Coxsackie B virus infection of mice: inoculation by the oral route protects the pancreas from damage, but not from infection

Bopegamage, Shubhada; Kovacova, Jana; Vargova, Agnesa; Motusova, J.; Petrovicová, A; M, Benkovicová; Gomolcák, P; Bakkers, Judith M. J. E.; Kuppeveld, Frank J. M. van; Melchers, Willem J. G.; Galama, J.M.D.

doi:10.1099/vir.0.81249-0

Cited by 47 publications

(68 citation statements)

References 40 publications

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“…injection models bypass the first stage of infection in the gastrointestinal tract. Relatively few studies have used oral inoculation of mice with coxsackievirus (19)(20)(21)(22)(23). Therefore, CVB3 replication and factors that influence viral replication in the intestine remain poorly understood.…”

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confidence: 99%

Sex-Dependent Intestinal Replication of an Enteric Virus

Robinson

Wang

Pfeiffer

2017

J Virol

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Coxsackievirus is an enteric virus that initiates infection in the gastrointestinal tract before disseminating to peripheral tissues to cause disease, but intestinal factors that influence viral replication are understudied. Furthermore, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. While mouse models mimicking human pathogenesis have been well characterized, many of these experiments use intraperitoneal injection of coxsackievirus to infect mice, bypassing the intestine. In light of recent studies identifying intestinal factors, such as the microbiota, that alter enteric viral replication, we sought to investigate coxsackievirus replication within the intestine. Here, we orally infected mice with coxsackievirus B3 (CVB3) and found that CVB3 replication in the intestine is sex dependent. CVB3 replicated efficiently in the intestine of male mice but not female mice. Additionally, we found that the type I interferon response and sex hormones can alter both viral replication and lethality. Overall, these data suggest that sex and the immune response play a vital role in CVB3 replication in the intestine and should be considered in light of the sex bias observed in human disease.IMPORTANCE Sex bias in severe sequelae from enteric viral infections has been observed. Since viruses have evolved to achieve optimal levels of fitness in their environmental niches, it is imperative to study viruses at the site of initial replication. Here, we used an oral inoculation system for CVB3, which follows the natural route of infection in the gastrointestinal tract. We found that sex can influence the replication of CVB3 in the intestine. Additionally, the type I interferon response and sex hormones alter both CVB3 intestinal replication and lethality. Overall this work highlights the fact that sex should be considered in investigations of enteric viral replication and pathogenesis.KEYWORDS coxsackievirus B3, intestine, pathogenesis, sex hormones S ex contributes to the frequency and severity of many human diseases (1-3). Epidemiological studies show that men are more susceptible to bacterial, viral, and fungal infections (2). Women, while more resistant to pathogens, are at an increased risk for autoimmune disorders. Sexual dimorphism in disease has been attributed to differential gene expression, sex hormones, and variations in immune function (4). However, sex as a variable in disease models is understudied, limiting our understanding of the mechanism of sex bias in various diseases.Coxsackievirus is a nonenveloped RNA virus from the Picornaviridae family and is implicated in a range of diseases (5-8). In humans, males are twice as likely as females to develop sequelae from coxsackievirus infection (9). While most coxsackievirus infections are self-limiting, they can cause severe disease. In particular, coxsackievirus B3 (CVB3) is a leading cause of viral myocarditis, and extensive cardiac damage can lead to cardiac failure (10, 11). Because there are no current vaccines or ...

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confidence: 99%

Sex-Dependent Intestinal Replication of an Enteric Virus

Robinson

Wang

Pfeiffer

2017

J Virol

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“…Although infection can be established by the enteral (oral [p.o.]) route in some murine models (15,16), the gastrointestinal tract has been reported to act as a barrier to infection, particularly beyond the neonatal period (17). Consistent with the idea of an intestinal barrier, our own experience has been that infection by the enteral route requires virus doses much higher (10,000-fold or more) than those needed to infect mice by intraperitoneal injection (unpublished data; see Fig.…”

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Expression of Human Decay-Accelerating Factor on Intestinal Epithelium of Transgenic Mice Does Not Facilitate Infection by the Enteral Route

Pan

Zhang

Odenwald

et al. 2015

J Virol

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In vitro, infection of polarized human intestinal epithelial cells by coxsackievirus B3 (CVB3) depends on virus interaction with decay-accelerating factor (DAF), a receptor expressed on the apical cell surface. Although mice are highly susceptible to CVB3 infection when virus is delivered by intraperitoneal injection, infection by the enteral route is very inefficient. Murine DAF, unlike human DAF, does not bind virus, and we hypothesized that the absence of an accessible receptor on the intestinal surface is an important barrier to infection by the oral route. We generated transgenic mice that express human DAF specifically on intestinal epithelium and measured their susceptibility to infection by a DAF-binding CVB3 isolate. Human DAF permitted CVB3 to bind to the intestinal surface ex vivo and to infect polarized monolayers of small-intestinal epithelial cells derived from DAF transgenic mice. However, expression of human DAF did not facilitate infection by the enteral route either in immunocompetent animals or in animals deficient in the interferon alpha/beta receptor. These results indicate that the absence of an apical receptor on intestinal epithelium is not the major barrier to infection of mice by the oral route. IMPORTANCE CVB3 infection of human intestinal epithelial cells depends on DAF at the apical cell surface, and expression of human DAF on murine intestinal epithelial cells permits their infection in vitro. However, expression of human DAF on the intestinal surface of transgenic mice did not facilitate infection by the oral route. Although the role of intestinal DAF in human infection has not been directly examined, these results suggest that DAF is not the critical factor in mice.C oxsackieviruses belong to the genus Enterovirus of the family Picornaviridae, a group of small, nonenveloped viruses with a single-strand, positive-sense RNA genome (1). Group B coxsackieviruses (CVBs) are important causes of viral myocarditis and meningitis, and they have been proposed to be a possible triggering agent for juvenile diabetes (1).CVBs, like other enteroviruses, are transmitted by the fecaloral route and are believed to initiate infection by crossing the intestinal mucosa, which is lined by polarized epithelial cells with distinct apical and basolateral surfaces. In polarized epithelial cells, the primary CVB receptor, the coxsackievirus and adenovirus receptor (CAR) (2-4), is not expressed on the apical cell surface but is instead confined to the basolateral surface, where it functions as part of the intercellular tight junction (5); CAR is thus inaccessible to virus approaching the apical cell surface from the intestinal lumen. Some CVB isolates bind to a second receptor, decay-accelerating factor (DAF) (6-8). Unlike CAR, DAF is highly expressed on the apical surface of polarized epithelial cells, and infection of polarized cells depends on virus attachment to DAF (9). In addition to providing a docking site for virus, DAF mediates a series of intracellular signals that permit virus to move ac...

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“…In fact, a single inoculation of the mutant Sabin3-like by i.p route protected all mice challenged 16 days later with a virulent CVB3 and CVB4 E2 which induced, respectively, myocarditis and pancreatitis in the unprotected control mice. Heart and pancreatic damages due to viral CVB3 and CVB4 replication have been demonstrated to be clearly evident at 10 days post-infection (Tracy et al 1992;Tu et al 1995;Bopegamage et al 2003Bopegamage et al , 2005Jaidane et al 2006). However, one mouse immunized with the attenuated Sabin3-like strain, developed pancreatitis after challenge by i.p route with CVB4 E2.…”

Section: Discussionmentioning

confidence: 99%

Inoculation of the attenuated Coxsackievirus B3 Sabin3-like strain induces a protection against virulent CVB3 Nancy and CVB4 E2 strains in Swiss mice by both oral and intraperitoneal routes

et al. 2013

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Abstract:We have previously addressed the question of whether the attenuating mutations of domain V of the Poliovirus IRES were specific for a given genomic context or whether they could be extrapolated to a genomic related virus, the Coxsackievirus B3 (CVB3). Accordingly, we have described that Sabin3-like mutation (U 473 →C) introduced in the CVB3 genome led to a defective mutant with a serious reduction in translation efficiency. In this study, we assessed the protection provided by the Sabin3-like mutant against CVB3 infection. For this purpose, we analyzed, in vivo, the Sabin3-like phenotype in Swiss mice inoculated with CVB3 and CVB4 E2 prototype strains either by oral or intraperitoneal (i.p) routes and explored the capacity of this mutant to act as a vaccine vector after the challenge. The Sabin3-like RNA was detected by semi-nested PCR in different organs: heart, pancreas and intestine at 10 days post-inoculation with both oral and i.p routes. Additionally, we did not observe any histological alterations in heart and intestine tissues. RNA was detected in the different organs of all mice immunized with the Sabin3-like strain and challenged with either CVB3 or CVB4 E2 by oral route at 7 days post-challenge. In contrast, no histological alteration of heart or pancreas tissues was observed after challenge with both wild-strains. Interestingly, the detection of viral RNA in heart, pancreas and intestine of mice immunized by i.p route was negative at 7 days post-challenge with CVB3 and CVB4 E2, and mice were protected from myocarditis and pancreatitis.

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Coxsackie B virus infection of mice: inoculation by the oral route protects the pancreas from damage, but not from infection

Cited by 47 publications

References 40 publications

Sex-Dependent Intestinal Replication of an Enteric Virus

Sex-Dependent Intestinal Replication of an Enteric Virus

Expression of Human Decay-Accelerating Factor on Intestinal Epithelium of Transgenic Mice Does Not Facilitate Infection by the Enteral Route

Inoculation of the attenuated Coxsackievirus B3 Sabin3-like strain induces a protection against virulent CVB3 Nancy and CVB4 E2 strains in Swiss mice by both oral and intraperitoneal routes

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