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Cholera toxin promotes pathogen acquisition of host-derived nutrients

Nature volume 572, pages 244–248 (2019)Cite this article

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Abstract

Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection1. Cholera toxin (CTX), a protein complex that is secreted by V. cholerae, is required for V. cholerae to cause severe disease. CTX is also thought to promote transmission of the organism, as infected individuals shed many litres of diarrhoeal fluid that typically contains in excess of 1011 organisms per litre. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CTX increases pathogen growth and induces a distinct V. cholerae transcriptomic signature that is indicative of an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, which is an essential nutrient for growth2. Most iron in the mammalian host is found in a chelated form within the porphyrin structure of haem, and the ability to use haem as a source of iron is genetically encoded by V. cholerae3. We show that the genes that enable V. cholerae to obtain iron via haem and vibriobactin confer a growth advantage to the pathogen only when CTX is produced. Furthermore, we found that CTX-induced congestion of capillaries in the terminal ileum correlated with an increased bioavailability of luminal haem. CTX-induced disease in the ileum also led to increased concentrations of long-chain fatty acids and l-lactate metabolites in the lumen, as well as the upregulation of V. cholerae genes that encode enzymes of the tricarboxylic acid (TCA) cycle that contain iron–sulfur clusters. Genetic analysis of V. cholerae suggested that pathogen growth was dependent on the uptake of haem and long-chain fatty acids during infection, but only in a strain capable of producing CTX in vivo. We conclude that CTX-induced disease creates an iron-depleted metabolic niche in the gut, which selectively promotes the growth of V. cholerae through the acquisition of host-derived haem and fatty acids.

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Fig. 1: CTX induces a unique V. cholerae transcriptomic signature during infection.
Fig. 2: Haem utilization confers a CTX-dependent fitness advantage to V. cholerae.
Fig. 3: Cholera toxin promotes the utilization of LCFAs by V. cholerae during infection.

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Data availability

The data that support the findings of this study are available from the corresponding author on request. The RNA-seq data have been deposited in the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under the accession number GSE132653.

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Acknowledgements

We thank F. Caro for advice on library preparation and RNA-seq analysis; Y. Fu and W. Zhao for technical advice on animal experiments and all other members of the J.J.M. laboratory for their helpful advice; the staff at the Biopolymers Facility at HMS for Illumina sequencing; the staff of Brooks Applied Labs for triple quadrupole ICP–MS; and the Rodent Histopathology Core at HMS for tissue staining and histopathological analysis. This work was supported by grants AI-018045 and T32 AI007061 from the US National Institute of Allergy and Infectious Diseases and National Institutes of Health.

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Authors and Affiliations

  1. Department of Microbiology, Harvard Medical School, Boston, MA, USA

    Fabian Rivera-Chávez & John J. Mekalanos

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  1. Fabian Rivera-Chávez
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Contributions

F.R.-C. performed and analysed the experiments. F.R.-C. and J.J.M. were responsible for the overall study design and for writing the manuscript.

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Correspondence to John J. Mekalanos.

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The authors declare no competing interests.

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Peer review information Nature thanks Lars Barquist, Shelley M. Payne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Fig. 1 V. cholerae CTX production rescues the growth of the ∆ctx mutant.

a, ELISA assay for CTX using GM-1 (the CTX receptor) from filtered supernatant of wild-type (n = 5) or ∆ctx-mutant (n = 3) V. cholerae grown in vitro under CTX-inducing (AKI medium) conditions (1.5% peptone, 0.4% yeast extract, 0.5% NaCl, 0.3% NaHCO3 at 37 °C for 4 h stationary and then 16 h in a shaking flask). Data represent mean ± s.d. b, Groups of CD-1 mice (n = 4) were infected with a 1:1 mixture of wild-type and ∆ctx-mutant V. cholerae. The competitive index was determined one day after infection. Dotted red lines connect strains from the same mouse. Each dot represents data from an individual mouse or experiment. Numbers of bacteria were compared using an unpaired two-sided Student’s t-test. SI, small intestine. This figure is related to Fig. 1.

Source data

Extended Data Fig. 2 RNA-seq analysis of V. cholerae gene expression in vivo.

a–d, RNA-seq normalized expression (RPKM = (CDS read count × 109)/(CDS length × total mapped read count)) from wild-type or ∆ctx-mutant V. cholerae during infection of 3-day-old neonatal rabbits. Total expression from chromosome I or chromosome II from wild-type V. cholerae that infected the ileum (a) or caecum (b), or ∆ctx-mutant V. cholerae that infected the ileum (c) or caecum (d). Pearson’s correlations (r) are shown between biological replicates (rabbit 1 and rabbit 2). This figure is related to Figs. 1–3.

Extended Data Fig. 3 RNA-seq analysis of wild-type C6706 V. cholerae during colonization of the ileum and caecum.

a, b, RNA-seq analysis of V. cholerae in the ileum and caecum during infection of neonatal rabbits. a, PCA plots for RNA-seq data from two biological replicates of wild-type V. cholerae from the ileum (black dots) or caecum (red dots) of neonatal rabbits (n = 2). b, Differential expression of all V. cholerae ORFs and genes involved in virulence (ToxT (VC0838), cholera toxin (VC1456–VC1457), toxin-coregulated pilus (TCP) (VC0825-VC0837), TagA (VC0820), HlyA (VCA0219) and accessory colonization factors (Acf) (VC0840–VC0844)) in wild-type V. cholerae during colonization of the ileum relative to the caecum. This figure is related to Fig. 1.

Source data

Extended Data Fig. 4 RNA-seq analysis of CTX-dependent V. cholerae gene expression during colonization of the gut.

a–e, RNA-seq analysis of V. cholerae in the ileum and caecum during infection of neonatal rabbits. a, Differential expression of all V. cholerae ORFs and genes involved in virulence (ToxT (VC0838), cholera toxin (VC1456–VC1457), TCP (VC0825-VC0837), TagA (VC0820), HlyA (VCA0219) and accessory colonization factors (VC0840–VC0844)) in wild-type relative to ∆ctx-mutant V. cholerae during colonization of the ileum or caecum. b, Transcript levels of tcpA were determined by RT–qPCR in wild-type (n = 3) relative to ∆ctx-mutant (n = 4) V. cholerae that colonized the ileum (red circles) and in LB (n = 3) (white circles), and in the ileum relative to LB in wild-type (grey circles) and ∆ctx-mutant (light-blue circles) V. cholerae. Data represent mean ± s.d. c, Percentage of raw RNA-seq reads that aligned to chromosome I or chromosome II, from wild-type or ∆ctx-mutant V. cholerae in the caecum. d, Percentage of genes in the chromosome II transcriptome that are involved in haem utilization (VCA0907–VCA0915, VCA0576; red), from wild-type or ∆ctx-mutant V. cholerae in the caecum. e, DAVID bioinformatics pathway analysis of RNA-seq data for significantly upregulated pathways in wild-type relative to ∆ctx-mutant V. cholerae during colonization of the ileum of neonatal rabbits (n = 2). P values from the RNA-seq differential expression analysis were determined and adjusted for multiple testing by the Benjamini–Hochberg method using the R package DESeq2. This figure is related to Figs. 1, 2.

Source data

Extended Data Fig. 5 RNA-seq analysis of the V. cholerae fur regulon during infection of neonatal rabbits.

a, Heat map of RNA-seq data from normalized expression (RPKM) of V. cholerae fur-regulated genes (listed in Supplementary Table 3) in wild-type relative to ∆ctx-mutant V. cholerae during colonization of the ileum or caecum of neonatal rabbits. b, Differential expression of hutA, viuA and viuB was determined by RT–qPCR analysis of wild-type or ∆ctx-mutant V. cholerae in the ileum (n = 3 for wild type hutA, viuA and viuB; n = 6 for ∆ctx hutA and viuA; n = 4 for ∆ctx viuB), or wild-type or ∆ctx-mutant V. cholerae grown in LB (n = 3), in LB with 2,2 dipyridyl (n = 3) or in LB with 2,2 dipyridyl and haemin (n = 3). Data represent mean ± s.d. of log2-transformed mRNA levels determined by RT–qPCR in the ileum relative to LB (red circles), LB with 2,2 dipyridyl relative to LB (white circles) and LB with 2,2 dipyridyl and haemin relative to LB (light-blue circles). A two-way ANOVA (Supplementary Table 7) was used to compare normalized expression (ΔΔCT) values between the strains (wild type and ∆ctx mutant) for each treatment (ileum; 2,2 dipyridyl; 2,2 dipyridyl + 5 µM haemin; and LB) followed by a Sidak’s multiple comparisons test. Blue outlines on red circles distinguish rabbits from different litters of ∆ctx-infected neonatal rabbits. c, Schematic representation of the genetic region for viuA, viuB and viuF. d, Luminal lipocalin 2 (LCN2) levels were determined by ELISA from the ileum and caecum of neonatal rabbits (n = 4) that were mock-infected or infected with wild-type or ∆ctx-mutant V. cholerae. Data represent mean ± s.d. This figure is related to Figs. 1, 2.

Source data

Extended Data Fig. 6 CTX induces capillary congestion and increases the luminal growth of V. cholerae in a mouse model of infection.

a–h, Groups of CD-1 mice were mock-infected; infected intragastrically with the wild type, the ∆ctx mutant or the ∆ctx mutant mixed with purified CTX (CT); or treated orally with purified CTX. Samples were collected one day after infection. a, Representative images of H&E-stained ileum tissue sections showing capillary congestion (arrows) from mice that were infected with the indicated strains or treated orally with purified CTX. All images were taken at 60× magnification. b, Expression of Cxc1 and Cxcl2 in the ileal mucosa of mice (n = 4) was determined by RT–qPCR analysis. Data represent mean ± s.d. of Cxcl1 and Cxcl2 mRNA levels as fold change over mRNA levels in mock-infected mice. An unpaired two-sided Student’s t-test was used to compare the difference in fold change between wild-type and ∆ctx-mutant V. cholerae. c, Fluid accumulation ratios for mice treated with the indicated strains or treated orally with purified CTX (n = 8 for wild type, ∆ctx and mock; n = 4 for CTX and ∆ctx + CTX; n = 5 for wild type and ∆ctx 6 h post-infection (p.i.)). The fluid accumulation ratios between groups were compared using a one-way ANOVA (F6,35 = 66.03, P < 0.0001) followed by Tukey’s multiple comparisons test. Lines represent median; black dots are individual mice. Different shapes indicate mice from different litters. d, Luminal haemin measurements from the ileum of mice (n = 4) treated with the indicated strains or treated orally with purified CTX. Haemin levels in the CTX-treated group were compared to the ∆ctx mutant and mock using a one-way ANOVA (F3,12 = 25.59, P < 0.0001) followed by Sidak’s multiple comparisons test. Lines represent median; black dots are individual mice. e, CFU per g and total CFU from the whole gastrointestinal tract (gut) from mice (n = 4) infected with wild-type or ∆ctx-mutant V. cholerae. An unpaired two-sided Student’s t-test was used to compare the bacterial concentrations from wild-type- and ∆ctx-mutant-infected mice. Data represent mean ± s.d. f, CFU per g of tissue (ileum) (n = 4) and total CFU from the lumen of the ileum (n = 11 for wild type; n = 9 for ∆ctx; n = 4 for ∆ctx + CTX) or lumen of the caecum (n = 8 for wild type; n = 7 for ∆ctx; n = 4 for ∆ctx + CTX) from mice infected with the indicated V. cholerae strains. An unpaired two-sided Student’s t-test was used to compare the CFU per g of tissue in wild-type- and ∆ctx-mutant-infected mice. The CFU in the ileum or caecum for the wild-type-infected groups were compared to the ∆ctx-mutant- or mock-infected groups using a one-way ANOVA (ileum: F2,21 = 50.24, P < 0.0001; caecum: F2,16 = 51.6, P < 0.0001) followed by Sidak’s multiple comparisons test. Data represent mean ± s.d. g, CFU in the lumen of the ileum in mice 6 h after infection with V. cholerae. An unpaired two-sided Student’s t-test was used to compare the CFU from wild-type- and ∆ctx-mutant-infected mice. Data represent mean ± s.d. Different shapes or different coloured shapes indicate mice from different litters (f, g). h, Measurements of luminal LCFAs (8-carbon chain or longer) from the ileum of mice that were treated with the indicated strains or treated orally with purified CTX (n = 3 for wild type, ∆ctx and mock; n = 4 for CTX). LCFA concentrations in the CTX-treated group were compared to the ∆ctx-mutant- and mock-infected groups using a one-way ANOVA (F3,9 = 7.814, P = 0.0071) followed by Sidak’s multiple comparisons test. Lines represent median; black dots are individual mice. This figure is related to Figs. 1–3.

Source data

Extended Data Fig. 7 Differential expression of CTX-dependent V. cholerae genes that are related to metabolism.

a, Groups of CD-1 mice (n = 4) were infected with a 1:1 mixture of wild-type V. cholerae and the indicated mutant (white), or with a 1:1 mixture of the mutant containing a control vector (pWSK129) and the mutant containing the complemented gene in pWSK29 (grey). The competitive index was determined one day after infection, and the competitive index for the wild type versus the fadL mutant from the first experiment (n = 4) in Fig. 3f is shown for comparison. Data represent mean ± s.d. b, Transcript levels of fadL and lldD were determined by RT–qPCR in wild-type (n = 3) and ∆ctx-mutant (n = 4) V. cholerae during colonization of the ileum relative to LB (white) and in the wild type relative to the ∆ctx mutant in LB (grey) (n = 3). An unpaired two-sided Student’s t-test was used to compare the log2-transformed fold change in expression of fadL and lldD (ileum relative to LB) between the wild type and the ∆ctx mutant. Data represent mean ± s.d. c, Differential expression of V. cholerae superoxide dismutase (VC2694) and nitric oxide dioxygenase (VCA0183) in wild-type relative to ∆ctx-mutant V. cholerae during colonization of the ileum or caecum. d, Iron concentrations from the ileum of individual rabbits infected with wild-type V. cholerae for the experiments shown in Fig. 2b. e, Fold change in transcript levels of wild-type V. cholerae genes: ctxA (VC1456), hutA (VCA0576), viuA (VC2211), viuB (VC2210), tcpA (VC0825), fadL (VC1043) and lldD (VCA0983) in the ileum relative to LB were determined by RT–qPCR from individual rabbits shown in Extended Data Figs. 4b, 5b, 7b. Red circle (rabbit 2) indicates data for a sample that had low expression of cholera toxin (ctxA) and that was determined to be a statistical outlier using the ROUT method (Q = 0.5) from log-transformed fold-change expression values. This figure is related to Figs. 1–3.

Source data

Supplementary information

Reporting Summary

Supplementary Table 1

Related to Extended Data Fig 3b: Summary of differential expression of wild type V. cholerae C6706 ORFs up-regulated in the Ileum relative to the cecum of 3-day old infant rabbits.

Supplementary Table 2

Related to Fig. 1f: Summary of number of sequences (reads) from RNA-sequencing that mapped to the V. cholerae chromosome I (chr.1) and chromosome 2 (chr. 2) from wild type and to the ∆ctx mutant during infection of the ileum or cecum of 3-day old infant rabbits.

Supplementary Table 3

Related to Fig. 2a and Extended Data Fig. 6: Summary of normalized expression for annotated V. cholerae ORFs predicted to be regulated by the Ferric Uptake Regulator (Fur) and low-iron in V. cholerae C6706 WT and ∆ctx mutant during infection of the ileum or cecum of 3-day old infant rabbits. Geometric means of normalized expression (RPKM) for rabbit 1 and rabbit 2 are shown. RPKM=(reads mapping to gene)/(length of gene/1000)/(total reads mapped to V. cholerae genome/1000000). nd = not detected.

Supplementary Tables 4-6

This file contains Supplementary Table 4 (V. cholerae and E. coli strains used in this study), Supplementary Table 5 (Plasmids used in this study) and Supplementary Table 6 (Primers used in this study).

Supplementary Table 7

Table of two-way ANOVA analysis for Fig. 2c, Fig. 3e, and Extended Data Fig. 6.

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Rivera-Chávez, F., Mekalanos, J.J. Cholera toxin promotes pathogen acquisition of host-derived nutrients. Nature 572, 244–248 (2019). https://doi.org/10.1038/s41586-019-1453-3

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