Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

ABSTRACT Haemophilus influenzae requires an exogenous heme source for aerobic growth in vitro. Hemoglobin or hemoglobin-haptoglobin satisfies this requirement. Heme acquisition from hemoglobin-haptoglobin is mediated by proteins encoded by hgp genes. Both Hgps and additional proteins, including those encoded by the hxu operon, provide independent pathways for hemoglobin utilization. Recently we showed that deletion of the set of three hgp genes from a nontypeable strain (86-028NP) of H. influenzae attenuated virulence in the chinchilla otitis media model of noninvasive disease. The present study was undertaken to investigate the role of the hgp genes in virulence of the wild-type serotype b clinical isolate HI689 in the infant rat model of hematogenous meningitis, an established model of invasive disease requiring aerobic growth. Bacteremia of high titer and long duration (>14 days) and histopathologically confirmed meningitis occurred in >95% of infant rats challenged at 5 days of age with strain HI689. While mutations disrupting either the Hgp- or Hxu-mediated pathway of heme acquisition had no effect on virulence in infant rats, an isogenic mutant deficient for both pathways was unable to sustain bacteremia or produce meningitis. In contrast, mutations disrupting either pathway decreased the limited ability of H. influenzae to initiate and sustain bacteremia in weanling rats. Biochemical and growth studies also indicated that infant rat plasma contains multiple heme sources that change with age. Taken together, these data indicate that both the hgp genes and the hxuC gene are virulence determinants in the rat model of human invasive disease.

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Draft Genome Sequences of Six NontypeableHaemophilus influenzaeStrains That Establish Bacteremia in the Infant Rat Model of Invasive Disease: TABLE 1

Genome Announcements ◽

10.1128/genomea.00899-15 ◽

2015 ◽

Vol 3 (5) ◽

Cited By ~ 2

Author(s):

Timothy M. VanWagoner ◽

Daniel J. Morton ◽

Thomas W. Seale ◽

Huda J. Mussa ◽

Brett K. Cole ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Rat Model ◽

Draft Genome ◽

Invasive Disease ◽

Genome Sequences ◽

Infant Rat

Haemophilus influenzaeis an important cause of invasive disease. The infant rat is the accepted model of invasiveH. influenzaedisease. Here, we report the genome sequences of six nontypeableH. influenzaestrains that establish bacteremia in the infant rat.

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The Periplasmic Disulfide Oxidoreductase DsbA Contributes to Haemophilus influenzae Pathogenesis

Infection and Immunity ◽

10.1128/iai.01378-07 ◽

2008 ◽

Vol 76 (4) ◽

pp. 1498-1508 ◽

Cited By ~ 19

Author(s):

Charles V. Rosadini ◽

Sandy M. S. Wong ◽

Brian J. Akerley

Keyword(s):

Haemophilus Influenzae ◽

Disulfide Bonds ◽

Invasive Disease ◽

Secreted Proteins ◽

Type B ◽

Aerobic Growth ◽

Heme Transport ◽

Disulfide Oxidoreductase

ABSTRACT Haemophilus influenzae is an obligate human pathogen that persistently colonizes the nasopharynx and causes disease when it invades the bloodstream, lungs, or middle ear. Proteins that mediate critical interactions with the host during invasive disease are likely to be secreted. Many secreted proteins require addition of disulfide bonds by the DsbA disulfide oxidoreductase for activity or stability. In this study, we evaluated the role in H. influenzae pathogenesis of DsbA, as well as HbpA, a substrate of DsbA. Mutants of H. influenzae Rd and type b strain Eagan having nonpolar deletions of dsbA were attenuated for bacteremia in animal models, and complemented strains exhibited virulence equivalent to that of the parental strains. Comparison of predicted secreted proteins in H. influenzae to known DsbA substrates in other species revealed several proteins that could contribute to the role of dsbA in virulence. One candidate, the heme transport protein, HbpA, was examined because of the importance of exogenous heme for aerobic growth of H. influenzae. The presence of a dsbA-dependent disulfide bond in HbpA was verified by an alkylation protection assay, and HbpA was less abundant in a dsbA mutant. The hbpA mutant exhibited reduced bacteremia in the mouse model, and complementation restored its in vivo phenotype to that of the parental strain. These results indicate that dsbA is required in vivo and that HbpA and additional DsbA-dependent factors are likely to participate in H. influenzae pathogenesis.

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Multicenter, Prospective Surveillance Study of Staphylococcus aureus Nasal Colonization in 28 Italian Intensive Care Units: The ISABEL Study

Infection Control and Hospital Epidemiology ◽

10.1086/657939 ◽

2011 ◽

Vol 32 (2) ◽

pp. 193-197 ◽

Cited By ~ 2

Author(s):

Pierluigi Viale ◽

Giovanni Gesu ◽

Gaetano Privitera ◽

Biagio Allaria ◽

Nicola Petrosillo ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Intensive Care ◽

Invasive Disease ◽

Invasive Infection ◽

Icu Admission ◽

Increased Risk ◽

Mrsa Colonization ◽

The Relationship ◽

Colonization Status

The role of methicillin-resistant Staphylococcus aureus (MRSA) colonization as a predictor of invasive disease in intensive care unit (ICU) patients was established many years ago. The role of mefhicillin-susceptible Staphylococcus aureus (MSSA) colonization is more debated, although in a recent report patients who were carriers of MRSA or MSSA at ICU admission were found to be at increased risk. Whether carriage at ICU admission involves a higher risk of invasive infection than carriage acquired during an ICU stay has not been established. We report the results of a study aimed at estimating the frequency of S. aureus (MRSA and MSSA) colonization at admission and at discharge in patients admitted to several ICUs in Italy and at estimating the relationship between colonization status and infection by S. aureus.

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Mechanism of Antibody-Mediated Reduction of Nasopharyngeal Colonization by Haemophilus influenzae Type b Studied in an Infant Rat Model

The Journal of Infectious Diseases ◽

10.1093/infdis/174.6.1337 ◽

1996 ◽

Vol 174 (6) ◽

pp. 1337-1340 ◽

Cited By ~ 33

Author(s):

M. Kauppi-Korkeila ◽

L. van Alphen ◽

D. Madore ◽

L. Saarinen ◽

H. Kayhty

Keyword(s):

Haemophilus Influenzae ◽

Rat Model ◽

Haemophilus Influenzae Type ◽

Haemophilus Influenzae Type B ◽

Type B ◽

Nasopharyngeal Colonization ◽

Infant Rat ◽

Mediated Reduction

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Neisseria meningitidis RTX Proteins Are Not Required for Virulence in Infant Rats

Infection and Immunity ◽

10.1128/iai.71.4.2253-2257.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 2253-2257 ◽

Cited By ~ 19

Author(s):

Stanislav Forman ◽

Irena Linhartova ◽

Radim Osicka ◽

Xavier Nassif ◽

Peter Sebo ◽

...

Keyword(s):

Neisseria Meningitidis ◽

Rat Model ◽

Gram Negative ◽

Infant Rat ◽

Infant Rats

ABSTRACT RTX cytotoxins play an important role in virulence of numerous gram-negative pathogens. Unexpectedly, however, we show here that the RTX proteins of Neisseria meningitidis are dispensable for virulence in the infant rat model of infection.

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