Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice

Berglind Bergmann,Abukar Ali,Guillaume Churlaud,Maria Bergquist,Zhicheng Hu,David Klatzmann,Catharina Lindholm,Inger Gjertsson,Ying Fei,Pernilla Jirholt,Tao Jin,Olov Ekwall

doi:10.1186/s12879-020-4880-8

Abstract

BackgroundStaphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.MethodsC57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.ResultsExpansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection.ConclusionsPre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

Highlights

Staphylococcus aureus (S. aureus) is one of the pathogens most commonly causing life-threatening conditions, especially in individuals with underlying health conditions; this is especially relevant to present-day society with its ageing population, its increased burden of chronic diseases such as cancers and autoimmune diseases, and the chemotherapeutic and immunosuppressive treatments that accompany them [1]
As these studies are very difficult to perform in humans, the aim of this study was to determine whether interleukin 2 (IL2) and its impact on T regulatory cells (Tregs) influence the course of S. aureus arthritis with respect to survival, bacterial clearance and joint damage in our well-established mouse model of hematogenously spread S. aureus septic arthritis [25]
The frequencies of CD4+CD25+Forkhead box protein 3 (FoxP3)+ Tregs in blood, spleen and lymph nodes increased during the natural course of S. aureus arthritis To study the physiological changes in Treg proportions during the natural course of S. aureus arthritis, mice were inoculated iv with S. aureus at day 0 and healthy uninfected mice were used as controls (Fig. 1a)

Summary

Introduction

Staphylococcus aureus (S. aureus) is one of the pathogens most commonly causing life-threatening conditions, especially in individuals with underlying health conditions; this is especially relevant to present-day society with its ageing population, its increased burden of chronic diseases such as cancers and autoimmune diseases, and the chemotherapeutic and immunosuppressive treatments that accompany them [1]. We hypothesize that the staphylococci themselves upregulate Tregs during the infection to evade the host immune response [8, 24], a further expansion of Tregs could ameliorate the excessive inflammatory response that is responsible for joint damage and the subsequent detrimental sequelae of this disease As these studies are very difficult to perform in humans, the aim of this study was to determine whether IL2 and its impact on Tregs influence the course of S. aureus arthritis with respect to survival, bacterial clearance and joint damage in our well-established mouse model of hematogenously spread S. aureus septic arthritis [25]. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis

Objectives

Methods

Results

Discussion

Conclusion