Aerobic growth deficient Haemophilus influenzae mutants are non-virulent: Implications on metabolism

Herbert, Mark; Kraiss, Anita; Hilpert, A.; Schlör, Stefan; Reidl, Joachim

doi:10.1078/1438-4221-00261

Cited by 25 publications

(28 citation statements)

References 18 publications

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“…Herbert and colleagues previously suggested that an enhanced lipid bilayer because of fatty acid synthesis is necessary for in vivo resistance against reactive oxygen intermediates (134). Our proteomic data support their hypothesis that the noncyclic, branched TCA pathway in NTHI likely evolved as a consequence of NTHI adaptive physiology and overall fitness to the host microenvironment (134). Our data provide the first evidence that NTHI use aerobic respiration during AOM.…”

Section: Discussionsupporting

confidence: 83%

“…Thus, generation of pyruvate via glycolysis and ␣-ketoglutarate as an entry point into the TCA cycle are critical metabolic processes active in NTHI during AOM. We detected dihydrolipoamide dehydrogenase, a key metabolic enzyme in aerobic respiration and essential functional subunit of both pyruvate dehydrogenase (catalyzes the conversion of pyruvate to acetyl-CoA), and ␣-ketoglutarate dehydrogenase (catabolism of ␣-ketoglutarate in the TCA cycle) (134). Because acetyl-CoA is not used in the TCA cycle in Haemophilus, the increased pool of acetyl-CoA may be used for synthesis of fatty acids.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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“…The infant rat model of hematogenous meningitis has been widely used to investigate the influence of bacterial virulence factors, host protective factors, and vaccine candidates on invasive disease caused by H. influenzae (21,26,39,61,66). Few investigations have examined the roles of hemoglobin and hemoglobin-haptoglobin binding proteins encoded by H. influenzae or by other bacterial species in proliferation in vivo and in pathogenesis (10,28,38,62).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence support this explanation. (i) At least one alternative heme source must be available to H. influenzae systemically infecting the infant rat, because the ability to grow aerobically is critical for the establishment of invasive disease by H. influenzae in this model (26) and H. influenzae requires heme for aerobic growth (15,53). Hemoglobin-haptoglobin, while serving as a heme source for the wild-type strain, does not support the aerobic growth of the ⌬hgp mutant strain in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…However, no significant extracellular source of free PPIX is believed to occur in vivo. Since the ability to grow aerobically is crucial for the establishment of invasive disease by H. influenzae (26), this bacterium must acquire heme from host sources to sustain an invasive infection. Heme is localized intracellularly in hemoglobin and heme-containing enzymes, where it is unavailable to many invading bacteria (18,59).…”

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confidence: 99%

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

Seale¹,

Morton²,

Whitby³

et al. 2006

Infect Immun

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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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Transposon insertion in a serine-specific minor tRNA coding sequence affects intraperitoneal survival of Haemophilus influenzae in the infant rat model

Gerlach

Anthony

Deadman

et al. 2010

International Journal of Medical Microbiology

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Aerobic growth deficient Haemophilus influenzae mutants are non-virulent: Implications on metabolism

Cited by 25 publications

References 18 publications

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

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

Transposon insertion in a serine-specific minor tRNA coding sequence affects intraperitoneal survival of Haemophilus influenzae in the infant rat model

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