Jang Hyun Park

Conference 2022 Live Talk

 

Talk title

Gut-derived vaginal microbiota regulates antiviral immunity through pseudonormoxia

 

Authors and Affiliations

Jang Hyun Park1, Heung Kyu Lee1

1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

 

Abstract

Background

The critical role of microbiota for regulating homeostasis and defense from exogenous pathogens. While gut microbiota are thought to be the most important due to large number, tissue microbiota also have critical role for local tissues. For example, vagina contains 10% of bacteria from whole microbiota. The relationship between sexually transmitted infections (STIs) and vaginal microbiota has been emphasized. However, clear evidences showing whether and how vaginal microbiota, but not gut microbiota, regulates antiviral responses remained unclear. Furthermore, model system studying microbiota such as germ free (GF) or antibiotics cocktail (ABX) treatment are artificial. Thus, we wanted to see more natural model inducing dysbiosis such as obesity.

Methods

Female mice were fed with standard chow diet (SCD) or 60%Kcal high fat diet (HFD). We analyzed gut and vaginal microbiota of SCD-fed lean mice and HFD-fed obese mice using 16S rRNA sequencing. To deplete microbiota, we used ABX via drinking water. We also used GF mice. We used herpes simplex virus 2 (HSV-2) for murine STI model. HSV-2 was intravaginally infected into the vaginal cavity. Though fecal microbiota or vaginal microbiota transplantation, we determined critical importance of vaginal microbiota against HSV-2 infection. By single cell RNA sequencing, confocal microscopy, and flow cytometry, we analyzed antiviral immune responses regulated by obesity and obesity-associated vaginal microbiota under HSV-2 infection.

Results

Obesity induced gut and vaginal dysbiosis. Although obesity is commonly related to increased risk for general diseases, obese mice were more resistant against vaginal HSV-2 infection. It was dependent on vaginal microbiota, but not gut microbiota. Interestingly, we found that vaginal microbiota contains gut-derived bacteria such as Escherichia coli. Due to increased gut permeability of obese mice, gut-derived E. coli was able to translocate into the vagina. Gut-derived vaginal E. coli produced L-Arg which activates γδ T cells. Because vagina is physiologically hypoxic organ, vaginal γδ T cells are under hypoxia-mediated suppression. However, L-Arg reduced HIF1A level of γδ T cells without changes of actual hypoxia. It was pseudonormoxia.

Conclusions

These findings demonstrate that obesity promotes translocation of microbiota to the distant organ and gut-derived vaginal bacteria is critical for defense against HSV-2 infection. It was mediated by L-Arg-HIF1A axis which is called pseudonormoxia. It may provide important information that obesity could be beneficial for genital herpes. In addition, this study implies that we have to consider crosstalk among bacteria from multiple sites when we studying the role of microbiota.