Multiple Class I and Class II Haemophilus ducreyi Strains Cause Cutaneous Ulcers in Children on an Endemic Island

Grant, Jacob C; González-Beiras, Camila; Amick, Kristen M.; Fortney, Kate R.; Gangaiah, Dharanesh; Humphreys, Tricia L.; Mitjà, Oriol; Abecasis, Ana; Spinola, Stanley M.

doi:10.1093/cid/ciy343

Cited by 4 publications

(4 citation statements)

References 37 publications

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“…ducreyi-associated CU in areas of endemicity (14), the organism was not eradicated (15), possibly due to environmental reservoirs containing H. ducreyi (16, 17). The failure of antibiotics to eradicate CU caused by H.…”

Section: Introductionmentioning

confidence: 99%

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host

Griesenauer

Tran

Fortney

et al. 2019

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A major gap in understanding infectious diseases is the lack of information about molecular interaction networks between pathogens and the human host. Haemophilus ducreyi causes the genital ulcer disease chancroid in adults and is a leading cause of cutaneous ulcers in children in the tropics. We developed a model in which human volunteers are infected on the upper arm with H. ducreyi until they develop pustules. To define the H. ducreyi and human interactome, we determined bacterial and host transcriptomic and host metabolomic changes in pustules. We found that in vivo H. ducreyi transcripts were distinct from those in the inocula, as were host transcripts in pustule and wounded control sites. Many of the upregulated H. ducreyi genes were found to be involved in ascorbic acid and anaerobic metabolism and inorganic ion/nutrient transport. The top 20 significantly expressed human pathways showed that all were involved in immune responses. We generated a bipartite network for interactions between host and bacterial gene transcription; multiple positively correlated networks contained H. ducreyi genes involved in anaerobic metabolism and host genes involved with the immune response. Metabolomic studies showed that pustule and wounded samples had different metabolite compositions; the top ion pathway involved ascorbate and aldarate metabolism, which correlated with the H. ducreyi transcriptional response and upregulation of host genes involved in ascorbic acid recycling. These data show that an interactome exists between H. ducreyi and the human host and suggest that H. ducreyi exploits the metabolic niche created by the host immune response. IMPORTANCE Dual RNA sequencing (RNA-seq) offers the promise of determining an interactome at a transcriptional level between a bacterium and the host but has yet to be done on any bacterial infection in human tissue. We performed dual RNA-seq and metabolomics analyses on wounded and infected sites following experimental infection of the arm with H. ducreyi. Our results suggest that H. ducreyi survives in an abscess by utilizing l-ascorbate as an alternative carbon source, possibly taking advantage of host ascorbic acid recycling, and that H. ducreyi also adapts by upregulating genes involved in anaerobic metabolism and inorganic ion and nutrient transport. To our knowledge, this is the first description of an interaction network between a bacterium and the human host at a site of infection.

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Section: Introductionmentioning

confidence: 99%

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host

Griesenauer

Tran

Fortney

et al. 2019

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“…For both yaws and H. ducreyi , the ulcers are primarily found on the lower leg and affect approximately 4-10% of children in endemic regions. While the prevalence of H. ducreyi -associated CU initially decreased following mass drug administration of azithromycin, the disease was not eliminated due to environmental reservoirs ( 12 , 13 ). Thus, there is a continuing need to understand H. ducreyi pathogenesis and the host response to this infection.…”

Section: Introductionmentioning

confidence: 99%

“…There are two classes of H. ducreyi isolates; class I and II strains can be differentiated based on several variable extracellular or secreted proteins (DsrA, NcaA, DltA, LspA1, LspA2, and others), and lipooligosaccharide (LOS) structure (14), but are otherwise highly conserved, clinically indistinguishable, and found in significant proportions of both CU and GU (12,(15)(16)(17). Although the majority of CU are typically caused by a single genotype, coinfections with both classes are common in CU (12); such studies have not been done in GU. Most in vitro work and experimental human infection utilizes H. ducreyi 35000HP, a human-passaged class I GU strain.…”

Section: Introductionmentioning

confidence: 99%

Interactions of the Skin Pathogen Haemophilus ducreyi With the Human Host

et al. 2021

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The obligate human pathogen Haemophilus ducreyi causes both cutaneous ulcers in children and sexually transmitted genital ulcers (chancroid) in adults. Pathogenesis is dependent on avoiding phagocytosis and exploiting the suppurative granuloma-like niche, which contains a myriad of innate immune cells and memory T cells. Despite this immune infiltrate, long-lived immune protection does not develop against repeated H. ducreyi infections—even with the same strain. Most of what we know about infectious skin diseases comes from naturally occurring infections and/or animal models; however, for H. ducreyi, this information comes from an experimental model of infection in human volunteers that was developed nearly three decades ago. The model mirrors the progression of natural disease and serves as a valuable tool to determine the composition of the immune cell infiltrate early in disease and to identify host and bacterial factors that are required for the establishment of infection and disease progression. Most recently, holistic investigation of the experimentally infected skin microenvironment using multiple “omics” techniques has revealed that non-canonical bacterial virulence factors, such as genes involved in central metabolism, may be relevant to disease progression. Thus, the immune system not only defends the host against H. ducreyi, but also dictates the nutrient availability for the invading bacteria, which must adapt their gene expression to exploit the inflammatory metabolic niche. These findings have broadened our view of the host-pathogen interaction network from considering only classical, effector-based virulence paradigms to include adaptations to the metabolic environment. How both host and bacterial factors interact to determine infection outcome is a current focus in the field. Here, we review what we have learned from experimental H. ducreyi infection about host-pathogen interactions, make comparisons to what is known for other skin pathogens, and discuss how novel technologies will deepen our understanding of this infection.

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“…Whole-genome sequencing shows that the classes represent two clades of the organism that diverged from each other ϳ1.9 million years ago and that CU strains diverged from both clades (14,20,21). Recent studies show that multiple class I and class II strains cause CU in regions of endemicity, that coinfections are common, and that strain composition is not affected by antibiotic pressure, consistent with environmental reservoirs (21,22). Thus, an effective vaccine must provide protective immunity against both class I and class II strains.…”

mentioning

confidence: 99%

A Class I Haemophilus ducreyi Strain Containing a Class II hgbA Allele Is Partially Attenuated in Humans: Implications for HgbA Vaccine Efficacy Trials

et al. 2019

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Haemophilus ducreyi causes chancroid and is a major cause of cutaneous ulcers in children. Due to environmental reservoirs, both class I and class II H. ducreyi strains persist in cutaneous ulcer regions of endemicity following mass drug administration of azithromycin, suggesting the need for a vaccine. The hemoglobin receptor (HgbA) is a leading vaccine candidate, but its efficacy in animal models is class specific. Controlled human infection models can be used to evaluate vaccines, but only a class I strain (35000HP) has been characterized in this model. As a prelude to evaluating HgbA vaccines in the human model, we tested here whether a derivative of 35000HP containing a class II hgbA allele (FX548) is as virulent as 35000HP in humans. In eight volunteers infected at three sites with each strain, the papule formation rate was 95.8% for 35000HP versus 62.5% for FX548 (P ϭ 0.021). Excluding doses of FX548 that were Ն2-fold higher than those of 35000HP, the pustule formation rate was 25% for 35000HP versus 11.7% for FX548 (P ϭ 0.0053). By Western blot analysis, FX548 and 35000HP expressed equivalent amounts of HgbA in whole-cell lysates and outer membranes. The growth of FX548 and 35000HP was similar in media containing hemoglobin or hemin. By whole-genome sequencing and single-nucleotide polymorphism analysis, FX548 contained no mutations in open reading frames other than hgbA. We conclude that by an unknown mechanism, FX548 is partially attenuated in humans and is not a suitable strain for HgbA vaccine efficacy trials in the model.

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Multiple Class I and Class II Haemophilus ducreyi Strains Cause Cutaneous Ulcers in Children on an Endemic Island

Cited by 4 publications

References 37 publications

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host

Interactions of the Skin Pathogen Haemophilus ducreyi With the Human Host

A Class I Haemophilus ducreyi Strain Containing a Class II hgbA Allele Is Partially Attenuated in Humans: Implications for HgbA Vaccine Efficacy Trials

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