No 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.

This study aims to describe the course of undergraduate education developed at the University of São Paulo at Ribeirão Preto College of Nursing throughout the 50 years of its history (1953-2003), offering tools for reflection about the historical and social context, about current curricular guidelines and political and pedagogical challenges with a view to nursing formation.

ArtinM, from Artocarpus heterophyllus, a lectin that binds to the manotriose core of N‐glycans, modulates immunity toward Th1 axis and confers resistance to intracellular pathogens. These properties were credited to the ArtinM binding to TLR2 N‐glycans on innate immune cells, with the consequent production of IL‐12. In this work we investigated the ArtinM effects on murine CD4+ T cells. ArtinM stimulated CD4+ T cells released high levels of IL‐2, IFN‐γ, IL‐6 and IL‐17A and increased the expression of CD25 and CTLA‐4. These effects were inhibited by D‐mannose. To determine the ArtinM glycotarget(s) on CD4+ T cells, specific antibodies for CD3εγ, CD3ε, CD28, CD45 and CD4 were assayed for the inhibition of the responses to ArtinM. Only anti‐CD3εγ antibody prevented the cytokines secretion and the ArtinM binding to CD4+ T cells. Because anti‐CD3ε had no effect on the responses to ArtinM, we inferred that CD3γ glycan(s) is(are) targeted by ArtinM and accounts for its ability to activate CD4+ T cells. By using pharmacological inhibitors of signaling molecules, we verified that PI3K, PTK and p42/44MAPK participate in the cytokine production induced by ArtinM. We conclude that ArtinM (1) activates CD4+ T cells through binding to glycans of CD3γ chain and (2) promotes naive CD4+ T cells differentiation into Th1 and Th17. We postulate that the effects exerted on CD4+ T cells contribute for the immunomodulatory activity of ArtinM. Grant Funding Source: Supported by FAPESP, CAPES, CNPq, FAEPA, FINEP

Introduction: The majority of studies regarding host-pathogen interactions have focused on a single pathogen. However, host organisms in a natural environment are commonly exposed to multiple pathogens, such as T. gondii infection, which induces a strong immune response by Th1 pathway, that can persists throughout the life of the host. Therefore, we hypothesized that chronic infection with T. gondii could alter the course of host response against bacterial infection. Methodology: C57BL/6 mice were orally infected with 5 cysts of ME-49 strain of T. gondii and 40 days post infection, subjected infection by cecal ligation and puncture (CLP) sepsis model. Results: Our data showed that, 12 and 24 hours after of CLP, the group of mice infected with T. gondii exhibited decreased bacterial count, increased inflammation characterized by an increase in myeloperoxidase content in lung and increase in IFN-γ and TNF cytokines levels, as compared mice subjected to the same stimulus infectious without previous T. gondii infection. Moreover, after CLP, these animals showed a significantly increase in mortality rate, which was reduced in mice TLR-2 knockout or treated with low concentrations of anti-IFN-γ or anti-TNF antibodies. Conclusion: This study demonstrates that T. gondii infection potentiates the host response against polymicrobial infection, which can be harmful to the host. The mechanism by which this happens seems to be mediated via the overproduction of IFN-γ and TNF.