Chronic Toxoplasma gondii Infection Exacerbates Secondary Polymicrobial Sepsis

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.

Infections, inflammation, and risk of neuropsychiatric disorders: the neglected role of “co-infection”

“…In this regard, Souza et al. [ 30 ] reported that chronic infection with T. gondii exacerbates secondary polymicrobial sepsis in an experimental mouse model and in a human survey. The results revealed that chronic T. gondii infection suppresses anti-inflammatory T helper (T H )-2 cells and simultaneously intensifies local and systemic inflammatory T H 1 cells and their inflammatory cytokines, such as IFN-γ and nitric oxide (NO) [ 30 ].…”

“…[ 30 ] reported that chronic infection with T. gondii exacerbates secondary polymicrobial sepsis in an experimental mouse model and in a human survey. The results revealed that chronic T. gondii infection suppresses anti-inflammatory T helper (T H )-2 cells and simultaneously intensifies local and systemic inflammatory T H 1 cells and their inflammatory cytokines, such as IFN-γ and nitric oxide (NO) [ 30 ]. These phenomena were resulted in reduced diastolic and systolic blood pressures after induction of sepsis and led to a severe outcome than uninfected T. gondii mice with sepsis [ 30 ].…”

“…The results revealed that chronic T. gondii infection suppresses anti-inflammatory T helper (T H )-2 cells and simultaneously intensifies local and systemic inflammatory T H 1 cells and their inflammatory cytokines, such as IFN-γ and nitric oxide (NO) [ 30 ]. These phenomena were resulted in reduced diastolic and systolic blood pressures after induction of sepsis and led to a severe outcome than uninfected T. gondii mice with sepsis [ 30 ]. A clinical study was also performed by the same group of the researchers [ 30 ] regarding the correlation of T. gondii seropositivity with inflammatory biomarkers in patients with sepsis.…”

“…These phenomena were resulted in reduced diastolic and systolic blood pressures after induction of sepsis and led to a severe outcome than uninfected T. gondii mice with sepsis [ 30 ]. A clinical study was also performed by the same group of the researchers [ 30 ] regarding the correlation of T. gondii seropositivity with inflammatory biomarkers in patients with sepsis. They found that the sepsis severity was positively correlated with increased IFN-γ levels in T. gondii seropositive patients compare with T. gondii seronegative septic patients [ 30 ].…”

“…Although association of single infection with NPDs have been investigated in many studies [ 18 , 19 , 20 , 21 ], little is known about the association of co-or-multiple infections and NPDs. Because co-or-multiple infections have more adverse outcome than single infection [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], the major question of this article is: May co-or-multiple infections enhance the risk of NPDs? And, what is the possible association of co-or-multiple infections with NPDs?…”