Rotavirus-related systemic diseases: clinical manifestation, evidence and pathogenesis

Figures & data

Figure 1. Rotavirus infection-induced acute gastroenteritis. The rotavirus particle contains 11 segments of dsRNA as its genome, and the capsid consists of three layers. The intestinal epithelium is characterized by the villi and crypt. Mature enterocytes locate at the top and middle of villi allow SGLT-1-mediated absorption of water and salt. The ECs locate at the middle of villi are highly specialized cells with endocrine function. Stem cells and Paneth cells locate in the crypt are functionally responsible for differentiation and secretion, respectively. Thus, under normal conditions, the intact intestinal membrane barrier can keep homeostasis (absorption and secretion). While rotavirus infection in mature enterocytes causes absorptive enterocyte death and secretory Paneth cell replacement, leading to shortening and blunting of villi, and increasing infiltration of inflammatory cells in the lamina propria. The NSP4 stimulates the epithelium and ECs to increase intracellular calcium, which further induces the secretion of 5-HT from ECs through a calcium-dependent manner. The secreted 5-HT activates EGCs to increase release of GDNF which induces the expression of tight junction-associated protein ZO-1 in infected and bystander cells. Thus neurotrophic factors and 5-HT can protect the intestinal barrier function during rotavirus insult. Moreover, the number of enterocytes remaining following infection is functionally sufficient to allow SGLT-1-mediated absorption of water and salt. However, 5-HT can also activate the intrinsic primary afferent nerves of the myenteric plexus. Such activation activates the nerves of the submucosal plexus and leads to increase of intestinal motility which can be attenuated by an opioid-receptor-antagonist (Loperamide). The activation of submucosal nerves further induce VIP release from nerve endings adjacent to crypt cells. Then, VIP induces crypt cells to secret NaCl and water into the intestinal lumen by increasing cellular cAMP levels, which ultimately leading to secretory diarrhoea. During these processes, the stimulated afferent vagal signalling activates the nausea and vomiting centre of the brain to generate efferent vagal signalling which then results in vomiting by stimulating a nerve-muscle vomiting reflex in the stomach. This event can be attenuated by 5-HT receptor antagonists (Ondansetron). Finally, intestinal rotavirus infection results in secretory-driven watery diarrhoea accompanying by vomiting. dsRNA: double-stranded RNA; VPs: rotavirus structural proteins (VP4 is cleaved into VP5* and VP8*); NSP4: rotavirus non-structural protein; ENS: enteric nervous system; NaCl: sodium chloride; Ca²⁺: calcium ions; SGLT-1: sodium/glucose cotransporter 1; 5-HT: 5-hydroxytryptamine (serotonin); VIP: vasoactive intestinal peptide; ECs: enterochromaffin cells; EGCs: enteric glial cells; GDNF: glial cell-derived neurotrophic factor; ZO-1: zona occludens 1; cAMP: cyclic adenosine monophosphate.

Figure 2. Rotavirus-related systemic diseases and proposed mechanisms. The primary infection of rotavirus in the intestine leads to acute gastroenteritis. However, the tropism and pathogenetic role of rotavirus infection is not only limited to the gastrointestinal tract. The extra-intestinal dissemination and infection of rotavirus in non-intestinal tissues such as the spleen, liver, heart, lung, kidney, testis, bladder, adrenal gland, pancreas and brain have been confirmed, which may sometimes lead to additional extra-intestinal complications. Here we present rotavirus-induced acute gastroenteritis and the frequently reported complications related to rotavirus extra-intestinal spread and propose the potential mechanisms. RV: rotavirus; VP7: viral structural protein; NSP4: non-structural protein; ENS: enteric nervous system; NO: nitric oxide; IFN-γ: interferon gamma.

Table 1. Clinical manifestation and evidence summary of rotavirus-related systemic diseases.

Systemic disease	Clinical manifestation	Evidence
		Human	Animal model
Acute gastroenteritis	major AG symptoms including watery diarrhoea, vomiting, low-grade fever, dehydration and electrolyte imbalance (Hjelt et al. 1985; Haffejee and Moosa 1990; Leung et al. 2005; Parashar et al. 2013; Esona and Gautam 2015); other associated symptoms including: low inflammation, shock, coma, abdominal cramps, nausea, malaise, lethargy, pharyngeal erythema, rhinitis and palpable cervical lymph nodes (Hjelt et al. 1985; Haffejee and Moosa 1990; Leung et al. 2005; Parashar et al. 2013; Esona and Gautam 2015)	RV infection is the leading cause of active gastroenteritis among young children (Tate et al. 2016; Crawford et al. 2017; Bányai et al. 2018; Troeger et al. 2018); RV induces more severe symptoms in the youngest children (Leung et al. 2005; Parashar et al. 2013; Hartman et al. 2019); RV hospitalizations and deaths decreased by 25–55% following vaccination (Crawford et al. 2017; Troeger et al. 2018; Aliabadi et al. 2019; Burke et al. 2019; Burnett et al., 2020); histological and pathological examinations indicate that RV infection and replication in the intestinal epithelium (mature enterocytes and ECs) leading to significant structural and functional alterations (severe mucosal damage including shortening and blunting of villi and increased immune infiltration in the lamina propria) (Hagbom et al. 2012; 2016; Crawford et al. 2017)	RV infection in animal models induces morphological, anatomical and functional changes in the small intestine (Hagbom et al. 2012; 2016; 2016; Crawford et al. 2017): piglets (thinning of the intestinal wall, completely eroded intestinal villi, conversion of columnar villus epithelium to cuboidal) (Shepherd et al. 1979); calves (blunting of villus, conversion of columnar villus epithelium to cuboidal) (Reynolds et al. 1985); lambs (less severe histopathological changes and mild clinical disease) (Greenberg et al. 1994); mice (remarkable swollen and vacuolated enterocytes but limited villus blunting) (Dharakul et al. 1988; Osborne et al. 1988; Ward et al. 1990; Lundgren and Svensson 2001; Hagbom et al. 2016)
Neurological diseases	seizures (diarrhoea, vomiting, fever, febrile, convulsions, generalized bleeding) (Lloyd et al. 2010; Yeom et al. 2019); meningitis (diarrhoea, vomiting, irritable, afebrile, convulsions) (Wong et al. 1984); encephalopathy (diarrhoea, fever, dehydration, lethargy, convulsions, coma) (Lynch et al. 2001; Wong 2001; Karampatsas et al. 2015); encephalitis (diarrhoea, vomiting, fever, dehydration, convulsions, afebrile) (Ushijima et al. 1986)	more CNS diseases (2–8% incidence of seizures (Iturriza-Gómara et al. 2002; Lloyd et al. 2010; Pardo-Seco et al. 2015 )) are reported in RV-gastroenteritis children (Wong et al. 1984; Ushijima et al. 1986; Nishimura et al. 1993; Lynch et al. 2001; Fukuda et al. 2009; Takanashi et al. 2010; Karampatsas et al. 2015; Laizane et al. 2019); higher positivity of RV in children with seizures or convulsions (Herrmann et al. 1993; Wong 2001; Yeom et al. 2019); rotavirus vaccination has resulted in reduced incidence of paediatric seizures in the USA and Spain (Payne et al. 2014; Pardo-Seco et al. 2015; Burke et al. 2018); RV particles, antigens, antibodies and RNA are found in CSF (Wong et al. 1984; Keidan et al. 1992; Pager et al. 2000; Lynch et al. 2001; Iturriza-Gómara et al. 2002); RV infection and replication (viral VP6, NSP1, NSP3, NSP4, and RNA) in brain tissue (Nakano et al. 2011); infection and replication (structural protein VP7 and non-structural protein NSP4) of RRV in neurons in vitro (Weclewicz et al. 1998)	isolation of virus particles by cell culture from the brain of porcine RV-inoculated neonatal pigs (Janke et al. 1988; Shaw et al. 1989); infectious virus is detected in the brain of heterologous RRV (MMU-18006) or homologous murine strain (EDIM-5099) inoculated mice (Kraft 1958; Shaw et al. 1989; Czech-Schmidt et al. 2001)
Hepatobiliary diseases	AG symptoms (diarrhoea, vomiting, fever, dehydration) (Gilger et al. 1992); liver dysfunction (elevated serum sodium and liver transaminases such as AST, ALT and GGT, hepatitis, liver steatosis, cirrhosis) (Gilger et al. 1992; Teitelbaum and Daghistani 2007); biliary symptoms (extrahepatic biliary atresia, choledochal cyst, cholestasis, fibrosis) (Gilger et al. 1992; Riepenhoff-Talty et al. 1996; Bezerra et al. 2002)	abnormal liver function results from RV infection (Kovacs et al. 1986; Teitelbaum and Daghistani 2007); RV infection (viral antigen) and replication (viral VP6, NSP1, NSP3, NSP4, and RNA) in liver tissue (Gilger et al. 1992; Riepenhoff-Talty et al. 1996; Nakano et al. 2011); continuous RV infection (viral RNA, VP4, VP6, and infectious virus) in human liver organoids results in direct cytopathogenesis (Chen et al. 2020)	RV infection (viral structural protein VP7) and active replication (viral RNA, NSP4 and virus particles) in murine biliary tracts and livers (Uhnoo et al. 1990; Riepenhoff-Talty et al. 1993; Shivakumar et al. 2004); hepatobiliary-tropic RVs strain-specifically induce high incidence of hepatitis, bile duct obstruction and mortality, as well as human BA-like symptoms and hispathological changes in murine models (Uhnoo et al. 1990; Riepenhoff-Talty et al. 1993; Shivakumar et al. 2004)
Type 1 diabetes	AG symptoms (diarrhoea, vomiting, fever, dehydration) (Parri et al. 2010; Basturk et al. 2017); acute pancreatitis (abdominal pain, elevated serum transaminases such as pancreatic amylase and lipase, transient moderately enlarged oedematous pancreas) (Parri et al. 2010; Basturk et al. 2017)	more acute pancreatitis cases with transient abnormal size and function of pancreas are reported in RV-gastroenteritis children (Nigro 1991; Parri et al. 2010; Basturk et al. 2017); the incidence of T1D decreased in RV-vaccinated children younger 4 years in the USA and Australia (Perrett et al. 2019; Rogers et al. 2019); RV infection (viral antigen and RNA) in the pancreas (Lynch et al. 2003; Ramig 2007)	replication of human and monkey RV (infectious virus) in monkey islet cells (Coulson et al. 2002); monkey RRV infection increases insulitis development and accelerates diabetes in NOD mouse (Graham et al. 2008); RRV antigen and infectious virus are found in the pancreas of NOD mice and rats (Crawford et al. 2006; Graham et al. 2007); RRV infection induces transient pancreatic involution and hyperglycaemia in weanling mice (Honeyman et al. 2014)
Respiratory illness	AG symptoms (diarrhoea, vomiting, fever, dehydration) (Santosham et al. 1983; Fragoso et al. 1986; Zheng et al. 1991; Grech et al. 2001); respiratory symptoms (cough, mild respiratory distress, rhinitis, rhinorrhea, nasal discharge, congestion, pneumonia, otitis media (Goldwater et al. 1979; Zhaori et al. 1991; Santosham et al. 1983; Gurwith et al. 1981)	respiratory illness is the major extra-intestinal symptom that preceded or concurrently occurred with rotavirus-induced gastroenteritis in children (Fragoso et al. 1986; Sharma et al. 2002; Grimprel et al. 2008); RV infection (viral antigen) in upper respiratory tract (oropharyngeal aspirates (Zheng et al. 1991) and nasopharyngeal secretions (Fragoso et al. 1986)) and lower respiratory tract (tracheal aspirate (Zhaori et al. 1991)); RV infection (viral RNA) in lung tissue (Lynch et al. 2003); RV as a part of virome frequently identified in respiratory tract samples (Taboada et al. 2014; Madi et al. 2018; Thi Kha Tu et al. 2020)	HRV (Wa) induces viremia, antigenemia and nasal virus shedding in piglets (Azevedo et al. 2005); respiratory infection (viral antigen in pnueumocytes and lymphoid cells of lungs, viral RNA in nasal fluid secretions and lungs) of GARV (KJ9-1) induces pneumonia and increases infiltration-mediated cellularity in calves (Kim et al. 2011); RRV infection and replication (viral antigen, structural and non-structural protein and infectious virus) in the lower respiratory tract (macrophages and pneumocytes) induce parenchymas inflammation and respiratory secretion of virus in rats (Crawford et al. 2006); homologous (murine rotavirus) and heterologous RRV infection and replication (viral RNA, NSP4 and virus particles) in the lung tissue of newborn mice (Fenaux et al. 2006); intranasal but not oral inoculation of RRV induces immune protection against challenge in mice (Coffin and Clark 2001)
Heart diseases	elevated level of CK-MB (Zheng et al. 2017); myocyte necrosis (Cioc and Nuovo 2002); myocarditis (Grech et al. 2001; Cioc and Nuovo 2002); hypertrophic cardiomyopathy with focal disorganized myocardial architecture (Nakano et al. 2011);	infection and replication (viral VP6, NSP1, NSP3, NSP4, and RNA) in heart tissue possibly induce hypertrophic cardiomyopathy and myocardial damage (Cioc and Nuovo 2002; Lynch et al. 2003; Nakano et al. 2011; Zheng et al. 2017)	viral antigen is detected in the heart of RRV-infected rats (Crawford et al. 2006)
Renal failure	AG symptoms (diarrhoea, vomiting, fever, dehydration) (Fujinaga et al. 2005; Ashida et al. 2012; Kira et al. 2016); renal and urogenital symptoms (acute obstructive uropathy-ureteral stones (Kira et al. 2016; Ashida et al. 2012; Fujinaga et al. 2005), oliguria (Fujinaga et al. 2005), hypovolemia (Fujinaga et al. 2005; Shirasu et al. 2015), aciduria (Tsukida et al. 2018), azotaemia (Fujinaga et al. 2005), hyperuricaemia and hyponatremia (Ashida et al. 2012; Tsukida et al. 2018))	diarrhoea-induced dehydration is associated with pre- and post-renal failure (Ashida et al. 2012; Kira et al. 2016; Tsukida et al. 2018); RV infection (viral antigen and RNA) and replication (viral non-structural protein) in kidney tissue (Gilger et al. 1992; Lynch et al. 2003)	infectious RV (EDIM) is found in the kidney of normal mice (Kraft 1958); RV-A induces cellular degeneration and immune infiltration in the kidney of suckling mice (Kashyap et al. 2018); homologous (murine rotavirus) and/or heterologous RRV infection and replication (viral antigen, NSP4, RNA and virus particles) in the kidney of newborn mice and rats (Crawford et al. 2006; Fenaux et al. 2006); monkey kidney cells are highly susceptible for RV infection in vitro (Ward et al. 1984)

AG: acute gastroenteritis; RV-A: species A rotavirus; RRV: rhesus rotavirus; HRV: human rotavirus; GARV: bovine rotavirus; ECs: enterochromaffin cells; NSP1/3/4: rotavirus non-structural proteins; VP6/7: rotavirus structural viral proteins; ENS: enteric nervous system; CSF: cerebrospinal fluid; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gammaglutamyl transferase; BA: biliary atresia; T1D: type 1 diabetes; NOD: Non-Obese Diabetic; CK-MB: Creatine Kinase-MB, an indication for myocardial damage.

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