The essential role of intestinal microbiota in cytomegalovirus reactivation

Abstract

ABSTRACT Human cytomegalovirus (HCMV) is a member of Herpesviridae. It has been reported that HCMV is reactivated in the breast milk of HCMV-seropositive lactating women. As we have reported various aspects of the roles of indigenous microbiota, its role in the murine CMV (MCMV) reactivation was examined in this study. MCMV was latently infected in the salivary gland, mammary tissues, and colon in the pregnant mice. When the salivary gland, mammary tissues, and colon were removed 5 days after delivery, MCMV reactivation of latent infection in each organ was confirmed by the detection of MCMV IE1 mRNA using reverse transcription-quantitative PCR. MCMV reactivation was observed in 100% of the mice during pregnancy. Next, for the elimination of intestinal microbiota, the pregnant mice were treated with low-dose or high-dose non-absorbable antibiotics. Although the numbers of aerobe/anaerobe in cecal content in low-dose antibiotic-treated mice were comparable to those in untreated controls, high-dose antibiotic treatment decreased the number of aerobe/anaerobe microbes from ca.9.0 Log10 to ca.3.0 Log10 (cfu/g). However, it could not be confirmed in 16S rRNA analysis that specific bacterial phylum or genus was eliminated by this high-dose treatment. Interestingly, MCMV reactivation was also observed in 100% of low-dose antibiotic-treated mice, whereas, in high-dose antibiotic-treated mice, MCMV reactivation was not observed in the salivary gland or colon. MCMV IE1 mRNA was detected only in 33% of the mammary tissues of those high-dose-treated mice. These results suggest that the indigenous microbiota played a crucial role in the reactivation of latent infection. IMPORTANCE Human cytomegalovirus (HCMV) infection via breast milk is a serious problem for very preterm infants such as developing a sepsis-like syndrome, cholestasis, or bronchopulmonary dysplasia, among others. It has been reported that HCMV is reactivated in the breast milk of HCMV-seropositive lactating women. In this study, the roles of indigenous microbiota in the murine CMV (MCMV) reactivation were examined using a mouse model. In MCMV latently infected mice, MCMV reactivation was observed in 100% of the mice during pregnancy. For the elimination of intestinal microbiota, MCMV-latent mice were treated with non-absorbable antibiotics. After delivery, MCMV reactivation was not observed in antibiotic-treated mice. This result suggested that the indigenous microbiota played a crucial role in the reactivation of latent infection.