Chronic Toxoplasma gondii Infection Exacerbates Secondary Polymicrobial Sepsis

Maria C Souza,Alexandre Kanashiro,Warrison A Andrade,João S Silva,Murilo S Dias,José C Alves-Filho,Marcondes A B Silva,Denise M Fonseca,Fernando Q Cunha,Ricardo T Gazzinelli,Aline Gozzi,Giuliano Bonfá,Tiago S Medina,Marcos C Borges,Luciana Benevides

doi:10.3389/fcimb.2017.00116

Abstract

Sepsis is a severe syndrome that arises when the host response to an insult is exacerbated, leading to organ failure and frequently to death. How a chronic infection that causes a prolonged Th1 expansion affects the course of sepsis is unknown. In this study, we showed that mice chronically infected with Toxoplasma gondii were more susceptible to sepsis induced by cecal ligation and puncture (CLP). Although T. gondii-infected mice exhibited efficient control of the bacterial burden, they showed increased mortality compared to the control groups. Mechanistically, chronic T. gondii infection induces the suppression of Th2 lymphocytes via Gata3-repressive methylation and simultaneously induces long-lived IFN-γ-producing CD4+ T lymphocytes, which promotes systemic inflammation that is harmful during CLP. Chronic T. gondii infection intensifies local and systemic Th1 cytokines as well as nitric oxide production, which reduces systolic and diastolic arterial blood pressures after sepsis induction, thus predisposing the host to septic shock. Blockade of IFN-γ prevented arterial hypotension and prolonged the host lifespan by reducing the cytokine storm. Interestingly, these data mirrored our observation in septic patients, in which sepsis severity was positively correlated to increased levels of IFN-γ in patients who were serologically positive for T. gondii. Collectively, these data demonstrated that chronic infection with T. gondii is a critical factor for sepsis severity that needs to be considered when designing strategies to prevent and control the outcome of this devastating disease.

Highlights

The majority of studies regarding host-pathogen relationships have focused on the interaction of a single pathogen with its host
We observed increased mortality of coinfected mice compared to sublethal cecal ligation and puncture (CLP)-subjected mice (Figure 1A). These data indicate that chronic T. gondii infection aggravated polymicrobial sepsis, which was not due to toxoplasmosis reactivation (Figures S1A,B)
We found that 24 h after CLP, coinfected mice were more efficient in controlling bacterial replication both systemically (Figure 1B) and locally (Figure 1C) compared to septic mice

Summary

Introduction

The majority of studies regarding host-pathogen relationships have focused on the interaction of a single pathogen with its host. Understanding how previous/simultaneous infections can modify the host immune response and affect the outcome of a secondary infection is crucial to designing new therapeutic strategies to control coinfections. A life-threatening disease associated with high morbidity and mortality worldwide, is caused by a dysregulation of the immune system to different infectious agents (Schmid et al, 2004). An uncontrolled infection induces a systemic inflammatory reaction that culminates in a cytokine storm. Such inflammatory mediators deregulate the cardiovascular system, cause vascular permeability, and lead to severe sepsis and septic shock characterized by severe hypotension, multi-organ failure, and death (Bone et al, 1997; Hotchkiss et al, 2009)

Methods

Results

Conclusion