Rotavirus infection

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Abstract

Rotavirus infections are a leading cause of severe, dehydrating gastroenteritis in children <5 years of age. Despite the global introduction of vaccinations for rotavirus over a decade ago, rotavirus infections still result in >200,000 deaths annually, mostly in low-income countries. Rotavirus primarily infects enterocytes and induces diarrhoea through the destruction of absorptive enterocytes (leading to malabsorption), intestinal secretion stimulated by rotavirus non-structural protein 4 and activation of the enteric nervous system. In addition, rotavirus infections can lead to antigenaemia (which is associated with more severe manifestations of acute gastroenteritis) and viraemia, and rotavirus can replicate in systemic sites, although this is limited. Reinfections with rotavirus are common throughout life, although the disease severity is reduced with repeat infections. The immune correlates of protection against rotavirus reinfection and recovery from infection are poorly understood, although rotavirus-specific immunoglobulin A has a role in both aspects. The management of rotavirus infection focuses on the prevention and treatment of dehydration, although the use of antiviral and anti-emetic drugs can be indicated in some cases.

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Figure 1: Rotavirus structure.
Figure 2: Rotavirus-associated mortality in children <5 years of age in 2013.
Figure 3: The number of rotavirus-positive tests in the United States before and after vaccine introduction.
Figure 4: The rotavirus replication cycle.
Figure 5: Duodenum histology of mice with rotavirus infection.
Figure 6: Schematic model of rotavirus-induced diarrhoea and vomiting.
Figure 7: Rotavirus-mediated inhibition of interferon induction and amplification.

References

  1. 1

    GBD Diarrhoeal Disease Collaborators. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect. Dis. 17, 909–948 (2017).

  2. 2

    Bishop, R. F. et al. Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 2, 1281–1283 (1973). This study shows visualization of rotavirus as the causative agent of viral gastroenteritis and the associated histopathology.

  3. 3

    Flewett, T. H. et al. Letter: Virus particles in gastroenteritis. Lancet 2, 1497 (1973).

  4. 4

    Estes, M. K. & Greenberg, H. B. in Field's Virology (eds Knipe, D. M. & Howley, P. M. ) 1347–1401 (Lippincott Williams & Wilkins, 2013).

  5. 5

    Matthijnssens, J. et al. VP6-sequence-based cutoff values as a criterion for rotavirus species demarcation. Arch. Virol. 157, 1177–1182 (2012).

  6. 6

    Mihalov-Kovács, E. et al. Candidate new rotavirus species in sheltered dogs, Hungary. Emerg. Infect. Dis. 21, 660–663 (2015).

  7. 7

    Bányai, K. et al. Candidate new rotavirus species in Schreiber's bats, Serbia. Infect. Genet. Evol. 48, 19–26 (2017).

  8. 8

    KU Leuven.Rotavirus Classification Working Group: RCWG. KU Leuven Laboratory of Viral Metagenomicshttps://rega.kuleuven.be/cev/viralmetagenomics/virus-classification/rcwg (2017).

  9. 9

    Matthijnssens, J. et al. Rotavirus disease and vaccination: impact on genotype diversity. Future Microbiol. 4, 1303–1316 (2009).

  10. 10

    Gentsch, J. R. et al. Serotype diversity and reassortment between human and animal rotavirus strains: implications for rotavirus vaccine programs. J. Infect. Dis. 192 (Suppl. 1), S146–S159 (2005).

  11. 11

    Santos, N. & Hoshino, Y. Global distribution of rotavirus serotypes/genotypes and its implication for the development and implementation of an effective rotavirus vaccine. Rev. Med. Virol. 15, 29–56 (2005).

  12. 12

    Matthijnssens, J. et al. Phylodynamic analyses of rotavirus genotypes G9 and G12 underscore their potential for swift global spread. Mol. Biol. Evol. 27, 2431–2436 (2010).

  13. 13

    Nakagomi, O. & Nakagomi, T. Genetic diversity and similarity among mammalian rotaviruses in relation to interspecies transmission of rotavirus. Arch. Virol. 120, 43–55 (1991).

  14. 14

    Martella, V. et al. Zoonotic aspects of rotaviruses. Vet. Microbiol. 140, 246–255 (2010).

  15. 15

    Hagbom, M. et al. Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting. PLoS Pathog. 7, e1002115 (2011). This report shows that rotavirus can stimulate 5-HT release from human enterochromaffin cells and activate the vomiting centre in the central nervous system.

  16. 16

    Leung, A. K. & Robson, W. L. Acute gastroenteritis in children: role of anti-emetic medication for gastroenteritis-related vomiting. Paediatr. Drugs 9, 175–184 (2007).

  17. 17

    Tate, J. E. et al. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect. Dis. 12, 136–141 (2012). This study is the 2008 estimate of rotavirus related mortality (450,000 deaths), the benchmark by which the impact of rotavirus vaccination programmes were measured.

  18. 18

    Tate, J. E. et al. Global, regional, and national estimates of rotavirus mortality in children &lt;5 years of age, 2000–2013. Clin. Infect. Dis. 62 (Suppl. 2), S96–S105 (2016).

  19. 19

    Gurwith, M. et al. A prospective study of rotavirus infection in infants and young children. J. Infect. Dis. 144, 218–224 (1981).

  20. 20

    Velazquez, F. R. et al. Rotavirus infection in infants as protection against subsequent infections. N. Engl. J. Med. 335, 1022–1028 (1996).

  21. 21

    Parashar, U. D. et al. Global illness and deaths caused by rotavirus disease in children. Emerg. Infect. Dis. 9, 565–572 (2003).

  22. 22

    Ramachandran, M. et al. Unusual diversity of human rotavirus G and P genotypes in India. J. Clin. Microbiol. 34, 436–439 (1996).

  23. 23

    Sanderson, C., Clark, A., Taylor, D. & Bolanos, B. Global review of rotavirus morbidity and mortality data by age and region. WHOhttp://www.who.int/immunization/sage/meetings/2012/april/Sanderson_et_al_SAGE_April_rotavirus.pdf (2011).

  24. 24

    Patel, M. M. et al. Global seasonality of rotavirus disease. Pediatr. Infect. Dis. J. 32, e134–e147 (2013).

  25. 25

    Burnett, E. et al. Global impact of rotavirus vaccination on childhood hospitalizations and mortality from diarrhea. J. Infect. Dis. 215, 1666–1672 (2017). This study summarizes the impact of rotavirus vaccination during the first 10 years after vaccine licensure and concludes that implementation of rotavirus vaccines substantially decreased hospitalizations from rotavirus and all-cause acute gastroenteritis.

  26. 26

    Tate, J. E. & Parashar, U. D. Rotavirus vaccines in routine use. Clin. Infect. Dis. 59, 1291–1301 (2014).

  27. 27

    Markkula, J. et al. Rotavirus epidemiology 5–6 years after universal rotavirus vaccination: persistent rotavirus activity in older children and elderly. Infect. Dis. 49, 388–394 (2017).

  28. 28

    Aliabadi, N. et al. Sustained decrease in laboratory detection of rotavirus after implementation of routine vaccination-United States, 2000–2014. MMWR. Morb. Mortal. Wkly Rep. 64, 337–342 (2015).

  29. 29

    Leshem, E. et al. Distribution of rotavirus strains and strain-specific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis. Lancet Infect. Dis. 14, 847–856 (2014).

  30. 30

    Doro, R. et al. Review of global rotavirus strain prevalence data from six years post vaccine licensure surveillance: is there evidence of strain selection from vaccine pressure? Infect. Genet. Evol. 28, 446–461 (2014).

  31. 31

    Correia, J. B. et al. Effectiveness of monovalent rotavirus vaccine (Rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. J. Infect. Dis. 201, 363–369 (2010).

  32. 32

    Ward, R. L. et al. Human rotavirus studies in volunteers: determination of infectious dose and serological response to infection. J. Infect. Dis. 154, 871–880 (1986).

  33. 33

    Ansari, S. A. et al. Survival and vehicular spread of human rotaviruses: possible relation to seasonality of outbreaks. Rev. Infect. Dis. 13, 448–461 (1991).

  34. 34

    Butz, A. M. et al. Prevalence of rotavirus on high-risk fomites in day-care facilities. Pediatrics 92, 202–205 (1993).

  35. 35

    Lundgren, O. & Svensson, L. Pathogenesis of rotavirus diarrhea. Microbes Infect. 3, 1145–1156 (2001).

  36. 36

    Saxena, K. et al. Human intestinal enteroids: a new model to study human rotavirus infection, host restriction, and pathophysiology. J. Virol. 90, 43–56 (2015). This study uses human intestinal enteroids to study rotavirus infections.

  37. 37

    Lopez, S. & Arias, C. F. Multistep entry of rotavirus into cells: a Versaillesque dance. Trends Microbiol. 12, 271–278 (2004).

  38. 38

    Arias, C. F. et al. Rotavirus entry: a deep journey into the cell with several exits. J. Virol. 89, 890–893 (2015).

  39. 39

    Ramani, S. et al. Diversity in rotavirus-host glycan interactions: a “sweet” spectrum. Cell. Mol. Gastroenterol. Hepatol. 2, 263–273 (2016).

  40. 40

    Nordgren, J. et al. Host genetic factors affect susceptibility to norovirus infections in Burkina Faso. PLoS ONE 8, e69557 (2013).

  41. 41

    Ramani, S. et al. The VP8* domain of neonatal rotavirus strain G10P[11] binds to type II precursor glycans. J. Virol. 87, 7255–7264 (2013).

  42. 42

    Morris, A. P. & Estes, M. K. Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VIII. Pathological consequences of rotavirus infection and its enterotoxin. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G303–G310 (2001).

  43. 43

    Chen, C. C. et al. Fecal calprotectin as a correlative marker in clinical severity of infectious diarrhea and usefulness in evaluating bacterial or viral pathogens in children. J. Pediatr. Gastroenterol. Nutr. 55, 541–547 (2012).

  44. 44

    Wiegering, V. et al. Gastroenteritis in childhood: a retrospective study of 650 hospitalized pediatric patients. Int. J. Infect. Dis. 15, e401–e407 (2011).

  45. 45

    Ball, J. M. et al. Age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein. Science 272, 101–104 (1996). This report identifies NSP4 as the first enterotoxin that induces diarrhoea in mouse pups.

  46. 46

    Holmes, I. H. et al. Infantile enteritis viruses: morphogenesis and morphology. J. Virol. 16, 937–943 (1975).

  47. 47

    Davidson, G. P. & Barnes, G. L. Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis. Acta Paediatr. Scand. 68, 181–186 (1979).

  48. 48

    Osborne, M. P. et al. Rotavirus-induced changes in the microcirculation of intestinal villi of neonatal mice in relation to the induction and persistence of diarrhea. J. Pediatr. Gastroenterol. Nutr. 12, 111–120 (1991).

  49. 49

    Ward, L. A. et al. Pathogenesis of an attenuated and a virulent strain of group A human rotavirus in neonatal gnotobiotic pigs. J. Gen. Virol. 77, 1431–1441 (1996).

  50. 50

    Hyser, J. M. et al. Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity. mBio 1, e00265-10 (2010).

  51. 51

    Boshuizen, J. A. et al. Changes in small intestinal homeostasis, morphology, and gene expression during rotavirus infection of infant mice. J. Virol. 77, 13005–13016 (2003).

  52. 52

    Bhowmick, R. et al. Rotaviral enterotoxin nonstructural protein 4 targets mitochondria for activation of apoptosis during infection. J. Biol. Chem. 287, 35004–35020 (2012).

  53. 53

    Tafazoli, F. et al. NSP4 enterotoxin of rotavirus induces paracellular leakage in polarized epithelial cells. J. Virol. 75, 1540–1546 (2001).

  54. 54

    Boshuizen, J. A. et al. Rotavirus enterotoxin NSP4 binds to the extracellular matrix proteins laminin-β3 and fibronectin. J. Virol. 78, 10045–10053 (2004).

  55. 55

    Svensson, L. Desselberger, U., Greenberg, H. B. & Estes, M. K. Viral gastroenteritis: molecular epidemiology and pathogenesis (Elsevier, 2016).

  56. 56

    Seo, N. S. et al. Integrins α1β1 and α2β1 are receptors for the rotavirus enterotoxin. Proc. Natl Acad. Sci. USA 105, 8811–8818 (2008).

  57. 57

    Ko, E. A. et al. Chloride channel inhibition by a red wine extract and a synthetic small molecule prevents rotaviral secretory diarrhoea in neonatal mice. Gut 63, 1120–1129 (2014).

  58. 58

    Pham, T. et al. The rotavirus NSP4 viroporin domain is a calcium-conducting ion channel. Sci. Rep. 7, 43487 (2017).

  59. 59

    Bialowas, S. et al. Rotavirus and serotonin cross-talk in diarrhoea. PLoS ONE 11, e0159660 (2016).

  60. 60

    Istrate, C. et al. Rotavirus infection increases intestinal motility but not permeability at the onset of diarrhea. J. Virol. 88, 3161–3169 (2014).

  61. 61

    Li, S. T. et al. Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis. PLoS Med. 4, e98 (2007).

  62. 62

    Andrews, P. L. & Horn, C. C. Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases. Auton. Neurosci. 125, 100–115 (2006).

  63. 63

    DeCamp, L. R. et al. Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. Arch. Pediatr. Adolesc. Med. 162, 858–865 (2008).

  64. 64

    Bardhan, P. K. et al. Gastric emptying of liquid in children suffering from acute rotaviral gastroenteritis. Gut 33, 26–29 (1992).

  65. 65

    Uhnoo, I. et al. Clinical features of acute gastroenteritis associated with rotavirus, enteric adenoviruses, and bacteria. Arch. Dis. Child. 61, 732–738 (1986).

  66. 66

    Brodal, P. The central nervous system: structure and function (Oxford Univ. Press, 2010).

  67. 67

    Eskilsson, A. et al. Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis. J. Neurosci. 34, 15957–15961 (2014).

  68. 68

    Jiang, B. et al. Cytokines as mediators for or effectors against rotavirus disease in children. Clin. Diagn. Lab. Immunol. 10, 995–1001 (2003).

  69. 69

    Blutt, S. E. et al. Rotavirus antigenemia in children is associated with viremia. PLoS Med. 4, e121 (2007). This is a key study that shows infectious virus in the serum of children with rotavirus infections.

  70. 70

    Ramani, S. et al. Rotavirus antigenemia in Indian children with rotavirus gastroenteritis and asymptomatic infections. Clin. Infect. Dis. 51, 1284–1289 (2010).

  71. 71

    Hemming, M. et al. Rotavirus antigenemia in children is associated with more severe clinical manifestations of acute gastroenteritis. Pediatr. Infect. Dis. J. 33, 366–371 (2014).

  72. 72

    Bass, D. M. et al. Molecular basis of age-dependent gastric inactivation of rhesus rotavirus in the mouse. J. Clin. Invest. 89, 1741–1745 (1992).

  73. 73

    Venkataram Prasad, B. V. et al. Structural basis of glycan interaction in gastroenteric viral pathogens. Curr. Opin. Virol. 7, 119–127 (2014).

  74. 74

    Franco, M. A. et al. Immunity and correlates of protection for rotavirus vaccines. Vaccine 24, 2718–2731 (2006).

  75. 75

    Desselberger, U. & Huppertz, H. I. Immune responses to rotavirus infection and vaccination and associated correlates of protection. J. Infect. Dis. 203, 188–195 (2011).

  76. 76

    Broquet, A. H. et al. RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium. J. Immunol. 186, 1618–1626 (2011).

  77. 77

    Lin, J. D. et al. Distinct roles of type I and type III interferons in intestinal immunity to homologous and heterologous rotavirus infections. PLoS Pathog. 12, e1005600 (2016).

  78. 78

    López, S. et al. Rotavirus strategies against the innate antiviral system. Annu. Rev. Virol. 3, 591–609 (2016).

  79. 79

    Uchiyama, R. et al. MyD88-mediated TLR signaling protects against acute rotavirus infection while inflammasome cytokines direct Ab response. Innate Immun. 21, 416–428 (2015).

  80. 80

    Uchiyama, R. et al. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J. Infect. Dis. 210, 171–182 (2014).

  81. 81

    Zhu, S. Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 546, 667–670 (2017).

  82. 82

    Pott, J. et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 8, e1002670 (2012).

  83. 83

    Holloway, G. et al. Rotavirus inhibits IFN-induced STAT nuclear translocation by a mechanism that acts after STAT binding to importin-alpha. J. Gen. Virol. 95, 1723–1733 (2014).

  84. 84

    Zhang, B. et al. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).

  85. 85

    Hernandez, P. P. et al. Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. Nat. Immunol. 16, 698–707 (2015).

  86. 86

    Chanda, S. et al. Rotavirus-induced miR-142-5p elicits proviral milieu by targeting non-canonical transforming growth factor beta signalling and apoptosis in cells. Cell. Microbiol. 18, 733–747 (2016).

  87. 87

    Rodriguez, L. S. et al. Immunomodulators released during rotavirus infection of polarized caco-2 cells. Viral Immunol. 22, 163–172 (2009).

  88. 88

    Liu, F. et al. Lactobacillus rhamnosus GG on rotavirus-induced injury of ileal epithelium in gnotobiotic pigs. J. Pediatr. Gastroenterol. Nutr. 57, 750–758 (2013).

  89. 89

    Franco, M. A. & Greenberg, H. B. Immunity to rotavirus in T cell deficient mice. Virology 238, 169–179 (1997).

  90. 90

    Angel, J. et al. Correlates of protection for rotavirus vaccines: possible alternative trial endpoints, opportunities, and challenges. Hum. Vaccin. Immunother. 10, 3659–3671 (2014).

  91. 91

    Mesa, M. C. et al. A TGF-β mediated regulatory mechanism modulates the T cell immune response to rotavirus in adults but not in children. Virology 399, 77–86 (2010).

  92. 92

    Jaimes, M. C. et al. Frequencies of virus-specific CD4+ and CD8+ T lymphocytes secreting gamma interferon after acute natural rotavirus infection in children and adults. J. Virol. 76, 4741–4749 (2002).

  93. 93

    Gladstone, B. P. et al. Protective effect of natural rotavirus infection in an Indian birth cohort. N. Engl. J. Med. 365, 337–346 (2011). The study by Velazquez et al. (Ref. 20) formed the basis for rotavirus vaccines. However, this study suggests that natural infections (and therefore vaccines) are not likely to be as effective in some populations.

  94. 94

    Gilger, M. A. et al. Extraintestinal rotavirus infections in children with immunodeficiency. J. Pediatr. 120, 912–917 (1992).

  95. 95

    Patel, N. C. et al. Vaccine-acquired rotavirus in infants with severe combined immunodeficiency. N. Engl. J. Med. 362, 314–319 (2010).

  96. 96

    VanCott, J. L. et al. Mice develop effective but delayed protective immune responses when immunized as neonates either intranasally with nonliving VP6/LT(R192G) or orally with live rhesus rotavirus vaccine candidates. J. Virol. 80, 4949–4961 (2006).

  97. 97

    Parra, M. et al. Circulating rotavirus-specific T cells have a poor functional profile. Virology 468–470, 340–350 (2014).

  98. 98

    Ward, R. L. et al. Reductions in cross-neutralizing antibody responses in infants after attenuation of the human rotavirus vaccine candidate 89–12. J. Infect. Dis. 194, 1729–1736 (2006).

  99. 99

    Florez, I. D. et al. The effectiveness and safety of treatments used for acute diarrhea and acute gastroenteritis in children: protocol for a systematic review and network meta-analysis. Syst. Rev. 5, 14 (2016).

  100. 100

    Bishop, R. F. et al. Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. N. Engl. J. Med. 309, 72–76 (1983).

  101. 101

    Kilgore, P. E. et al. Neonatal rotavirus infection in Bangladesh: strain characterization and risk factors for nosocomial infection. Pediatr. Infect. Dis. J. 15, 672–677 (1996).

  102. 102

    Payne, D. C. et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics 122, 1235–1243 (2008).

  103. 103

    Raul, V. F. et al. Cohort study of rotavirus serotype patterns in symptomatic and asymptomatic infections in Mexican children. Pediatr. Infect. Dis. J. 12, 54–61 (1993).

  104. 104

    Glass, R. I. et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J. Infect. Dis. 174 (Suppl. 1), S5–S11 (1996).

  105. 105

    Echeverria, P. et al. Rotavirus as a cause of severe gastroenteritis in adults. J. Clin. Microbiol. 18, 663–667 (1983).

  106. 106

    Nakajima, H. et al. Winter seasonality and rotavirus diarrhoea in adults. Lancet 357, 1950 (2001).

  107. 107

    Pickering, L. K. et al. Asymptomatic excretion of rotavirus before and after rotavirus diarrhea in children in day care centers. J. Pediatr. 112, 361–365 (1988).

  108. 108

    Richardson, S. et al. Extended excretion of rotavirus after severe diarrhoea in young children. Lancet 351, 1844–1848 (1998).

  109. 109

    Kang, G. et al. Quantitation of group A rotavirus by real-time reverse-transcription-polymerase chain reaction: correlation with clinical severity in children in South India. J. Med. Virol. 73, 118–122 (2004).

  110. 110

    Ramani, S. et al. Comparison of viral load and duration of virus shedding in symptomatic and asymptomatic neonatal rotavirus infections. J. Med. Virol. 82, 1803–1807 (2010).

  111. 111

    Amar, C. F. et al. Detection by PCR of eight groups of enteric pathogens in 4,627 faecal samples: re-examination of the English case-control Infectious Intestinal Disease Study (1993–1996). Eur. J. Clin. Microbiol. Infect. Dis. 26, 311–323 (2007).

  112. 112

    Teitelbaum, J. E. & Daghistani, R. Rotavirus causes hepatic transaminase elevation. Dig. Dis. Sci. 52, 3396–3398 (2007).

  113. 113

    Akelma, A. Z. et al. Serum transaminase elevation in children with rotavirus gastroenteritis: seven years’ experience. Scand. J. Infect. Dis. 45, 362–367 (2013).

  114. 114

    Patel, M. M. et al. Fulfilling the promise of rotavirus vaccines: how far have we come since licensure? Lancet Infect. Dis. 12, 561–570 (2012).

  115. 115

    Vesikari, T. et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 354, 23–33 (2006).

  116. 116

    Ruiz-Palacios, G. M. et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N. Engl. J. Med. 354, 11–22 (2006).

  117. 117

    Leshem, E. et al. Rotavirus vaccines and health care utilization for diarrhea in the United States (2007–2011). Pediatrics 134, 15–23 (2014).

  118. 118

    Armah, G. E. et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet 376, 606–614 (2010). This is a key study that shows lower efficacy of RV5 vaccine in Asian children relative to previous studies in developed countries and Latin America.

  119. 119

    Madhi, S. A. et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N. Engl. J. Med. 362, 289–298 (2010). This is a key study that shows lower efficacy of RV1 vaccine in African children relative to previous studies in developed countries and Latin America.

  120. 120

    Zaman, K. et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Lancet 376, 615–623 (2010).

  121. 121

    Harris, V. C. et al. Significant correlation between the infant gut microbiome and rotavirus vaccine response in rural Ghana. J. Infect. Dis. 215, 34–41 (2017). This study indicates that the microbiome can impact rotavirus vaccines.

  122. 122

    Harris, V. et al. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbeshttp://dx.doi.org/10.1080/19490976.2017.1376162 (2017).

  123. 123

    Becker-Dreps, S. et al. The association between fecal biomarkers of environmental enteropathy and rotavirus vaccine response in Nicaraguan infants. Pediatr. Infect. Dis. J. 36, 412–416 (2017).

  124. 124

    Emperador, D. M. et al. Interference of monovalent, bivalent, and trivalent oral poliovirus vaccines on monovalent rotavirus vaccine immunogenicity in rural Bangladesh. Clin. Infect. Dis. 62, 150–156 (2016).

  125. 125

    Chilengi, R. et al. Association of maternal immunity with rotavirus vaccine immunogenicity in Zambian infants. PLoS ONE 11, e0150100 (2016).

  126. 126

    Ali, A. et al. Impact of withholding breastfeeding at the time of vaccination on the immunogenicity of oral rotavirus vaccine-a randomized trial. PLoS ONE 10, e0145568 (2015).

  127. 127

    Kazi, A. M. et al. Secretor and salivary ABO blood group antigen status predict rotavirus vaccine-take in infants. J. Infect. Dis. 215, 786–789 (2017).

  128. 128

    Armah, G. et al. A randomized, controlled trial of the impact of alternative dosing schedules on the immune response to human rotavirus vaccine in rural Ghanaian infants. J. Infect. Dis. 213, 1678–1685 (2016).

  129. 129

    Murphy, T. V. et al. Intussusception among infants given an oral rotavirus vaccine. N. Engl. J. Med. 344, 564–572 (2001).

  130. 130

    Tate, J. E. et al. Intussusception rates before and after the introduction of rotavirus vaccine. Pediatrics 138, e20161082 (2016).

  131. 131

    Groome, M. J. et al. Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet Infect. Dis. 17, 843–853 (2017). This clinical trial reports the use of a non-replicating rotavirus vaccine.

  132. 132

    Bhandari, N. et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet 383, 2136–2143 (2014).

  133. 133

    Chen, M. Y. et al. Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand. Hum. Vaccin. Immunother. 13, 1126–1135 (2017).

  134. 134

    Isanaka, S. et al. Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger. N. Engl. J. Med. 376, 1121–1130 (2017).

  135. 135

    O'Ryan, G. M. et al. Management of acute infectious diarrhea for children living in resource-limited settings. Expert Rev. Anti. Infect. Ther. 12, 621–632 (2014).

  136. 136

    Guarino, A. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J. Pediatr. Gastroenterol. Nutr. 59, 132–152 (2014).

  137. 137

    Bhattacharya, S. K. History of development of oral rehydration therapy. Indian J. Public Health 38, 39–43 (1994).

  138. 138

    Kotloff, K. L. et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 382, 209–222 (2013).

  139. 139

    King, C. K. et al. Managing acute infectious gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm. Rep. 52, 1–16 (2003).

  140. 140

    Ruuska, T. & Vesikari, T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand. J. Infect. Dis. 22, 259–267 (1990).

  141. 141

    Duggan, C. et al. Scientific rationale for a change in the composition of oral rehydration solution. JAMA 291, 2628–2631 (2004).

  142. 142

    Churgay, C. A. & Aftab, Z. Gastroenteritis in children: Part II. Prevention and management. Am. Fam. Physician 85, 1066–1070 (2012).

  143. 143

    Gaffey, M. F. et al. Dietary management of childhood diarrhea in low- and middle-income countries: a systematic review. BMC Public Health 13 (Suppl. 3), S17 (2013).

  144. 144

    Lo, V. A. et al. An international consensus report on a new algorithm for the management of infant diarrhoea. Acta Paediatr. 105, e384–e389 (2016).

  145. 145

    Bzik, V. A. et al. Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions. J. Pharm. Pharmacol. 64, 644–653 (2012).

  146. 146

    de Queiroz, C. A. et al. Zinc treatment ameliorates diarrhea and intestinal inflammation in undernourished rats. BMC Gastroenterol. 14, 136 (2014).

  147. 147

    World Health Organization. Department of Child and Adolescent Health and Development & UNICEF. Clinical management of acute diarrhoea: WHO/UNICEF joint statement (WHO, 2004).

  148. 148

    Lukacik, M. et al. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics 121, 326–336 (2008).

  149. 149

    O'Ryan, M. et al. An update on management of severe acute infectious gastroenteritis in children. Expert Rev. Anti Infect. Ther. 8, 671–682 (2010).

  150. 150

    Freedman, S. B. et al. Gastroenteritis therapies in developed countries: systematic review and meta-analysis. PLoS ONE. 10, e0128754 (2015).

  151. 151

    Ahmadi, E. et al. Efficacy of probiotic use in acute rotavirus diarrhea in children: a systematic review and meta-analysis. Caspian J. Intern. Med. 6, 187–195 (2015).

  152. 152

    Vlasova, A. N. et al. Comparison of probiotic lactobacilli and bifidobacteria effects, immune responses and rotavirus vaccines and infection in different host species. Vet. Immunol. Immunopathol. 172, 72–84 (2016).

  153. 153

    Sindhu, K. N. et al. Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. 58, 1107–1115 (2014).

  154. 154

    Das, S. et al. Efficacy and safety of Saccharomyces boulardii in acute rotavirus diarrhea: double blind randomized controlled trial from a developing country. J. Trop. Pediatr. 62, 464–470 (2016).

  155. 155

    Rossignol, J. F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 110, 94–103 (2014).

  156. 156

    Rossignol, J. F. et al. Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Lancet 368, 124–129 (2006).

  157. 157

    Mahapatro, S. et al. Nitazoxanide in acute rotavirus diarrhea: a randomized control trial from a developing country. J. Trop. Med. 2017, 7942515 (2017).

  158. 158

    La, F. S. et al. Thiazolides, a new class of antiviral agents effective against rotavirus infection, target viral morphogenesis, inhibiting viroplasm formation. J. Virol. 87, 11096–11106 (2013).

  159. 159

    Das, J. K. et al. The effect of antiemetics in childhood gastroenteritis. BMC Public Health 13 (Suppl. 3), S9–S13 (2013).

  160. 160

    Primi, M. P. et al. Racecadotril demonstrates intestinal antisecretory activity in vivo. Aliment. Pharmacol. Ther. 13 (Suppl. 6), 3–7 (1999).

  161. 161

    Emparanza Knörr, J. I. et al. Systematic review of the efficacy of racecadotril in the treatment of acute diarrhoea [Spanish]. An. Pediatr. 69, 432–438 (2008).

  162. 162

    Gordon, M. & Akobeng, A. Racecadotril for acute diarrhoea in children: systematic review and meta-analyses. Arch. Dis. Child. 101, 234–240 (2016).

  163. 163

    Gharial, J. et al. Racecadotril for the treatment of severe acute watery diarrhoea in children admitted to a tertiary hospital in Kenya. BMJ Open Gastroenterol. 4, e000124 (2017).

  164. 164

    Kang, G. et al. Racecadotril in the management of rotavirus and non-rotavirus diarrhea in under-five children: two randomized, double-blind, placebo-controlled trials. Indian Pediatr. 53, 595–600 (2016).

  165. 165

    Das, R. R. et al. Efficacy and safety of diosmectite in acute childhood diarrhoea: a meta-analysis. Arch. Dis. Child. 100, 704–712 (2015).

  166. 166

    Dupont, C. et al. Oral diosmectite reduces stool output and diarrhea duration in children with acute watery diarrhea. Clin. Gastroenterol. Hepatol. 7, 456–462 (2009).

  167. 167

    Beutels, P. et al. Funding of drugs: do vaccines warrant a different approach? Lancet Infect. Dis. 8, 727–733 (2008).

  168. 168

    Griebsch, I. et al. Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health. Pediatrics 115, e600–e614 (2005).

  169. 169

    Diez, D. J. et al. The impact of childhood acute rotavirus gastroenteritis on the parents’ quality of life: prospective observational study in European primary care medical practices. BMC Pediatr. 12, 58 (2012).

  170. 170

    Rochanathimoke, O. et al. Quality of life of diarrheal children and caregivers in Thailand. Value Health 17, A368–A369 (2014).

  171. 171

    Sénécal, M. et al. Measuring the Impact of Rotavirus Acute Gastroenteritis Episodes (MIRAGE): a prospective community-based study. Can. J. Infect. Dis. Med. Microbiol. 19, 397–404 (2008).

  172. 172

    Kolling, G. et al. Enteric pathogens through life stages. Front. Cell. Infect. Microbiol. 2, 114 (2012).

  173. 173

    Aballea, S. et al. A critical literature review of health economic evaluations of rotavirus vaccination. Hum. Vaccin. Immunother. 9, 1272–1288 (2013).

  174. 174

    Atherly, D. E. et al. Projected health and economic impact of rotavirus vaccination in GAVI-eligible countries: 2011–2030. Vaccine 30 (Suppl. 1), A7–A14 (2012).

  175. 175

    Ogden, K. M. et al. Predicted structure and domain organization of rotavirus capping enzyme and innate immune antagonist VP3. J. Virol. 88, 9072–9085 (2014).

  176. 176

    Ogden, K. M. et al. Structural basis for 2′-5′-oligoadenylate binding and enzyme activity of a viral RNase L antagonist. J. Virol. 89, 6633–6645 (2015).

  177. 177

    Brandmann, T. & Jinek, M. Crystal structure of the C-terminal 2′,5′-phosphodiesterase domain of group A rotavirus protein VP3. Proteins 83, 997–1002 (2015).

  178. 178

    Suzuki, H. et al. Electron microscopic evidence for budding process-independent assembly of double-shelled rotavirus particles during passage through endoplasmic reticulum membranes. J. Gen. Virol. 74, 2015–2018 (1993).

  179. 179

    Cheung, W. et al. Rotaviruses associate with cellular lipid droplet components to replicate in viroplasms, and compounds disrupting or blocking lipid droplets inhibit viroplasm formation and viral replication. J. Virol. 84, 6782–6798 (2010).

  180. 180

    Hu, L. et al. Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen. Nature 485, 256–259 (2012). This paper demonstrates that the A-type HBGA is a cell attachment factor for a human rotavirus strain and structurally characterizing the HBGA binding to VP8*.

  181. 181

    Asano, K. M. et al. Group A rotavirus in Brazilian bats: description of novel T15 and H15 genotypes. Arch. Virol. 161, 3225–3230 (2016).

  182. 182

    Richards, J. E. et al. Experimental pathways towards developing a rotavirus reverse genetics system: synthetic full length rotavirus ssRNAs are neither infectious nor translated in permissive cells. PLoS ONE 8, e74328 (2013).

  183. 183

    De, L. G. et al. An inhibitory motif on the 5’UTR of several rotavirus genome segments affects protein expression and reverse genetics strategies. PLoS ONE 11, e0166719 (2016).

  184. 184

    Kanai, Y. et al. Entirely plasmid-based reverse genetics system for rotaviruses. Proc. Natl Acad. Sci. USA 114, 2349–2354 (2017). This study reports the use of a plasmid-based reverse genetics system for rotavirus.

  185. 185

    Saxena, K. et al. A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection. Proc. Natl Acad. Sci. USA 114, E570–E579 (2017).

  186. 186

    Kandasamy, S. et al. Differential effects of Escherichia coli Nissle and Lactobacillus rhamnosus Strain GG on human rotavirus binding, infection, and B cell immunity. J. Immunol. 196, 1780–1789 (2016).

  187. 187

    Angel, J. et al. Rotavirus immune responses and correlates of protection. Curr. Opin. Virol. 2, 419–425 (2012).

  188. 188

    Kirkpatrick, B. D. et al. The “Performance of Rotavirus and Oral Polio Vaccines in Developing Countries” (PROVIDE) study: description of methods of an interventional study designed to explore complex biologic problems. Am. J. Trop. Med. Hyg. 92, 744–751 (2015).

  189. 189

    Bucardo, F. et al. Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua. Infect. Genet. Evol. 12, 1282–1294 (2012).

  190. 190

    Hemming, M. & Vesikari, T. Detection of rotateq vaccine-derived, double-reassortant rotavirus in a 7-year-old child with acute gastroenteritis. Pediatr. Infect. Dis. J. 33, 655–656 (2014).

  191. 191

    Nair, N. et al. VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans. Sci. Transl Med. 9, eaam5434 (2017).

  192. 192

    Ettayebi, K. et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387–1393 (2016).

  193. 193

    Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

  194. 194

    Wong, C. J. et al. Aseptic meningitis in an infant with rotavirus gastroenteritis. Pediatr. Infect. Dis. 3, 244–246 (1984).

  195. 195

    Wong, V. Acute gastroenteritis-related encephalopathy. J. Child Neurol. 16, 906–910 (2001).

  196. 196

    Nakagomi, T. & Nakagomi, O. Rotavirus antigenemia in children with encephalopathy accompanied by rotavirus gastroenteritis. Arch. Virol. 150, 1927–1931 (2005).

  197. 197

    Ushijima, H. et al. Suspected rotavirus encephalitis. Arch. Dis. Child. 61, 692–694 (1986).

  198. 198

    Payne, D. C. et al. Protective association between rotavirus vaccination and childhood seizures in the year following vaccination in US children. Clin. Infect. Dis. 58, 173–177 (2014).

  199. 199

    Riepenhoff-Talty, M. et al. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J. Infect. Dis. 174, 8–15 (1996).

  200. 200

    Hertel, P. M. & Estes, M. K. Rotavirus and biliary atresia: can causation be proven? Curr. Opin. Gastroenterol. 28, 10–17 (2012).

  201. 201

    Riepenhoff-Talty, M. et al. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr. Res. 33, 394–399 (1993).

  202. 202

    Pane, J. A. et al. Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling. Sci. Rep. 6, 29697 (2016).

  203. 203

    Pane, J. A. et al. Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells. PLoS Pathog. 10, e1003998 (2014).

  204. 204

    Graham, K. L. et al. Rotavirus infection of infant and young adult nonobese diabetic mice involves extraintestinal spread and delays diabetes onset. J. Virol. 81, 6446–6458 (2007).

  205. 205

    Blomqvist, M. et al. Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. Clin. Exp. Immunol. 128, 511–515 (2002).

  206. 206

    Makela, M. et al. Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes. Clin. Exp. Immunol. 145, 261–270 (2006).

  207. 207

    Angel, J. et al. Rotavirus vaccines: recent developments and future considerations. Nat. Rev. Microbiol. 5, 529–539 (2007).

  208. 208

    World Health Organization. Rotavirus mortality rate in children younger than 5 years, 2013. World Health Organizationhttp://www.who.int/immunization/monitoring_surveillance/burden/estimates/rotavirus/rotavirus_deaths_map_b.jpg?ua=1 (2017).

  209. 209

    Centers for Disease Control and Prevention. Sustained decrease in laboratory detection of rotavirus after implementation of routine vaccination — United States, 2000–2014. CDChttps://www.cdc.gov/mmwr/preview/mmwrhtml/mm6413a1.htm (2015).

  210. 210

    Fleming, F. E. et al. Relative roles of GM1 ganglioside, N-acylneuraminic acids, and α2β1 integrin in mediating rotavirus infection. J. Virol. 88, 4558–4571 (2014).

  211. 211

    Guerrero, C. A. et al. Heat shock cognate protein 70 is involved in rotavirus cell entry. J. Virol. 76, 4096–4102 (2002).

  212. 212

    Zarate, S. et al. Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5. J. Virol. 77, 7254–7260 (2003).

  213. 213

    Torres-Flores, J. M. et al. The tight junction protein JAM-A functions as coreceptor for rotavirus entry into MA104 cells. Virology 475, 172–178 (2015).

  214. 214

    Diaz-Salinas, M. A. et al. The spike protein VP4 defines the endocytic pathway used by rotavirus to enter MA104 cells. J. Virol. 87, 1658–1663 (2013).

  215. 215

    Kordasti, S. et al. Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea. Gut 53, 952–957 (2004).

  216. 216

    Trask, S. D., McDonald, S. M. & Patton, J. T. Structural insights into the coupling of virion assembly and rotavirus replication. Nat. Rev. Microbiol. 10, 165–177 (2012).

  217. 217

    Hagbom, M. et al. Towards a human rotavirus disease model. Curr. Opin. Virol. 2, 408–418 (2012).

  218. 218

    Graff, J. W. et al. Rotavirus NSP1 inhibits NFκB activation by inducing proteasome-dependent degradation of β-TrCP: a novel mechanism of IFN antagonism. PLoS Pathog. 5, e1000280 (2009).

  219. 219

    Ding, S. et al. Comparative proteomics reveals strain-specific β-TrCP degradation via rotavirus NSP1 hijacking a host cullin-3-Rbx1 complex. PLoS Pathog. 12, e1005929 (2016).

  220. 220

    Sen, A. et al. Rotavirus NSP1 protein inhibits interferon-mediated STAT1 activation. J. Virol. 88, 41–53 (2014).

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Acknowledgements

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC).

Author information

Introduction (S.E.C. and S.R.); Epidemiology (J.E.T. and U.D.P.); Mechanisms/pathophysiology (L.S. and M.H.); Diagnosis, screening and prevention (M.A.F. and H.B.G.); Management (M.O.); Quality of life (G.K.); Outlook (U.D. and M.K.E.); Overview of Primer (S.E.C., S.R. and M.K.E.).

Correspondence to Mary K. Estes.

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Crawford, S., Ramani, S., Tate, J. et al. Rotavirus infection. Nat Rev Dis Primers 3, 17083 (2017) doi:10.1038/nrdp.2017.83

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