Abstract
Rotavirus is recognized as one of the main diarrheal pathogens in young children and animals. The prevailing central dogma of rotavirus infection states that the infection is confined in the gastrointestinal tract. However, increasing evidences indicate that rotavirus infection is systemic. Clinical case reports of systemic manifestations to rotavirus infection in children has continued to accumulate over the past years. The use of animal models provided pathological and molecular evidences for extra-intestinal infection of rotaviruses. The mechanism correlated with the extra-intestinal spread of rotavirus infection from the intestine is through cell-free and cell-associated viremia. The extent of the extra-intestinal spread of rotavirus infection has not yet been fully elucidated; whether it can only affect a limited number of organs and tissues or capable of involving the body as a whole. Moreover, the influence of systemic rotavirus infections remains to be determined. In this review, combination of previous and new data are outlined to help in better understanding of the extra-intestinal infections of rotaviruses.
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References
Ahmed K, Bozdayi G, Mitui MT, Ahmed S, Kabir L, Buket D, Bostanci I. Nishizono. Circulating rotaviral RNA in children with rotavirus antigenemia. J Negat Results Biomed. 2013;12:5.
Alam MN, Alam MM, Nahar A, Kobayashi N. Molecular epidemiological studies on rotavirus infection causing severe diarrhea in human, animals and poultry. Bangl J Vet Med. 2011;9:167–75.
Allen SR, Jafri M, Donnelly B, McNeal M, Witte D, Bezerra J, Ward R, Tiao GM. Effect of rotavirus strain on the murine model of biliary atresia. J Virol. 2007;81:1671–9.
Azevedo MS, Yuan L, Jeong KI, Gonzalez A, Nguyen TV, Pouly S, Gochnauer M, Zhang W, Azevedo A, Saif LJ. Viremia and nasal and rectal shedding of rotavirus in gnotobiotic pigs inoculated with Wa human rotavirus. J Virol. 2005;79:5428–36.
Brown KA, Offit PA. Rotavirus-specific proteins are detected in murine macrophages in both intestinal and extraintestinal lymphoid tissues. Microb Pathog. 1998;24:327–31.
Blutt SE, Kirkwood CD, Parreno V, Warfield KL, Ciarlet M, Estes MK, Bok K, Bishop RF, Conner ME. Rotavirus antigenaemia and viraemia: a common event? Lancet. 2003;362:1445–9.
Blutt SE, Fenaux M, Warfield KL, Greenberg HB, Conner ME. Active viremia in rotavirus-infected mice. J Virol. 2006;80:6702–5.
Blutt SE, Conner ME. Rotavirus: to the gut and beyond. Curr Opin Gastroenterol. 2007;23:39–43.
Blutt SE, Matson DO, Crawford SE, Staat MA, Azimi P, Bennett BL, Piedra PA, Conner ME. Rotavirus antigenemia in children is associated with viremia. PLoS Med. 2007;4:e121.
Carreno-Torres JJ, Gutierrez M, Arias CF, Lopez S, Isa P. Characterization of viroplasm formation during the early stages of rotavirus infection. Virol J. 2010;7:350.
Chiappini E, Azzari C, Moriondo M, Galli L, de Martino M. Viremia is a common finding in immunocompetent children with rotavirus infection. J Med Virol. 2005;76:265–7.
Crawford SE, Patel DG, Cheng E, Berkova Z, Hyser JM, Ciarlet M, Finegold MJ, Conner ME, Estes MK. Rotavirus viremia and extraintestinal viral infection in the neonatal rat model. J Virol. 2006;80:4820–32.
Delmas O, Durand-Schneider AM, Cohen J, Colard O, Trugnan G. Spike protein VP4 assembly with maturing rotavirus requires a postendoplasmic reticulum event in polarized caco-2 cells. J Virol. 2004;78:10987–94.
Dickey M, Jamison L, Michaud L, Care L, Bernstein DI, Staat MA. Rotavirus mengioencephalitis in a previously healthy child and a review of the literature. Pediatr Infect Dis J. 2009;28:318–21.
Dyce KM, Sack WO, Wensing CJG. Textbook of veterinary anatomy. 4th ed. Missouri: Saunders Elsevier; 2010. p. 223–67.
Estes MK, Kapikian AZ. Rotaviruses. In: Knipe DM, Griffin DE, Lamb RA, Straus SE, Howley PM, Martin MA, Roizman B, editors. Fields virology. Philidelphia: Lippincott Williams & Wilkin; 2007. p. 1917–74.
Fenaux M, Cuadras MA, Feng N, Jaimes M, Greenberg HB. Extraintestinal spread and replication of a homologous EC rotavirus strain and heterologous rhesus rotavirus in BALB/c mice. J Virol. 2007;80:5219–32.
Feng J, Li M, Cai T, Tang H, Gu W. Rotavirus-induced murine biliary atresia is mediated by nuclear factor-κB. J Pediatr Surg. 2005;40:630–66.
Feng N, Kim B, Fenaux M, Nguyen H, Vo P, Omary MB, Greenberg HB. Role of interferon in homologous and heterologous rotavirus infection in the intestines and extraintestinal organs of suckling mice. J Virol. 2008;82(15):7578–90.
Feng N, Sen A, Wolf M, Vo P, Hoshino Y, Greenberg HB. Roles of VP4 and NSP1 in determining the distinctive replication capacities of simian rotavirus RRV and bovine rotavirus UK in the mouse biliary tract. J Virol. 2011;84:2686–94.
Fischer TK, Ashley D, Kerin T, Reynolds-Hedmann E, Gentsch J, Widdowson MA, Westerman L, Puhr N, Turcios RM, Glass RI. Rotavirus antigenemia in patients with acute gastroenteritis. J Infect Dis. 2005;192:913–9.
Giordano S, Serra G, Dones P, Gangi MD, Failla MC, Iaria C, Ricciardi F, Pernice LM, Pantaleo D, Cascio A. Acute pancreatitis in children and rotavirus infection. Description of a case and minireview. New Microbiol. 2013;36:97–101.
Gliger MA, Matson DO, Conner NE, Rosenblatt HM, Finegold MJ, Estes MK. Extraintestinal rotavirus infections in children with immunodeficiency. J Pediatr. 1992;120:912–7.
Graham KL, O’Donnell JA, Tan Y, Sanders N, Carrington EM, Allison J, Coulson BS. Rotavirus infection of infant and young adult nonobese diabetic mice involves extraintestinal spread and delays diabetes onset. J Virol. 2007;81:6446–58.
Greenberg HB, Estes MK. Rotaviruses: from pathogenesis to vaccination. Gastroenteroloy. 2009;136:1939–51.
Guerrero CA, Mendez E, Zarate S, Isa P, Lopez S, Arias CF. Integrin alpha(v)beta(3) mediates rotavirus cell entry. Proc Natl Acad Sci USA. 2000;97:14644–9.
Gutierrez M, Isa P, Sanchez-San MC, Perez-Vargas J, Espinosa R, Arias CF, Lopez S. Different rotavirus strains enter MA 104 cells through different endocytic pathways: the role of clathrin-mediated endocytosis. J Virol. 2010;84:9161–9.
Huang XL, Chen J, Yu YP, Chen LQ, Li ZY, Zhao ZY. Viremia and extraintestinal involvement after rotavirus infection. Zhejiang Da Xue Xue Bao Yi Bue Ban. 2006;35:69–75 (Article in Chinese).
Huang P, Xia M, Tan M, Zhong W, Wei C, Wang L, Morrow A, Jiang X. Spike protein recognizes histo-blood group antigens in a type-specific manner. J Virol. 2012;86:4833–43.
Hung JJ, Wen HY, Yen MH, Chen HW, Yan DC, Lin KL, Lin SJ, Lin TY, Hsu CY. Rotavirus gastroenteritis associated with afebrile convulsion in children: clinical analysis of 40 cases. Chang Gung Med J. 2003;26:654–9.
Isa P, Arias CF, Lopez S. Role of sialic acids in rotavirus infection. Glycoconj J. 2006;23:27–37.
Kim HJ, Park JG, Matthijnssens J, Lee JH, Bae YC, Alfajaro MM, Park SI, Kang MI, Cho KO. Intestinal and extra-intestinal pathogenicity of a bovine reassortant rotavirus in calves and piglets. Vet Microbiol. 2011;152:291–303.
Kim HJ, Park JG, Alfajaro MM, Kim DS, Hosmillo M, Son KY, Lee JH, Bae YC, Park SI, Kang MI, Cho KO. Pathogenicity characterization of a bovine triple reassortant rotavirus in calves and piglets. Vet Microbiol. 2012;159:11–22.
Kim HH, Park JG, Matthijnssens J, Kim HJ, Kwon HJ, Son KY, Ryu EH, Kim DS, Lee WS, Kang MI, Yang DK, Lee JH, Park SJ, Cho KO. Pathogenicity of porcine G9P[23] and G9P[7] rotaviruses in piglets. Vet Microbiol. 2013;166:123–37.
Kraft LM. Observations on the control and natural history of epidemic diarrhea of infant mice (EDIM). Yale J Biol and Med Inc. 1958;31:121–37.
Kumagai H, Matsumoto S, Ebashi M, Ohsone T. Acute pancreatitis associated with rotavirus infection. Indian Pediatr. 2009;46:1099–101.
Lynch M, Lee B, Azimi P, Gentsch J, Glaser C, Gilliam S, Chang HGH, Ward R, Glass RI. Rotavirus and central nervous system symptoms: cause or contaminant? case reports and review. Clin Infect Dis. 2001;33:932–8.
Martinez MA, Lopez S, Arias CF, Isa P. Gangliosides have a functional role during rotavirus cell entry. J Virol. 2013;87:1115–22.
Medici MC, Abelli LA, Guerra P, Dodi I, Dettori G, Chezzi C. Case report: detection of rotavirus RNA in the cerebrospinal fluid of a child with rotavirus gastroenteritis and meningism. J Med Virol. 2011;83:1637–40.
Minami K, Tamura A, Komori Y, Yanagawa T, Izumi G, Kioka N, Yoshikawa N. Acute encephalopathy and rhabdomyolysis following gastroenteritis. J Paediatr Child Health. 2007;43:90–1.
Moon S, Wang Y, Dennehy P, Simonse KA, Zhang J, Jiang B. Antigenemia, RNAemia, and innate immunity in children with acute rotavirus diarrhea. FEMS Immunol Med Microbiol. 2012;64:382–91.
Morris AP, Scott JK, Ball JM, Zeng CQ, O’Neal WK, Estes MK. NSP4 elicits age-dependent diarrhea and Ca(2+) mediated l(−) influx into intestinal crypts of CF mice. Am J Physiol. 1999;277:G431–44.
Mossel EC, Ramig RF. Rotavirus genome segment 7 (NSP3) is a determinant of extraintestinal spread in the neonatal mouse. J Virol. 2002;76:6502–9.
Mossel EC, Ramig RF. A lymphatic mechanism of rotavirus extraintestinal spread in the neonatal mouse. J Virol. 2003;77:12352–6.
Nakagomi T, Nakagomi O. Rotavirus antigenemia in children with encephalopathy accompanied by rotavirus gastroenteritis. Arch Virol. 2005;150:1927–31.
Nakano I, Taniguchi K, Ishibashi-Ueba H, Maeno Y, Yamamoto N, Yui A, Komoto S, Wakata Y, Matsubara T, Ozaki N. Sudden death from systemic rotavirus infection and detection of non-structural rotavirus proteins. J Clin Microbiol. 2011;49:4382–5.
Nigrovic LE, Lumeng C, Landrigan C, Chiang VW. Rotavirus cerebellitis? Clin Infect Dis. 2002;34:130.
Ozalp E, Aydin-Teke T, Tanir G, Ozkan M, Bayhan GI. Transient acute flaccid paralysis and seizures associated with rotavirus gastroenteritis in a child. Turk J Pediatr. 2012;54:661–3.
Paul SP, Candy DCA. Extra-intestinal manifestation of rotavirus infection…beyond the gut. Indian J Pediatr. 2013. doi:10.1007/s12098-013-1189-2.
Perez JF, Chemello ME, Liprandi F, Ruiz MC, Michelangeli F. Oncosis in MA104 is induced by rotavirus infection through an increase in intracellular Ca2+ concentration. Virology. 1998;252:17–27.
Ramani S, Paul A, Saravanabavan A, Menon VK, Arumugam R, Sowmyanarayanan TV, Samuel P, Kang G. Rotavirus antigenemia in Indian children with rotavirus gastroenteritis and asymptomatic infection. CID. 2010;51:1284–9.
Ramig RF. Systemic rotavirus infection. Expert Rev Anti Infect Ther. 2007;5:591–612.
Ray P, Fenaux M, Sharma S, Malik J, Subodh S, Bhatnagar S, Greenberg H, Glass RI, Gentsch J, Bhan MK. Quantitative evaluation of rotavirus antigenemia in children with acute rotaviral diarrhea. J Infect Dis. 2006;194:588–93.
Rotavirus vaccines. WHO position paper. Wkly Epidemil Rec. 2013;88:49–64.
Riepenhoff-Talty M, Schaekel K, Clark HF, Mueller W, Uhnoo I, Rossi T, Fisher J, Ogra J. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pedriatr Res. 1993;33:394–9.
Sugata K, Taniguchi K, Yui A, Miyake F, Suga S, Asano Y, Ohashi M, Suzuki K, Nishimura N, Ozaki T, Yoshikawa T. Analysis of rotavirus antigenemia and extraintestinal manifestation in children with rotavirus gastroenteritis. Pediatrics. 2008;122:392–7.
Thompson MJ, Gowdie PJ, Kirkwood CD, Doherty RR, Fahey M. Rotavirus cerebellitis: new aspects to an old foe? Pediatr Nuerol. 2012;46:48–50.
Uhnoo I, Riepenhoff-Talty M, Dharakul T, Chegas P, Fisher JE, Greenberg HB, Ogra PL. Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus. J Virol. 1990;64:361–8.
Yu TH, Tsai CN, Lai MW, Chen CC, Chao HC, Lin CW, Chui CH, Chen SY. Antigenemia and cytokine expression in rotavirus gastroenteritis in children. J Microbiol Immunol Infect. 2012;45:265–70.
Zhao W, Xia M, Bridges-Malveo T, Cantu M, Mc Neal MM, Choi AH, Ward RL, Sestak K. Evaluation of rotavirus dsRNA load in specimen and body fluids from experimentally infected juvenile macaques by real-time PCR. Virology. 2005;341:248–56.
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This study was supported by the National Research Foundation grant funded by the Korean government (MSIP) (No. 2013M3A9AA6003126).
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Alfajaro, M.M., Cho, KO. Evidences and consequences of extra-intestinal spread of rotaviruses in humans and animals. VirusDis. 25, 186–194 (2014). https://doi.org/10.1007/s13337-014-0197-9
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DOI: https://doi.org/10.1007/s13337-014-0197-9