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Chronic Toxoplasma gondii Infection Exacerbates Secondary Polymicrobial Sepsis

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

The T. gondii-primed immune response promotes a storm of cytokines associated with CLP. C57BL/6 mice were infected with 5 cysts of T. gondii, and 40 days after infection, the mice were subjected to CLP. Twenty-four hours after CLP, the serum and peritoneal lavage were collected for cytokine analysis. The levels of pro-inflammatory cytokines IFN-γ (A,E), TNF-ɑ (B,F), IL-6 (C,G), and the chemokine KC (D,H) were determined using ELISA. Data are presented as the means ± SEM for 4 animals per group in three different experiments (ANOVA followed by Tukey's test; *p < 0.05; **p < 0.01; ***p < 0.001).
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Figure 2: The T. gondii-primed immune response promotes a storm of cytokines associated with CLP. C57BL/6 mice were infected with 5 cysts of T. gondii, and 40 days after infection, the mice were subjected to CLP. Twenty-four hours after CLP, the serum and peritoneal lavage were collected for cytokine analysis. The levels of pro-inflammatory cytokines IFN-γ (A,E), TNF-ɑ (B,F), IL-6 (C,G), and the chemokine KC (D,H) were determined using ELISA. Data are presented as the means ± SEM for 4 animals per group in three different experiments (ANOVA followed by Tukey's test; *p < 0.05; **p < 0.01; ***p < 0.001).

Mentions: The major factor leading to host susceptibility during sepsis is the increased production of inflammatory cytokines, which can promote septic shock (Ebong et al., 1999). To evaluate whether the high mortality of coinfected mice mirrored the production of inflammatory mediators, we quantified the cytokines in the serum and peritoneal lavage 24 h after CLP. Notably, coinfected mice showed increased levels of IFN-γ (Figures 2A,E), TNF-α (Figures 2B,F), IL-6 (Figures 2C,G), and KC (Figures 2D,H) in both the serum and peritoneal lavage compared to the control groups. For the immuneregulatory cytokines, IL-4 was not detected and the levels of IL-10 in the peritoneal lavage were similar in all groups studied. Splenic CD4+ and CD8+ T cells of T. gondii-infected mice produced elevated levels of IFN-γ and TNF-α even in the absence of a secondary stimulus (Figures 3A–D). Although the size of the spleen from T. gondii-infected mice was similar to naïve mice, after the induction of sepsis, T. gondii-infected mice experienced a notable reduction in spleen size along with a striking emergence of IFN-γ- and TNF-α-producing CD4+ (Figures 3E–G) and CD8+ (Figures 3H–J) T cells into the peritoneum. These data suggest that inflammatory cells were leaving the spleen/bloodstream and reaching the peritoneal cavity. Thus, T. gondii-programmed CD4+ and CD8+ T cells may be recruited to the site of sepsis and are the primary source of inflammatory mediators during sepsis in infected mice.


Chronic Toxoplasma gondii Infection Exacerbates Secondary Polymicrobial Sepsis
The T. gondii-primed immune response promotes a storm of cytokines associated with CLP. C57BL/6 mice were infected with 5 cysts of T. gondii, and 40 days after infection, the mice were subjected to CLP. Twenty-four hours after CLP, the serum and peritoneal lavage were collected for cytokine analysis. The levels of pro-inflammatory cytokines IFN-γ (A,E), TNF-ɑ (B,F), IL-6 (C,G), and the chemokine KC (D,H) were determined using ELISA. Data are presented as the means ± SEM for 4 animals per group in three different experiments (ANOVA followed by Tukey's test; *p < 0.05; **p < 0.01; ***p < 0.001).
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Figure 2: The T. gondii-primed immune response promotes a storm of cytokines associated with CLP. C57BL/6 mice were infected with 5 cysts of T. gondii, and 40 days after infection, the mice were subjected to CLP. Twenty-four hours after CLP, the serum and peritoneal lavage were collected for cytokine analysis. The levels of pro-inflammatory cytokines IFN-γ (A,E), TNF-ɑ (B,F), IL-6 (C,G), and the chemokine KC (D,H) were determined using ELISA. Data are presented as the means ± SEM for 4 animals per group in three different experiments (ANOVA followed by Tukey's test; *p < 0.05; **p < 0.01; ***p < 0.001).
Mentions: The major factor leading to host susceptibility during sepsis is the increased production of inflammatory cytokines, which can promote septic shock (Ebong et al., 1999). To evaluate whether the high mortality of coinfected mice mirrored the production of inflammatory mediators, we quantified the cytokines in the serum and peritoneal lavage 24 h after CLP. Notably, coinfected mice showed increased levels of IFN-γ (Figures 2A,E), TNF-α (Figures 2B,F), IL-6 (Figures 2C,G), and KC (Figures 2D,H) in both the serum and peritoneal lavage compared to the control groups. For the immuneregulatory cytokines, IL-4 was not detected and the levels of IL-10 in the peritoneal lavage were similar in all groups studied. Splenic CD4+ and CD8+ T cells of T. gondii-infected mice produced elevated levels of IFN-γ and TNF-α even in the absence of a secondary stimulus (Figures 3A–D). Although the size of the spleen from T. gondii-infected mice was similar to naïve mice, after the induction of sepsis, T. gondii-infected mice experienced a notable reduction in spleen size along with a striking emergence of IFN-γ- and TNF-α-producing CD4+ (Figures 3E–G) and CD8+ (Figures 3H–J) T cells into the peritoneum. These data suggest that inflammatory cells were leaving the spleen/bloodstream and reaching the peritoneal cavity. Thus, T. gondii-programmed CD4+ and CD8+ T cells may be recruited to the site of sepsis and are the primary source of inflammatory mediators during sepsis in infected mice.

View Article: PubMed Central - PubMed

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-&gamma;-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-&gamma; 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-&gamma; 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.

No MeSH data available.


Related in: MedlinePlus