Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

“Sequenced reads were quality-tested using FASTQC (Andrews, 2010) and aligned to the mm10 mouse genome using the STAR aligner (Dobin et al., 2013) version 2.”

“, 2010) analysis suite, and differential gene expression was carried out with edgeR (Robinson et al., 2010) using triplicates to compute within-group dispersion.”

“(H) Top KEGG pathways showing overrepresentation of genes up in IH compared to IM.”

“1) (Bankevich et al., 2012) then contigs were reordered and aligned against the ICC168 chromosome using MAUVE genome alignment software (version 2.”

“Uniquely mapped reads were quantified across all gene exons using the top-expressed isoform as proxy for gene expression with the HOMER (Heinz et al., 2010) analysis suite, and differential gene expression was carried out with edgeR (Robinson et al., 2010) using triplicates to compute within-group dispersion.”

“Heatmaps were constructed with JTreeView (Saldanha, 2004).”

“The raw sequencing data was uploaded to the Galaxy Web platform (Afgan et al., 2016) (public server: https://galaxyproject.”

“Antagonistic strategies include resistance and avoidance mechanisms that protect the host by having a negative impact on pathogen fitness (Medzhitov et al., 2012; Schneider and Ayres, 2008).”

“In response to infections, the host employs mechanisms that reduce the amount of circulating iron and sequesters iron within host tissues, and this has traditionally been believed to serve as an antagonistic defense mechanism (Cassat and Skaar, 2013).”

“HFD has been previously suggested to cause leaky gut in C57BL/6 mice and render mice more susceptible to CR extraintestinal dissemination (Thaiss et al., 2018) but does not in DBA/2J mice (Figures S6A–S6D).”

“This is determined by challenging the host with different doses of pathogen and generating a dose-response curve to examine howhost health is affected by the different doses of pathogen under dietary iron and control diet conditions (Råberg et al., 2007).”

“Antagonistic strategies include resistance and avoidance mechanisms that protect the host by having a negative impact on pathogen fitness (Medzhitov et al., 2012; Schneider and Ayres, 2008).”

“In agreement with experimental and clinical data (Choi et al., 2013; Fargion et al., 2005; Fernández-Real et al., 2002; Simcox and McClain, 2013), we found that dietary iron caused IR in our infection models, and this was necessary for iron-mediated protection from infection.”

“In humans, clinical data support our findings that dietary iron supplementation provides beneficial outcomes, especially in developing countries where low iron status may be prevalent (Loukas et al., 2016; Mwangi et al., 2017; Oppenheimer, 1989, 1998, 2001).”

“…and persisting in their hosts but do not cause disease, such as with subclinical or latent infections and ‘‘healthy’’ carriers that harbor ‘‘pathogenic’’ microbes (Bruner et al., 2015; Chen et al., 2016; Furuya-Kanamori et al., 2016; Ganguly et al., 2013; Marineli et al., 2013; Riggs et al., 2007).”

“10 Cell 175, 1–13, September 20, 2018 saccharide (LPS)-induced anorexia prevents the virulent behavior of the resident microbiota during sickness (Pickard et al., 2014; Rao et al., 2017).”

“In agreement with experimental and clinical data (Choi et al., 2013; Fargion et al., 2005; Fernández-Real et al., 2002; Simcox and McClain, 2013), we found that dietary iron caused IR in our infection models, and this was necessary for iron-mediated protection from infection.”

“Dietary Iron Prevents CR-Induced Intestinal Pathology CR colonization of the intestinal mucosa causes colonic damage, inflammation, increased permeability, and increased extraintestinal dissemination of the pathogen (Collins et al., 2014; Mundy et al., 2005).”

“Dietary Iron Prevents CR-Induced Intestinal Pathology CR colonization of the intestinal mucosa causes colonic damage, inflammation, increased permeability, and increased extraintestinal dissemination of the pathogen (Collins et al., 2014; Mundy et al., 2005).”

“Intestinal glucose is taken up from the lumen into small intestinal epithelial cells via sodium-glucose linked transporter 1 (SGTL1) (Röder et al., 2014).”

“…and persisting in their hosts but do not cause disease, such as with subclinical or latent infections and ‘‘healthy’’ carriers that harbor ‘‘pathogenic’’ microbes (Bruner et al., 2015; Chen et al., 2016; Furuya-Kanamori et al., 2016; Ganguly et al., 2013; Marineli et al., 2013; Riggs et al., 2007).”

“In humans, clinical data support our findings that dietary iron supplementation provides beneficial outcomes, especially in developing countries where low iron status may be prevalent (Loukas et al., 2016; Mwangi et al., 2017; Oppenheimer, 1989, 1998, 2001).”

“Interestingly, HO-1 has been shown to promote cooperative defenses against Plasmodium and in sepsis models (Ferreira et al., 2011; Jeney et al., 2014; Seixas et al., 2009).”

“A recent study has suggested that liver iron sequestration regulates blood glucose levels by inducing ferritin to maintain liver gluconeogenesis during sepsis (Weis et al., 2017).”

“Interestingly, HO-1 has been shown to promote cooperative defenses against Plasmodium and in sepsis models (Ferreira et al., 2011; Jeney et al., 2014; Seixas et al., 2009).”

“This is supported by a study showing that heme-oxygenase-1 (HO-1) induces IR in the context of metabolic disease (Jais et al., 2014).”

“Furthermore, consistent with our studies demonstrating that HFD reduced glucose absorption from the intestine, HFD has been reported to reduce SGLT1 expression (Bauer et al., 2018).”

“This is best appreciated in cases for which disease is a direct function of microbial burden–for example, with opportunistic infections in immuno- compromised individuals and infections in individuals who have traits restricting growth (Elguero et al., 2015; Luzzatto, 2012).”

“What is less well understood are the contexts in which pathogens are capable of infecting, replicating, and persisting in their hosts but do not cause disease, such as with subclinical or latent infections and ‘‘healthy’’ carriers that harbor ‘‘pathogenic’’ microbes (Bruner et al., 2015; Chen et al., 2016; Furuya-Kana…”

“For germ free studies, Swiss Webster mice were bred and maintained in our germ free barrier facility in sterile semi-flexible isolators and screened for bacterial, fungal, and viral contamination (Schieber et al., 2015).”

“Consistent with previous studies (Dongiovanni et al., 2013), we found the systemic IR was associated with reduced insulin signaling in WAT deposits (Figures 6E and S5E).”

“…studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014; Powell and Frelinger, 2017; Soe-Lin et al., 2009).”

“Tradeoffs between virulence and transmission have been reported previously (Mackinnon et al., 2008; Paul et al., 2004; Rao et al., 2017).”

“It is important to note that the strain of mouse used for most of these studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014…”

“coli strains is dependent on the metabolic state of the pathogen (Njoroge et al., 2012).”

“Tradeoffs between virulence and transmission have been reported previously (Mackinnon et al., 2008; Paul et al., 2004; Rao et al., 2017).”

“Acute IR is a common response triggered during infectious diseases (Yki-Järvinen et al., 1989), suggesting that acute IR is an evolved strategy to promote host defense during infections by increasing availability of glucose to non-insulin dependent tissues.”

“host while having a neutral to positive impact onmicrobial fitness (Ayres, 2016).”

“This is best appreciated in cases for which disease is a direct function of microbial burden–for example, with opportunistic infections in immunocompromised individuals and infections in individuals who have traits restricting growth (Elguero et al., 2015; Luzzatto, 2012).”

“In agreement with experimental and clinical data (Choi et al., 2013; Fargion et al., 2005; Fernández-Real et al., 2002; Simcox and McClain, 2013), we found that dietary iron caused IR in our infection models, and this was necessary for iron-mediated protection from infection.”

“What is less well understood are the contexts in which pathogens are capable of infecting, replicating, and persisting in their hosts but do not cause disease, such as with subclinical or latent infections and ‘‘healthy’’ carriers that harbor ‘‘pathogenic’’ microbes (Bruner et al., 2015; Chen et al., 2016; Furuya-Kana…”

“In agreement with experimental and clinical data (Choi et al., 2013; Fargion et al., 2005; Fernández-Real et al., 2002; Simcox and McClain, 2013), we found that dietary iron caused IR in our infection models, and this was necessary for iron-mediated protection from infection.”

“However, in malaria endemic areas, iron supplementation was associated with a negative outcome for patients (Clark et al., 2014).”

“Interestingly, HO-1 has been shown to promote cooperative defenses against Plasmodium and in sepsis models (Ferreira et al., 2011; Jeney et al., 2014; Seixas et al., 2009).”

“What is less well understood are the contexts in which pathogens are capable of infecting, replicating, and persisting in their hosts but do not cause disease, such as with subclinical or latent infections and ‘‘healthy’’ carriers that harbor ‘‘pathogenic’’ microbes (Bruner et al., 2015; Chen et al., 2016; Furuya-Kana…”

“It is important to note that the strain of mouse used for most of these studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014…”

“In humans, clinical data support our findings that dietary iron supplementation provides beneficial outcomes, especially in developing countries where low iron status may be prevalent (Loukas et al., 2016; Mwangi et al., 2017; Oppenheimer, 1989, 1998, 2001).”

“Tradeoffs between virulence and transmission have been reported previously (Mackinnon et al., 2008; Paul et al., 2004; Rao et al., 2017).”

“Studies withmetformin have shown that in addition to IR, metformin increases expression of SGLT1 and intestinal uptake of glucose (Bauer et al., 2018; Lenzen et al., 1996).”

“In experimental studies, iron-enriched diets conferred protection against certain infections, including Helicobacter pylori and Mycobacterium bovis (Agoro et al., 2017; Beckett et al., 2016) but exacerbated infections with Salmonella (Nairz et al., 2017).”

“In humans, clinical data support our findings that dietary iron supplementation provides beneficial outcomes, especially in developing countries where low iron status may be prevalent (Loukas et al., 2016; Mwangi et al., 2017; Oppenheimer, 1989, 1998, 2001).”

“It is important to note that the strain of mouse used for most of these studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014…”

“In humans, clinical data support our findings that dietary iron supplementation provides beneficial outcomes, especially in developing countries where low iron status may be prevalent (Loukas et al., 2016; Mwangi et al., 2017; Oppenheimer, 1989, 1998, 2001).”

“In experimental studies, iron-enriched diets conferred protection against certain infections, including Helicobacter pylori and Mycobacterium bovis (Agoro et al., 2017; Beckett et al., 2016) but exacerbated infections with Salmonella (Nairz et al.”

“CR virulence in germ-free mice is dependent on the dose of pathogen administered to the mice and the mouse strain (Buschor et al., 2017; Itoh et al., 1988).”

“CR virulence in germ-free mice is dependent on the dose of pathogen administered to the mice and the mouse strain (Buschor et al., 2017; Itoh et al., 1988).”

“In experimental studies, iron-enriched diets conferred protection against certain infections, including Helicobacter pylori and Mycobacterium bovis (Agoro et al., 2017; Beckett et al., 2016) but exacerbated infections with Salmonella (Nairz et al.”

“HOMER was used to test for overrepresentation of differentially expressed genes within KEGG (Kanehisa and Goto, 2000) pathways corrected for multiple testing using the Benjamini and Yekutieli general correction for multiple testing (Li et al., 2015).”

“It is important to note that the strain of mouse used for most of these studies has been C57BL/6 mice, which has a non-functional allele of Nramp1, a divalent metal (iron and manganese) transporter that renders themmore susceptible to infections (Canonne-Hergaux et al., 1999; Fritsche et al., 2012; Loomis et al., 2014…”

“Notably, all of these studies find that metabolic alterations in the setting of infection play a critical role in tolerance (Rao et al., 2017; Sanchez et al., 2018; Wang et al., 2016; Weis et al., 2017).”