Group 1 innate lymphoid cells in Toxoplasma gondii infection.

Innate lymphoid cells (ILCs) are a group of lymphocytes that carry out important functions in immunity to infections and in organ homeostasis at epithelial barrier surfaces. ILCs are innate immune cells that provide an early source of cytokines to initiate immune responses against pathogens. Cytotoxic ILCs (i.e. conventional (c)NK cells) and several subsets of helper-like ILCs are the major branches of the ILC family. Conventional NK cells and group 1 ILCs share several characteristics such as surface receptors and the ability to produce IFN-γ upon activation, but they differ in their developmental paths and in their dependence on specific transcription factors. Infection of mice with the intracellular parasite Toxoplasma gondii is followed by a strong Th1-mediated immune response. Previous studies indicate that NK1.1+ cells contribute to the production of IFN-γ and TNF and cytotoxicity during acute T. gondii infection. Upon oral infection, the parasite infects intestinal enterocytes, and within the lamina propria, innate immune responses lead to initial parasite control although the infection disseminates widely and persists long-term in immune privileged sites despite adaptive immunity. Upon parasite entry into the small intestine, during the acute stage, ILC1 produce high levels of IFN-γ and TNF protecting barrier surfaces, thus essentially contributing to early parasite control. We will discuss here the role of innate lymphocytes during T. gondii infection in the context of the only recently appreciated diversity of ILC subsets.

Batf3 deficiency proves the pivotal role of CD8α+ dendritic cells in protection induced by vaccination with attenuated Plasmodium sporozoites.

Increasing evidence indicates that hepatic CD8α+ dendritic cells (DCs) are important antigen cross-presenting cells (APC) involved in the priming of protective CD8+ T-cell responses induced by live-attenuated Plasmodium sporozoites. Experimental proof for a critical role of CD8α+ DCs in protective pre-erythrocytic malaria immunizations has pivotal implications for vaccine development, including improved vectored subunit vaccines. Employing Batf3-/- mice, which lack functional CD8α+ DCs, we demonstrate that deficiency of these particular APCs completely abolishes protection and corresponding signatures of vaccine-induced immunity. We show that in wild-type, but not in Batf3-/- , mice CD8α+ DCs accumulate in the liver after immunization with live irradiation-attenuated P. berghei sporozoites. IFN-γ production by Plasmodium antigen-specific CD8+ T cells is dependent on functional Batf3. In addition, our results demonstrate that the dysfunctional cDC-CD8+ T-cell axis correlates with MHC class II upregulation on splenic CD8α- DCs. Collectively, these findings underscore the essential role of CD8α+ DCs in robust protection induced by experimental live-attenuated malaria vaccines.

Persistence of Toxoplasma gondii in the central nervous system: a fine-tuned balance between the parasite, the brain and the immune system.

Upon infection of humans and animals with Toxoplasma gondii, the parasites persist as intraneuronal cysts that are controlled, but not eliminated by the immune system. In particular, intracerebral T cells are crucial in the control of T. gondii infection and are supported by essential functions from other leukocyte populations. Additionally, brain-resident cells including astrocytes, microglia and neurons contribute to the intracerebral immune response by the production of cytokines, chemokines and expression of immunoregulatory cell surface molecules, such as major histocompatibility (MHC) antigens. However, the in vivo behaviour of these individual cell populations, specifically their interaction during cerebral toxoplasmosis, remains to be elucidated. We discuss here what is known about the function of T cells, recruited myeloid cells and brain-resident cells, with particular emphasis on the potential cross-regulation of these cell populations, in governing cerebral toxoplasmosis.

Toxoplasma gondii-induced neuronal alterations.

The zoonotic pathogen Toxoplasma gondii infects over 30% of the human population. The intracellular parasite can persist lifelong in the CNS within neurons modifying their function and structure, thus leading to specific behavioural changes of the host. In recent years, several in vitro studies and murine models have focused on the elucidation of these modifications. Furthermore, investigations of the human population have correlated Toxoplasma seropositivity with changes in neurological functions; however, the complex underlying mechanisms of the subtle behavioural alteration are still not fully understood. The parasites are able to induce direct modifications in the infected cells, for example by altering dopamine metabolism, by functionally silencing neurons as well as by hindering apoptosis. Moreover, indirect effects of the peripheral immune system and alterations of the immune status of the CNS, observed during chronic infection, might also contribute to changes in neuronal connectivity and synaptic plasticity. In this review, we will provide an overview and highlight recent advances, which describe changes in the neuronal function and morphology upon T. gondii infection.

Spinal cord pathology in chronic experimental Toxoplasma gondii infection.

Infection with the protozoan Toxoplasma (T.) gondii causes chronic infection of the central nervous system and can lead to life-threatening encephalomyelitis in immunocompromised patients. While infection with T. gondii has long time been considered asymptomatic in immunocompetent hosts, this view is challenged by recent reports describing links between seropositivity and behavioral alterations. However, past and current researches are mainly focused on the brain during Toxoplasma encephalitis, neglecting the spinal cord as a key structure conveying brain signals into motion. Therefore, our study aimed to fill the gap and describes the spinal cord pathology in an experimental murine model of toxoplasmosis. In the spinal cord, we found distinct histopathological changes, inflammatory foci and T. gondii cysts similar to the brain. Furthermore, the recruitment of immune cells from the periphery was detected. Moreover, resident microglia as well as recruited monocytes displayed an increased MHC classes I and II expression. Additionally, the expression of pro- and anti-inflammatory cytokines was enhanced in the brain as well as in the spinal cord. In summary, the pathology observed in the spinal cord was similar to the previously described changes in the brain during the infection. This study provides the first detailed description of histopathological and immunological alterations due to experimental T. gondii induced myelitis in mice. Thus, our comparison raises awareness of the importance of the spinal cord in chronic T. gondii infection.

Pro-inflammatory potential of Escherichia coli strains K12 and Nissle 1917 in a murine model of acute ileitis.

Non-pathogenic Escherichia coli (Ec) strains K12 (EcK12) and Nissle 1917 (EcN) are used for gene technology and probiotic treatment of intestinal inflammation, respectively. We investigated intestinal colonization and potential pro-inflammatory properties of EcK12, EcN, and commensal E. coli (EcCo) strains in Toxoplasma (T.) gondii-induced acute ileitis. Whereas gnotobiotic animals generated by quintuple antibiotic treatment were protected from ileitis, mice replenished with conventional microbiota suffered from small intestinal necrosis 7 days post-T. gondii infection (p.i.). Irrespective of the Ec strain, recolonized mice revealed mild to moderate histopathological changes in their ileal mucosa. Upon stable recolonization with EcK12, EcN, or EcCo, development of inflammation was accompanied by pro-inflammatory responses at day 7 p.i., including increased ileal T lymphocyte and apoptotic cell numbers compared to T. gondii-infected gnotobiotic controls. Strikingly, either Ec strain was capable to translocate to extra-intestinal locations, such as MLN, spleen, and liver. Taken together, Ec strains used in gene technology and probiotic treatment are able to exert inflammatory responses in a murine model of small intestinal inflammation. In conclusion, the therapeutic use of Ec strains in patients with broad-spectrum antibiotic treatment and/or intestinal inflammation should be considered with caution.

Monocytes in health and disease - Minireview.

Monocytes are important cell types of the innate immune system. Recent scientific evidence suggests that monocytes not only play a crucial role in our innate immune system by defending the host from intruding microbial pathogens but they also contribute to the pathogenesis and progression of diseases such as liver fibrosis, atherosclerosis, multiple sclerosis, and tumor metastasis. In addition, monocytes and monocyte-derived macrophages play a crucial beneficial role in the liver fibrosis regression, muscle regeneration, and the clearance of the ß-amyloid plaques in Alzheimer's disease. Here, we summarize the origin, plasticity, and pathogenic potential of monocytes and monocyte-derived macrophages, as well as their positive role in the regression of some common diseases. Elucidating the comprehensive immunological role of monocytes will provide therapeutic advantages in either controlling disease progression or favoring the regression of the disease state.

Selective gelatinase blockage ameliorates acute DSS colitis.

In the experimental models of intestinal inflammation and humans with inflammatory bowel diseases (IBD), increased levels of the matrix metalloproteinases (MMPs), MMP-2 and -9 (also referred to as gelatinase A and B, respectively), in inflamed tissue sites can be detected. In the presented study, we investigated potential beneficial effects exerted by doxycycline nonselectively blocking MMPs and the selective gelatinase inhibitor RO28-2653 in acute DSS colitis. Treatment with either compound for 8 days ameliorated clinical colitis pathology with a superior outcome in RO28-2653-treated animals. As compared to placebo controls, histopathological changes in the colon were less distinct following MMP blockage and IL-6 secretion in ex vivo biopsies was downregulated, paralleled by a diminished influx of pro-inflammatory immune cells and lack of overgrowth of the colonic lumen by potentially pro-inflammatory Escherichia coli of the commensal colon flora. We conclude that selective gelatinase inhibition not only exerts beneficial effects by disrupting the vicious cycle of positive feedback between immune cell stimulation and MMP induction but also prevents overgrowth of the colonic lumen by pro-inflammatory E. coli despite a lack of direct anti-bacterial properties, thus unaffecting the commensal gut microbiota. These findings put RO28-2653 into a center stage for development of intervention strategies in human IBD.

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis.

Expression of gelatinases A and B, also referred to matrixmetalloproteinases (MMP)-2 and -9, respectively, is increased in inflamed tissues of experimental intestinal inflammation and humans with inflammatory bowel disease (IBDs). Given that we recently reported that treatment with the selective gelatinase inhibitor RO28-2653 ameliorates acute dextrane sulfate sodium (DSS) colitis, we asked whether gelatinase A or B expression is pivotal in mediating large intestinal inflammation. Results from our study reveal that symptoms of acute DSS colitis as well as histopathological colonic changes were ameliorated in MMP-2-, but not MMP-9-deficient mice, and were paralleled by a diminished influx of immune cells. In MMP-2-deficient mice, we observed lower expression of pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 in colonic biopsies and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. We conclude that rather MMP-2 than MMP-9 is causative for the establishment of DSS colitis in mice. The discrepancy of these data to prior reports might be due to substantial differences in the intestinal microbiota composition of the mice bred at different animal facilities impacting susceptibility to inflammatory stimuli. Consequently, a detailed survey of the gut microbiota should be implemented in immunological/inflammatory studies in the future in order to allow comparison of data from different facilities.