Heidi Snider

Macrophage Migration Inhibitory Factor Contributes to Host Defense against Acute Trypanosoma cruzi Infection

ABSTRACT Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is involved in the host defense against several pathogens. Here we used MIF−/− mice to determine the role of endogenous MIF in the regulation of the host immune response against Trypanosoma cruzi infection. MIF−/− mice displayed high levels of blood and tissue parasitemia, developed severe heart and skeletal muscle immunopathology, and succumbed to T. cruzi infection faster than MIF+/+ mice. The enhanced susceptibility of MIF−/− mice to T. cruzi was associated with reduced levels of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-12 (IL-12), IL-18, gamma interferon (IFN-γ), and IL-1β, in their sera and reduced production of IL-12, IFN-γ, and IL-4 by spleen cells during the early phase of infection. At all time points, antigen-stimulated splenocytes from MIF+/+ and MIF−/− mice produced comparable levels of IL-10. MIF−/− mice also produced significantly less Th1-associated antigen-specific immunoglobulin G2a (IgG2a) throughout the infection, but both groups produced comparable levels of Th2-associated IgG1. Lastly, inflamed hearts from T. cruzi-infected MIF−/− mice expressed increased transcripts for IFN-γ, but fewer for IL-12 p35, IL-12 p40, IL-23, and inducible nitric oxide synthase, compared to MIF+/+ mice. Taken together, our findings show that MIF plays a role in controlling acute T. cruzi infection.

Sex Hormones and Modulation of Immunity against Leishmaniasis

Sex-associated hormones such as estradiol, testosterone and progesterone have all been shown to modulate immune responses, which can result in differential disease outcomes between males and females, as well as between pregnant and nonpregnant females. Most parasitic diseases, including leishmaniasis, usually result in more severe disease in males compared with females. This review highlights our current knowledge concerning the role of sex hormones in modulating leishmaniasis in both clinical settings and experimental disease models.

Cutting Edge: STAT1 and T-bet Play Distinct Roles in Determining Outcome of Visceral Leishmaniasis Caused by Leishmania donovani

T-bet and STAT1 regulate IFN-γ gene transcription in CD4+ T cells, which mediate protection against Leishmania. Here we show that T-bet and STAT1 are required for the induction of an efficient Th1 response during Leishmania donovani infection, but they play distinct roles in determining disease outcome. Both STAT1−/− and T-bet−/− mice failed to mount a Th1 response, but STAT1−/− mice were highly resistant to L. donovani and developed less immunopathology, whereas T-bet−/− mice were highly susceptible and eventually developed liver inflammation. Adoptive cell transfer studies showed that RAG2−/− recipients receiving STAT1+/+ or STAT1−/− T cells developed comparable liver pathology, but those receiving STAT1−/− T cells were significantly more susceptible to infection. These unexpected findings reveal distinct roles for T-bet and STAT1 in mediating host immunity and liver pathology during visceral leishmaniasis.

Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection

The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN‐γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild‐type (WT) and STAT1−/− C57BL/6 mice into Rag2−/− C57BL/6 mice. Rag2−/− mice reconstituted with unfractionated STAT1−/− splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL‐4, and developed large lesions full of parasites. In contrast, Rag2−/− mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self‐resolving lesions. Studies using Rag2−/− recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1−/− mice revealed that STAT1 deficiency in CD4+ T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2−/− recipients of WT Thy1.1+ and STAT1−/− Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up‐regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.—Barbi, J., Snider, H. M., Bhardwaj, N., Lezama‐Davila, C. M., Durbin, J. E., Satoskar, A. R. Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection. FASEB J. 23, 3990–3999 (2009). www.fasebj.org

STAT4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis

We and others have previously shown that IL‐12 is indispensable for immunity and is required for the optimal antiparasitic activity of antimonials in experimental visceral leishmaniasis caused by Leishmania donovani. Here we investigated the role of STAT4 in immunity against L. donovani using STAT4 knockout mice and also determined the effect of STAT4 deficiency in response to antimonial therapy. Upon infection with L. donovani, stat4−/− BALB/c and C57BL/6 mice showed enhanced susceptibility to Leishmania during late time points of infection which was associated with a marked reduction in Th1 responses and hepatic immunopathology. Interestingly, these defects in Th1 responses in stat4−/− did not impair the antimonial chemotherapy as both stat4−/− and WT mice showed comparable levels of parasite clearance from the liver and spleen. These findings highlight the role of STAT4 in immunity to L. donovani infection and also provide evidence that STAT4 is dispensable for antimonial‐based chemotherapy.

Sex Hormones and Regulation of Host Responses Against Parasites

Sex hormones play an influential role in the control of parasitic infection by their ability to modulate different components of both the innate and adaptive immune responses. The parasites themselves are phylogenetically diverse, target a range of different tissues, and have evolved numerous alternative strategies to evade or inhibit protective immune responses. Consequently, the influence of sex hormones on these infective agents can be complex. For example, while females exhibit greater resistance to infection by parasites including Trypanosoma cruzi, Trypanosoma brucei, Giardia lamblia, Leishmania mexicana, Plasmodium chabaudi, and Trichinella spiralis, their male counterparts are found to be more resistant to infection with Trichomonas vaganalis, Toxoplasma gondii and Schistosoma mansoni. This chapter will discuss: (1) the role of sex hormones in regulating the outcome of parasite infection, (2) mechanisms by which these hormones modulate host immune responses, and (3) the implications of these observations for the pathogenesis of human parasitic disease.

A Novel Sterol Isolated from a Plant Used by Mayan Traditional Healers Is Effective in Treatment of Visceral Leishmaniasis Caused by Leishmania donovani.

Visceral leishmaniasis (VL), caused by the protozoan parasite Leishmania donovani, is a global health problem affecting millions of people worldwide. Treatment of VL largely depends on therapeutic drugs such as pentavalent antimonials, amphotericin B, and others, which have major drawbacks due to drug resistance, toxicity, and high cost. In this study, for the first time, we have successfully demonstrated the synthesis and antileishmanial activity of the novel sterol pentalinonsterol (PEN), which occurs naturally in the root of a Mexican medicinal plant, Pentalinon andrieuxii. In the experimental BALB/c mouse model of VL induced by infection with L. donovani, intravenous treatment with liposome-encapsulated PEN (2.5 mg/kg) led to a significant reduction in parasite burden in the liver and spleen. Furthermore, infected mice treated with liposomal PEN showed a strong host-protective TH1 immune response characterized by IFN-γ production and formation of matured hepatic granulomas. These results indicate that PEN could be developed as a novel drug against VL.