Related Enteric Viruses Have Different Requirements for Host Microbiota in Mice

Abstract

Accumulating evidence suggests that intestinal bacteria promote enteric virus infection in mice. For example, previous work demonstrated that antibiotic treatment of mice prior to oral infection with poliovirus reduced viral replication and pathogenesis. Here, we examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a picornavirus closely related to poliovirus. We treated mice with a mixture of five antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis following oral inoculation. We found that, as seen with poliovirus, CVB3 shedding and pathogenesis were reduced in antibiotic-treated mice. While treatment with just two antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and pathogenesis, this treatment had no effect on poliovirus. The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin. To determine whether more-subtle changes in bacterial populations impact viral replication, we examined viral infection in mice treated with milder antibiotic regimens. Mice treated with one-tenth the standard concentration of the normal antibiotic cocktail supported replication of poliovirus but not CVB3. Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 shedding and pathogenesis while having no effect on poliovirus shedding and pathogenesis. Overall, replication and pathogenesis of CVB3 are more sensitive to antibiotic treatment than poliovirus, indicating that closely related viruses may differ with respect to their reliance on microbiota. IMPORTANCE Recent data indicate that intestinal bacteria promote intestinal infection of several enteric viruses. Here, we show that coxsackievirus, an enteric virus in the picornavirus family, also relies on microbiota for intestinal replication and pathogenesis. Relatively minor depletion of the microbiota was sufficient to decrease coxsackievirus infection, while poliovirus infection was unaffected. Surprisingly, a single dose of one antibiotic was sufficient to reduce coxsackievirus infection. Therefore, these data indicate that closely related viruses may differ with respect to their reliance on microbiota.

Microbiota-Independent Antiviral Effects of Antibiotics on Enteric Viruses

“…Work performed in several labs has shown that antibiotic treatment reduces replication and pathogenesis of orally inoculated enteric viruses (6,(11)(12)(13)(14). However, the influence of antibiotics on systemic enteric virus infection is unclear.…”

“…Of note, a single dose of the aminoglycoside antibiotic streptomycin promoted the infiltration of neutrophils and inflammatory monocytes to the cecum (20). Interestingly, oral CVB3 infection is highly sensitive to antibiotics, where a single dose of streptomycin can significantly decrease viral replication and pathogenesis (6). Given that we and others have shown noncanonical effects of antibiotics, it is possible that systemic enteric virus infection could be influenced by antibiotic-induced innate immune response and/or immune cell infiltrates, although future experiments will be needed to test this hypothesis.…”

“…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).…”

“…Recently, we have shown that CVB3 is dependent on a vast intestinal microbial ecosystem of approximately 10 14 organisms, termed the microbiota, to establish infection in both intestinal and extra-intestinal tissues following oral inoculation (6). Furthermore, we showed that orally delivered CVB3 is relatively sensitive to antibiotic treatment, as a single dose of one antibiotic was sufficient to reduce CVB3 replication and pathogenesis (6). However, it remains unknown if antibiotics reduce systemic CVB3 infection through a microbiota-dependent or independent mechanism.…”

“…Our group and others have used antibiotics to deplete the host microbiota to study virus-host-microbiota interactions (6,(11)(12)(13)(14). However, antibiotics can have microbiota-independent effects, and alter host metabolic pathways, gene expression profiles, and immune cell function (15)(16)(17)(18)(19).…”