilus influenzaeIs a Ubiquitous Highly Conserved Adhesin

Phase variation and host immunity against high molecular weight (HMW) adhesins shape population dynamics of nontypeable Haemophilus influenzae within human hosts

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