# cGAS-STING dependent type I IFN reduces Leptospira interrogans renal colonization in mice

## TL;DR

This study shows that the cGAS-STING pathway and type I interferon help mice fight Leptospira bacteria in the kidneys.

## Contribution

First demonstration of cytosolic DNA sensing and type I IFN's role in controlling Leptospira interrogans infection.

## Key findings

- L. interrogans triggers a strong type I IFN response in macrophages via cGAS-STING.
- Mice lacking IFNAR1 or STING had higher bacterial kidney colonization.
- cGAS-STING-dependent type I IFN is essential for host defense against L. interrogans.

## Abstract

Leptospira interrogans is the major causative agent of leptospirosis. Humans, canines and agricultural animals are susceptible to Leptospira species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to Leptospira spp. remains poorly defined. We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection in vivo suggesting that cGAS-STING-driven type I IFN is required for the host defense against L. interrogans. These findings demonstrate the significance of cGAS-STING- dependent type I IFN signaling in mammalian innate immune responses to L. interrogans.

Leptospirosis is a zoonotic disease primarily caused by infection with the Leptospira interrogans bacteria. The manifestation of this infection is variable depending on the type of animal infected. For example, while the disease can be very severe and even fatal in people, livestock, and dogs, rodents do not die or become significantly ill after infection. Instead, mice and rats develop persistent but asymptomatic colonization by the bacteria within their kidneys. They then shed the bacteria in their urine, allowing the infection to spread through the environment to other animals. Despite the significant global burden of leptospirosis, the innate immune pathways that detect this pathogen and regulate renal colonization remain poorly understood. In this study we demonstrate that L. interrogans induces a robust innate immune response from macrophages with release of pro-inflammatory type I IFNs after the sensing of cytosolic DNA. Using in vivo mouse models of L. interrogans infection we further show that activation of this pathway is required to control bacterial burdens and reduce long-term kidney colonization. This study is the first to demonstrate a critical role for cytosolic DNA sensing and type I IFN in controlling L. interrogans infection.