Absence of Receptor Guanylyl Cyclase C Enhances Ileal Damage and Reduces Cytokine and Antimicrobial Peptide Production during Oral Salmonella enterica Serovar Typhimurium Infection
Authors: Abinaya Raghavan
Sandhya S Visweswariah
Anaxee Barman
Dipankar Nandi
Vishwas Mishra
Somesh Nandi
Shamik Majumdar
Mudabir Abdullah
Journal: Infection and Immunity (2018)
Discipline: IMMUNOLOGY
Keywords: Salmonella enterica serovar Typhimurium; goblet cell; guanylin; guanylyl cyclase C; thymic atrophy
Affiliations: Department of Biochemistry, Indian Institute of Science, Bengaluru, India., Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India .

Abstract:  Nontyphoidal Salmonella disease contributes toward significant morbidity and mortality across the world. Host factors, including gamma interferon, tumor necrosis factor alpha, and gut microbiota, significantly influence the outcome of Salmonella pathogenesis. However, the entire repertoire of host protective mechanisms contributing to Salmonella pathogenicity is not completely appreciated. Here, we investigated the roles of receptor guanylyl cyclase C (GC-C), which is predominantly expressed in the intestine and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C (Gucy2c-/-) displayed accelerated mortality compared with that for wild-type mice following infection via the oral route, even though both groups possessed comparable systemic Salmonella infection burdens. Survival following intraperitoneal infection remained similar in both groups, indicating that GC-C offered protection via a gut-mediated response. The serum cortisol level was higher in Gucy2c-/- mice than wild-type (Gucy2c+/+) mice, and an increase in infection-induced thymic atrophy with a loss of immature CD4+ CD8+ double-positive thymocytes was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting, and distortion of the villus architecture, was seen in Gucy2c-/- mice concomitantly with a larger number of ileal tissue-associated bacteria. Transcription of key mediators of Salmonella-induced inflammation (interleukin-22/Reg3β) was altered in Gucy2c-/- mice in comparison to that in Gucy2c+/+ mice. A reduction in fecal lactobacilli, which are protective against Salmonella infection, was observed in Gucy2c-/- mice. Gucy2c-/- mice cohoused with wild-type mice continued to show reduced amounts of lactobacilli and increased susceptibility to infection. Our study, therefore, suggests that the receptor GC-C confers a survival advantage during gut-mediated Salmonella enterica serovar Typhimurium pathogenesis, presumably by regulating Salmonella effector mechanisms and maintaining a beneficial microbiome. 

Retracted: No

PubPeer comments:
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 The following will be published in the journal AUTHOR CORRECTION Running Head: Author Correction Correction for Majumdar et al., u201cAbsence of Receptor Guanylyl Cyclase C Enhances Ileal Damage and Reduces Cytokine and Antimicrobial Peptide Production during Oral Salmonella enterica Serovar Typhimurium Infectionu201d Shamik Majumdar,a Vishwas Mishra,b Somesh Nandi,b Mudabir Abdullah,b Anaxee Barman,b Abinaya Raghavan,a Dipankar Nandi,a Sandhya S. Visweswariahb aDepartment of Biochemistry, Indian Institute of Science, Bengaluru, India bDepartment of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India Address correspondence to Sandhya S. Visweswariah, sandhya@iisc.ac.in. Volume 86, no. 5, e00799-17, 2018, https: doi.org 10.1128 IAI.00799-17. Page 7: The PkgII panel of Fig. 4 should appear as given in this correction. , 
 #1 Ghostly statistics: Authors claimed to have performed ANNOVA, while they basically did the pairwise comparisons. Neither the variance of the samples looks similar, nor ANNOVA seems suitable for pairwise comparison of independent samples (inf uninf, WT mutant ) of varying sample sizes. Not clear why the routine t-test or MW U test were overlooked. I pulled out the approximate values from the plots and performed the t-test MWU tests. The -St and +St values for Pde5 gene in Gucy2c+ + shows significant difference (p=0.02, p=0.03 respectively for t-test and MW U test). Following are the approximate data (pulled from figure) and the associated statistics performed on R. similary, Guca2a gene in Gucy - - does not show significant difference (p=0.08, p=0.15 resp. for test and MW test). Moreover, above statistics seems coherent with the visual impression of these plots. Can the authors provide the original raw data to verify the same for all the figures in the article? Pde5 gene: -------------- t.test(c(0.2,0.18, 0.17, 0.12), c(0.15, 0.13, 0.10, 0.09, 0.08, 0.07)) tWelch Two Sample t-test data: c(0.2, 0.18, 0.17, 0.12) and c(0.15, 0.13, 0.1, 0.09, 0.08, 0.07) t = 3.0338, df = 6.0772, p-value = 0.02262 alternative hypothesis: true difference in means is not equal to 0 95 percent confidence interval: 0.0125712 0.1157621 sample estimates: mean of x mean of y 0.1675000 0.1033333 wilcox.test(c(0.2,0.18, 0.17, 0.12), c(0.15, 0.13, 0.10, 0.09, 0.08, 0.07)) tWilcoxon rank sum test data: c(0.2, 0.18, 0.17, 0.12) and c(0.15, 0.13, 0.1, 0.09, 0.08, 0.07) W = 22, p-value = 0.0381 alternative hypothesis: true location shift is not equal to 0 Guca2a gene ------------------ t.test(c(0.18,0.17, 0.13, 0.11), c(0.17, 0.14, 0.13, 0.08, 0.07, 0.05, 0.06)) tWelch Two Sample t-test data: c(0.18, 0.17, 0.13, 0.11) and c(0.17, 0.14, 0.13, 0.08, 0.07, 0.05, 0.06) t = 1.9763, df = 8.2791, p-value = 0.08231 alternative hypothesis: true difference in means is not equal to 0 95 percent confidence interval: -0.007601128 0.102601128 sample estimates: mean of x mean of y 0.1475 0.1000 wilcox.test(c(0.18,0.17, 0.13, 0.11), c(0.17, 0.14, 0.13, 0.08, 0.07, 0.05, 0.06)) tWilcoxon rank sum test with continuity correction data: c(0.18, 0.17, 0.13, 0.11) and c(0.17, 0.14, 0.13, 0.08, 0.07, 0.05, 0.06) W = 22, p-value = 0.1545 alternative hypothesis: true location shift is not equal to 0 ,