Balancing the functions of DNA extracellular traps in intracellular parasite infections: implications for host defense, disease pathology and therapy.

The release of DNA to the extracellular milieu is a biological process referred to as etosis, which is involved in both physiological and pathological functions. Although the release of DNA extracellular traps (ETs) was initially attributed to innate immune cells such as neutrophils, eosinophils, and macrophages, recent studies have shown that T cells, as well as non-immune cells, are capable of releasing ETs. These structures were described primarily for their potential to trap and kill pathogens, presenting an important strategy of host defense. Intriguingly, these functions have been associated with intracellular pathogens such as the parasites Leishmania sp. and Trypanosoma cruzi, causative agents of leishmaniasis and Chagas disease, respectively. These are two devastating tropical diseases that lead to thousands of deaths every year. In an apparent contradiction, ETs can also induce and amplify inflammation, which may lead to worsening disease pathology. This has prompted the concept of targeting ETs' release as a means of controlling tissue destruction to treat human diseases. What is the best approach to prevent disease severity: inducing ETs to kill pathogens or preventing their release? In this Perspective article, we will discuss the importance of understanding ETs released by different cell types and the need to balance their potentially complementary functions. In addition, we will explore other functions of ETs and their translational applications to benefit individuals infected with intracellular parasites and other pathogens. Ultimately, a better understanding of the role of ETs in disease pathogenesis will provide valuable insights into developing novel therapies for human diseases.

Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum.

Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection Neospora caninum could be used as a relevant model to study the role of the kynurenine pathway in the neuroinflammatory response and the subset of cells involved.

Apoptotic mimicry as a strategy for the establishment of parasitic infections: parasite- and host-derived phosphatidylserine as key molecule.

The establishment of parasitic infection is dependent on the development of efficient strategies to evade the host defense mechanisms. Phosphatidylserine (PS) molecules are pivotal for apoptotic cell recognition and clearance by professional phagocytes. Moreover, PS receptors are able to trigger anti-inflammatory and immunosuppressive responses by phagocytes, either by coupled enzymes or through the induction of regulatory cytokine secretion. These PS-dependent events are exploited by parasites in a mechanism called apoptotic mimicry. Generally, apoptotic mimicry refers to the effects of PS recognition for the initiation and maintenance of pathogenic infections. However, in this context, PS molecules can be recognized on the surface of the infectious agent or in the surface of apoptotic host debris, leading to the respective denomination of classical and non-classical apoptotic mimicry. In this review, we discuss the role of PS in the pathogenesis of several human infections caused by protozoan parasites. Video Abstract.

Analysis of Predicted Host-Parasite Interactomes Reveals Commonalities and Specificities Related to Parasitic Lifestyle and Tissues Tropism.

The study of molecular host-parasite interactions is essential to understand parasitic infection and adaptation within the host system. As well, prevention and treatment of infectious diseases require a clear understanding of the molecular crosstalk between parasites and their hosts. Yet, large-scale experimental identification of host-parasite molecular interactions remains challenging, and the use of computational predictions becomes then necessary. Here, we propose a computational integrative approach to predict host-parasite protein-protein interaction (PPI) networks resulting from the human infection by 15 different eukaryotic parasites. We used an orthology-based approach to transfer high-confidence intraspecies interactions obtained from the STRING database to the corresponding interspecies homolog protein pairs in the host-parasite system. Our approach uses either the parasites predicted secretome and membrane proteins, or only the secretome, depending on whether they are uni- or multi-cellular, respectively, to reduce the number of false predictions. Moreover, the host proteome is filtered for proteins expressed in selected cellular localizations and tissues supporting the parasite growth. We evaluated the inferred interactions by analyzing the enriched biological processes and pathways in the predicted networks and their association with known parasitic invasion and evasion mechanisms. The resulting PPI networks were compared across parasites to identify common mechanisms that may define a global pathogenic hallmark. We also provided a study case focusing on a closer examination of the human-S. mansoni predicted interactome, detecting central proteins that have relevant roles in the human-S. mansoni network, and identifying tissue-specific interactions with key roles in the life cycle of the parasite. The predicted PPI networks can be visualized and downloaded at http://orthohpi.jensenlab.org.

Dendritic cells and parasites: from recognition and activation to immune response instruction.

The effective defense against parasite infections requires the ability to mount an appropriate and controlled specific immune response able to eradicate the invading pathogen while limiting the collateral damage to self-tissues. Dendritic cells are key elements for the development of immunity against parasites; they control the responses required to eliminate these pathogens while maintaining host homeostasis. Ligation of dendritic cell pattern recognition receptors by pathogen-associated molecular pattern present in the parasites initiates signaling pathways that lead to the production of surface and secreted proteins that are required, together with the antigen, to induce an appropriate and timely regulated immune response. There is evidence showing that parasites can influence and regulate dendritic cell functions in order to promote a more permissive environment for their survival. In this review, we will focus on new insights about the ability of protozoan and helminth parasites or their products to modify dendritic cell function and discuss how this interaction is crucial in shaping the host response.

Role of gap junctions and hemichannels in parasitic infections.

In vertebrates, connexins (Cxs) and pannexins (Panxs) are proteins that form gap junction channels and/or hemichannels located at cell-cell interfaces and cell surface, respectively. Similar channel types are formed by innexins in invertebrate cells. These channels serve as pathways for cellular communication that coordinate diverse physiologic processes. However, it is known that many acquired and inherited diseases deregulate Cx and/or Panx channels, condition that frequently worsens the pathological state of vertebrates. Recent evidences suggest that Cx and/or Panx hemichannels play a relevant role in bacterial and viral infections. Nonetheless, little is known about the role of Cx- and Panx-based channels in parasitic infections of vertebrates. In this review, available data on changes in Cx and gap junction channel changes induced by parasitic infections are summarized. Additionally, we describe recent findings that suggest possible roles of hemichannels in parasitic infections. Finally, the possibility of new therapeutic designs based on hemichannel blokers is presented.

Parasite infections in multiple sclerosis modulate immune responses through a retinoic acid-dependent pathway.

We recently demonstrated better outcomes in helminth-infected multiple sclerosis (MS) patients, compared with uninfected ones. The present study evaluates the role of TLR2 and retinoic acid (RA) in parasite-driven protection in MS patients. RA serum levels were significantly higher in helminth-infected MS patients than in uninfected MS subjects or healthy controls. Genes involved in RA biosynthesis and metabolism, such as Adh1 and Raldh2, as well as RA receptors and IL-10, were induced in dendritic cells (DCs) via TLR2-dependent ERK signaling. This programmed DCs to induce FOXP3(+) T regulatory cells and suppressed production of proinflammatory cytokines (IL-6, IL-12, IL-23, and TNF-α) via induction of suppressor of cytokine signaling 3 (SOCS3), an effect mediated by soluble egg Ag (SEA) obtained from Schistosoma mansoni, and by RA. SEA-activated DCs also inhibited IL-17 and IFN-γ production through autoreactive T cells. These inhibitory effects were abrogated when SOCS3 gene expression was silenced, indicating that SEA-mediated signaling inhibited production of these cytokines by T cells, through a SOCS3-dependent pathway. Overall, helminth-related immunomodulation observed in MS patients was mediated by TLR2- and RA-dependent pathways, through two different mechanisms, as follows: 1) induction of IL-10 and FOXP3(+) T regulatory cells, and 2) suppression of proinflammatory cytokine production mediated by SOCS3.

Lipid bodies in innate immune response to bacterial and parasite infections.

Lipid bodies (also known as lipid droplets, adiposomes) are dynamic organelles with key roles in regulating storage and turnover of lipids in different cells and organisms. The emerging role of lipid bodies as inflammatory organelles raises lipid body status to critical regulators of different inflammatory and infectious diseases and key markers of cell activation. Notably, lipid body biogenesis is highly regulated and is cell and stimuli specific. Lipid body structural features, including lipid and protein composition may vary according to the cell type, activation state and inflammatory environment and thus may determine different cellular functions for lipid bodies. Here we will review the morphological and structural aspects of lipid bodies, the regulated mechanisms of formation, as well as lipid body functions in cells involved in the innate immune response during bacterial and parasite infections.

Host gender in parasitic infections of mammals: an evaluation of the female host supremacy paradigm.

A review of current literature on mammalian hosts' sexual dimorphism (SD) in parasitic infections revealed that (1) it is a scarcely and superficially studied biological phenomenon of considerable significance for individual health, behavior, and lifestyles and for the evolution of species; (2) there are many notable exceptions to the rule of a favorable female bias in susceptibility to infection; (3) a complex network of molecular and cellular reactions connecting the host's immuno-neuroendocrine systems with those of the parasite is responsible for the host-parasite relationship rather than just an adaptive immune response and sex hormones; (4) a lack of gender-specific immune profiles in response to different infections; (5) the direct effects of the host hormones on parasite physiology may significantly contribute to SD in parasitism; and (6) the need to enrich the reductionist approach to complex biological issues, like SD, with more penetrating approaches to the study of cause-effect relationships, i.e., network theory. The review concludes by advising against generalization regarding SD and parasitism and by pointing to some of the most promising lines of research.

Extracellular matrix degradation in parasitic diseases.

1. Fibrosis is an important manifestation of several parasitic diseases, but is not irreversible. A marked degree of extracellular matrix degradation can occur after cure of parasitism. Patients with the hepatosplenic form of schistosomiasis undergo considerable resorption of portal fibrosis months or years after curative treatment as demonstrated by ultrasonography and pathological examination. 2. Studies of the post-treatment degradation of extracellular matrix in schistosomal periovular granulomas have demonstrated two forms of collagen degradation: in hepatic granulomas formed during early infection a rapid process occurs, with the extracellular breakdown of fibers and internalization of collagen fragments, whereas during late infection, degradation is slow and is accompanied by focal electrondense and/or lytic changes. 3. Extensive extracellular matrix degradation and resorption occurring after curative treatment was recently described in the liver of a man with advanced visceral leishmaniasis and in the heart of mice with chronic Chagas' disease.

Extracellular matrix degradation in parasitic diseases

Fibrosis is an important manifestation of several parasitic diseases, but is not irreversible. A marked degree of extracellular matrix degradation can occur after cure of parasitism. Patients with the hepatosplenic form of schistosomiasis undergo considerable resorption of portal fibrosis monts or years after curative treatment as demonstrated by ultrasonography and pathological exmaination. 2. Studies of the post-treatment degradation of extracellular matrix in schistosomal periocular granulomas have demosntrated two forms of collagen degradation: in hepatic granulomas formed during early infection a rapid process occurs, with extracellular breakdown of fibers and internalization of collagen fragments, whereas during late infection, degradation in slow and is accompanied by focal electrondense and/or lytic changes. 3. Extensive extracellular matrix degradation and resorption occuring after curative treatment was recently described in the liver of a man with advanced visceral leishmaniasis and in the heart of mice with chronic Chagas' disease

The effect of zinc supplementation on parasitic reinfestation of Guatemalan schoolchildren.

One hundred thirty children (65-95 mo old) from a low-socioeconomic neighborhood of Guatemala City participated in a randomized, double-blind, controlled trial of zinc supplementation. One group received 10 mg Zn/d (n = 65) and the other group received a placebo (n = 65); 90 +/- 9.2 doses were given over 120-150 d. Stools were examined for prevalence and intensity of helminths and prevalence of protozoa at the beginning and end of the study. The initial prevalence was 42% for helminths and 18% for protozoa, with no differences between groups. Mebendazole was administered to all children, and protozoal infections were treated specifically at the beginning of the study. The reinfection rates were 17% (11 of 65) for helminths and 12.3% (8 of 65) for protozoa in the zinc group and 15% (10 of 65) and 10.7% (7 of 65), respectively, in the placebo group (P > 0.05). Analysis by specific parasites revealed no treatment effect. We conclude that neither plasma or hair zinc status nor oral zinc supplementation had an effect on parasite status in children.

A new dosing regimen for metronidazole in malnourished children.

The use of metronidazole for the treatment of intestinal parasitosis has increased markedly, particularly in developing countries, where the association of malnutrition and parasitosis is very common. Since biotransformation of metronidazole is significantly affected by severe malnutrition, and undesirable effects of the drug seem to be related to its plasma concentration, it was decided to carry out a study to establish a dosing-regimen of metronidazole in severely malnourished children. A single dose of 30 mg/kg body weight, and computer simulation of a steady-state was studied in 10 malnourished and in 10 patients undergoing nutritional rehabilitation. Due to ethical considerations (refusal of parents to allow a second dose of metronidazole) acute malnourished children and rehabilitated patients are 2 distinct groups. The results indicate that a predicted drug cumulation would occur in malnourished children with the ordinary dosage regimen (30 mg/kg/day). Based on the clearance data, daily maintenance doses for pediatric patients with severe malnutrition should be 12.0 mg/kg/day, corresponding to a 60% reduction of the common dose calculated to achieve and maintain a plasma concentration of 6.0 micrograms/ml of metronidazole. The study illustrates the need for pharmacokinetic data to establish the individual dose of a drug particularly under conditions that alter biotransformation processes.

Nutritional requirements in parasitic diseases.

"Nutritional requirements" means different things in different contexts. Generally, the term refers to national or international standards or allowances of nutrients. Concern here involves the potential need for a change of standards where conditions of disease prevail, because disease increases the nutritional requirements of most individuals. "Nutritional requirements" may also be viewed in terms of food supplies. Analysis of a number of studies indicates that the average growth deficit due to endemic infectious diseases in early life is less than or equal to 20 kcal per day (calculated as 5 kcal/g of tissue). Increased weight gain following treatment of intestinal parasites such as Ascaris lumbricoides or Giardia lamblia provides similar estimates, as does measurement of energy and protein absorption. These values are within normal variance estimates. Sick children do not eat well and apparently do not eat enough on healthy days to correct for the accrued food deficit. Research on nutritional requirements of children needs to focus on management of food resources in entire families.