Sex-Dependent Intestinal Replication of an Enteric Virus

Robinson, C. M.; Wang, Yao; Pfeiffer, Julie K.

doi:10.1128/jvi.02101-16

Cited by 32 publications

(77 citation statements)

References 44 publications

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“…These data suggest that treatment with ampicillin and vancomycin does not alter poliovirus replication in the intestine. However, high fecal titers are not always indicative of poliovirus replication in the intestine (9, 20). Input inoculum virus can be shed for a few days following infection and confound interpretation of viral titer data, particularly during antibiotic treatment due to reduced peristalsis (9, 20).…”

Section: Resultsmentioning

confidence: 99%

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Related enteric viruses have different requirements for host microbiota in mice

Robinson

Acevedo

McCune

et al. 2019

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24Accumulating evidence suggests that intestinal bacteria promote enteric virus infection 25 in mice. For example, previous work demonstrated that antibiotic treatment of mice prior 26 to oral infection with poliovirus reduced viral replication and pathogenesis. Here we 27 examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a 28 picornavirus closely related to poliovirus. We treated mice with a mixture of five 29 antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis 30 following oral inoculation. We found that, like poliovirus, CVB3 shedding and 31 pathogenesis were reduced in antibiotic-treated mice. While treatment with just two 32 antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and 33 pathogenesis, this treatment had no effect on poliovirus. Quantity and composition of 34 bacterial communities were altered by treatment with the five antibiotic cocktail and by 35 treatment with vancomycin and ampicillin. To determine whether more subtle changes 36 in bacterial populations impact viral replication, we examined viral infection in mice 37 treated with milder antibiotic regimens. Mice treated with one-tenth the concentration of 38 the normal antibiotic cocktail supported replication of poliovirus but not CVB3. 39Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 40 shedding and pathogenesis, while having no effect on poliovirus shedding and 41 pathogenesis. Overall, replication and pathogenesis of CVB3 is more sensitive to 42 antibiotic treatment than poliovirus, indicating that closely related viruses may differ in 43 their reliance on microbiota. 44 45 46 3 Importance 47 Recent data indicate that intestinal bacteria promote intestinal infection of several 48 enteric viruses. Here we show that coxsackievirus, an enteric virus in the picornavirus 49 family, also relies on microbiota for intestinal replication and pathogenesis. Relatively 50 minor depletion of the microbiota was sufficient to decrease coxsackievirus infection, 51 while poliovirus infection was unaffected. Surprisingly, a single dose of one antibiotic 52 was sufficient to reduce coxsackievirus infection. Therefore, these data indicate that 53 microbiota can influence enteric virus infection through distinct mechanisms, even for 54 closely related viruses.55 56 57 Enteric viruses are spread through the fecal-oral route and cause morbidity and 58 mortality in humans worldwide (1-4). These viruses initiate infection in the 59 gastrointestinal tract, which is home to a community of bacteria, fungi, and viruses, 60 termed the microbiota. Microbiota play important roles in human development, 61 metabolism, and immunity (5). We and others have shown that intestinal bacteria can 62 enhance viral replication and pathogenesis of enteric viruses, including poliovirus, 63 reovirus, rotavirus, mouse mammary tumor virus, and noroviruses (6-11). While the 64 mechanisms underlying bacterial promotion of enteric virus repl...

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Section: Resultsmentioning

confidence: 99%

“…Previously, we established an oral inoculation model for CVB3 to study viral replication within the gastrointestinal tract (20, 21), and here we examined whether bacteria influence coxsackievirus infection. Similar to our observations with poliovirus (9), we found that intestinal bacteria enhance CVB3 fecal shedding and pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Related enteric viruses have different requirements for host microbiota in mice

Robinson

Acevedo

McCune

et al. 2019

Preprint

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“…Upon disease onset mice were euthanized by isoflurane followed by cervical dislocation. Male mice were used throughout, since CVB3 has a sex-dependent enhancement of replication and lethality (7).…”

Section: Methodsmentioning

confidence: 99%

“…CVB3 is spread through the fecal-oral route and has been associated with a wide range of diseases due to systemic viral dissemination, including gastrointestinal distress, type 1 diabetes, myocarditis, aseptic meningitis, cardiac arrhythmias, and death (1)(2)(3)(4)(5). Mouse models of CVB3 infection and pathogenesis have used a variety of inoculation routes, including the natural oral route of infection (6,7), or intraperitoneal (IP) injection, which bypasses the intestinal tract and induces systemic infection of a variety of tissues (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Acevedo

Pfeiffer²

2020

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Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown that bacteria promote oral infection with a variety of enteric viruses. However, it is unknown whether antibiotics have microbiota-independent antiviral effects for enteric viruses or whether antibiotics influence extra-intestinal, systemic infection. Here, we examined the effects of antibiotics on systemic enteric virus infection by performing intraperitoneal injections of either coxsackievirus B3 (CVB3) or poliovirus followed by quantification of viral titers. We found that antibiotic treatment reduced systemic infection for both viruses. Interestingly, antibiotics reduced CVB3 titers in germ-free mice, suggesting that antibiotic treatment alters CVB3 infection through a microbiota-independent mechanism. Overall, these data provide further evidence that antibiotics can have noncanonical effects on viral infection.

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“…Immune competent mice are orally susceptible to CVB3 infection, but do not succumb to disease. Immune deficient mice lacking the interferon alpha/beta receptor ( Ifnar-/- ) support high levels of viral replication and succumb to disease, providing a more tractable model to study infection with enteroviruses by the natural oral route (14–17).…”

Section: Introductionmentioning

confidence: 99%

Rapid dissemination and monopolization of viral populations in mice revealed using a panel of barcoded viruses

McCune

Lanahan

tenOever

et al. 2019

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17The gastrointestinal tract presents a formidable barrier for pathogens to initiate infection. 18Despite this barrier, enteroviruses, including coxsackievirus B3 (CVB3), successfully penetrate 19 the intestine to initiate infection and spread systemically prior to shedding in stool. However, the 20 effect of the gastrointestinal barrier on CVB3 population dynamics is relatively unexplored, nor 21 are the selective pressures acting on CVB3 in the intestine well-characterized. To examine viral 22 population dynamics in orally infected mice, we produced over one hundred CVB3 viruses 23 harboring unique nine nucleotide "barcodes." Using this collection of barcoded viruses, we 24 found diverse viral populations throughout each mouse within the first day post-infection, but by 25 48 hours the viral populations were dominated by less than three barcoded viruses in intestinal 26 and extra-intestinal tissues. Using light-sensitive viruses to track replication status, we found 27 diverse viruses had replicated prior to loss of diversity. Sequencing whole viral genomes from 28 samples later in infection did not reveal detectable viral adaptations. Surprisingly, orally 29 inoculated CVB3 was detectable in pancreas and liver as soon as 20 minutes post inoculation, 30indicating rapid systemic dissemination. These results suggest rapid dissemination of diverse 31 viral populations, followed by a major restriction in population diversity and monopolization in all 32 examined tissues. These results underscore a complex dynamic between dissemination and 33 clearance for an enteric virus. 35 Importance 36Enteric viruses initiate infection in the gastrointestinal tract but can disseminate to systemic 37 sites. However, the dynamics of viral dissemination are unclear. In this study, we created a 38 library of 135 barcoded coxsackieviruses to examine viral population diversity across time and 39 space following oral inoculation of mice. Overall, we found that the broad population of viruses 40 disseminates early, followed by monopolization of mouse tissues with three or fewer pool 41 members at later time points. Interestingly, we detected virus in systemic tissues such as 42 pancreas and liver just 20 minutes post-oral inoculation. These results suggest rapid 43 dissemination of diverse viral populations, followed by a major restriction in population diversity 44 and monopolization in all examined tissues. 45 46 Introduction 47 RNA virus populations are dynamic. Population diversity arises through mutations introduced by 48 the viral RNA-dependent RNA polymerases, which lack proofreading. Although many mutations 49 are detrimental, viruses can benefit from diversity within viral populations since diversity may 50 facilitate replication and dissemination within hosts (1,2). Viral diversity can be reduced through 51 selective pressures or stochastic events. Because viral diversity is a fundamental parameter in 52 viral evolution and virulence, understanding population dynamics and the factors that influence 53 viral populations is a c...

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Sex-Dependent Intestinal Replication of an Enteric Virus

Cited by 32 publications

References 44 publications

Related enteric viruses have different requirements for host microbiota in mice

Related enteric viruses have different requirements for host microbiota in mice

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

Rapid dissemination and monopolization of viral populations in mice revealed using a panel of barcoded viruses

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