The potential role of necroptosis in clinical diseases (Review).

As an important type of programmed cell death in addition to apoptosis, necroptosis occurs in a variety of pathophysiological processes, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors. It can be triggered by a variety of factors, such as tumor necrosis factor receptor and Toll­like receptor families, intracellular DNA and RNA sensors, and interferon, and is mainly mediated by receptor­interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain­like protein. A better understanding of the mechanism of necroptosis may be useful in the development of novel drugs for necroptosis­related diseases. In this review, the focus is on the molecular mechanisms of necroptosis, exploring the role of necroptosis in different pathologies, discussing their potential as a novel therapeutic target for disease therapy, and providing suggestions for further study in this area.

[Behavioural Changes Caused by Parasites: The Parasite Manipulation Hypothesis]. / Wie beeinflussen Parasiten das Verhalten ihres Wirts? Die parasitäre Manipulationshypothese.

Bacteria, archaeae, fungi and viruses of the intestinal microbiome play an important role as symbionts in the complex human ecosystem. Parasites, which account for about 40 % of the earth's biodiversity, depend on hosts to complete their life cycle. This article explains how they use them and which signalling pathways play a role in this, using toxoplasmosis and malaria as examples. The parasitic manipulation hypothesis is based on impressive observations in the wild and under laboratory conditions, especially in invertebrates. For the assumption of an adaptive manipulation, every step from the genotype, the translated messenger, and its source via the used signalling pathways to the altered host behaviour must be proven. The assumption of an adaptive manipulation of humans by T. gondii in the sense of a cause-effect relationship is not proven. Alternative explanations include the inflammatory and immunological processes on the host side, which change the neuronal signal transduction as concomitant symptoms of an infection. Even without confirmation of parasitic manipulation in humans, it could be worthwhile to further investigate the observed associations in order to develop new possibilities for diagnosis and therapy, e. g. for schizophrenia.

Diagnosis of severe respiratory infections in immunocompromised patients.

An increasing number of critically ill patients are immunocompromised. Acute hypoxemic respiratory failure (ARF), chiefly due to pulmonary infection, is the leading reason for ICU admission. Identifying the cause of ARF increases the chances of survival, but may be extremely challenging, as the underlying disease, treatments, and infection combine to create complex clinical pictures. In addition, there may be more than one infectious agent, and the pulmonary manifestations may be related to both infectious and non-infectious insults. Clinically or microbiologically documented bacterial pneumonia accounts for one-third of cases of ARF in immunocompromised patients. Early antibiotic therapy is recommended but decreases the chances of identifying the causative organism(s) to about 50%. Viruses are the second most common cause of severe respiratory infections. Positive tests for a virus in respiratory samples do not necessarily indicate a role for the virus in the current acute illness. Invasive fungal infections (Aspergillus, Mucorales, and Pneumocystis jirovecii) account for about 15% of severe respiratory infections, whereas parasites rarely cause severe acute infections in immunocompromised patients. This review focuses on the diagnosis of severe respiratory infections in immunocompromised patients. Special attention is given to newly validated diagnostic tests designed to be used on non-invasive samples or bronchoalveolar lavage fluid and capable of increasing the likelihood of an early etiological diagnosis.

Mitochondrial dynamics in parasitic protists.

The shape and number of mitochondria respond to the metabolic needs during the cell cycle of the eukaryotic cell. In the best-studied model systems of animals and fungi, the cells contain many mitochondria, each carrying its own nucleoid. The organelles, however, mostly exist as a dynamic network, which undergoes constant cycles of division and fusion. These mitochondrial dynamics are driven by intricate protein machineries centered around dynamin-related proteins (DRPs). Here, we review recent advances on the dynamics of mitochondria and mitochondrion-related organelles (MROs) of parasitic protists. In contrast to animals and fungi, many parasitic protists from groups of Apicomplexa or Kinetoplastida carry only a single mitochondrion with a single nucleoid. In these groups, mitochondrial division is strictly coupled to the cell cycle, and the morphology of the organelle responds to the cell differentiation during the parasite life cycle. On the other hand, anaerobic parasitic protists such as Giardia, Entamoeba, and Trichomonas contain multiple MROs that have lost their organellar genomes. We discuss the function of DRPs, the occurrence of mitochondrial fusion, and mitophagy in the parasitic protists from the perspective of eukaryote evolution.

Kaposi's sarcoma-associated herpesvirus seropositivity is associated with parasite infections in Ugandan fishing communities on Lake Victoria islands.

We investigated the impact of helminths and malaria infection on Kaposi's sarcoma associated herpesvirus (KSHV) seropositivity, using samples and data collected from a cluster-randomised trial of intensive versus standard anthelminthic treatment. The trial was carried out in 2012 to 2016 among fishing communities on Lake Victoria islands in Uganda. Plasma samples from 2881 participants from two household surveys, the baseline (1310 participants) and the final (1571 participants) surveys were tested for KSHV IgG antibody responses to K8.1 and ORF73 recombinant proteins using ELISA. The baseline survey was carried out before the trial intervention while the final survey was carried out after three years of the trial intervention. Additionally, a subset sample of 372 participants from the final survey was tested for IgE, IgG and IgG4 antibody concentrations to S. mansoni adults worm antigen (SWA) and S. mansoni egg antigen (SEA) using ELISA. Infection by helminths (S. mansoni, N. americanus, T. trichiura and S. stercoralis) was diagnosed using real-time PCR, urine circulating cathodic antigen (CCA) and stool microscopy (Kato-Katz method) while malaria infection was diagnosed using microscopy. We analysed the relationship between helminth and malaria infections and KSHV seropositivity using regression modelling, allowing for survey design. At baseline, 56% of the participants were male while 48% of the participants were male in the final survey. The most prevalent helminth infection was S. mansoni (at baseline 52% and 34% in the final survey by microscopy, 86% by CCA and 50% by PCR in the final survey). KSHV seropositivity was 66% (baseline) and 56% (final survey) among those 1-12 years and >80% in those 13+ years in both surveys; malaria parasitaemia prevalence was 7% (baseline) and 4% (final survey). At baseline, individuals infected with S. mansoni (detected by microscopy) were more likely to be KSHV seropositive (aOR = 1.86 (1.16, 2.99) p = 0.012) and had higher anti-K8.1 antibody levels (acoefficient = 0.03 (0.01, 0.06) p = 0.02). In the final survey, S. mansoni (by microscopy, adjusted Odds Ratio (aOR = 1.43 (1.04-1.95), p = 0.028) and malaria parasitaemia (aOR = 3.49 (1.08-11.28), p = 0.038) were positively associated with KSHV seropositivity. Additionally, KSHV seropositive participants had higher S. mansoni-specific IgE and IgG antibody concentrations in plasma. Furthermore, HIV infected individuals on cART were less likely to be KSHV seropositive compared to HIV negative individuals (aOR = 0.46 (0.30, 0.71) p = 0.002). Schistosoma species skew the immune response towards Th2 and regulatory responses, which could impact on KSHV reactivation if co-infected with both organisms.

How Individual Variation in Host Tolerance Affects Competence to Transmit Parasites.

Tolerance, or the maintenance of host health or fitness at a given parasite burden, has often been studied in evolutionary and medical contexts, particularly with respect to effects on the evolution of parasite virulence and individual patient outcomes. These bodies of work have provided insight about tolerance for evolutionary phenomena (e.g., virulence) and individual health (e.g., recovering from an infection). However, due to the specific motivations of that work, few studies have considered the ecological ramifications of variation in tolerance, namely, how variation in forms of tolerance could mediate parasite movement through populations and even community-level disease dynamics. Tolerance is most commonly regarded as the relationship between host fitness and parasite burden. However, few if any studies have actually quantified host fitness, instead utilizing proxies of fitness as the response variables to be regressed against parasite burden. Here, we address how attention to the effects of parasite burden on traits that are relevant to host competence (i.e., the ability to amplify parasites to levels transmissible to other hosts/vectors) will enhance our understanding of disease dynamics in nature. We also provide several forms of guidance for how to overcome the challenges of quantifying tolerance in wild organisms.

The Complex Interplay of Parasites, Their Hosts, and Circadian Clocks.

Parasites have evolved various mechanisms to favor infection of their hosts and enhance the success of the infection. In this respect, time-of-day effects were found during the course of parasitic infections, which can be caused or controlled by circadian rhythms in the physiology of their vertebrate hosts. These include circadian clock-controlled rhythms in metabolism and in immune responses. Conversely, parasites can also modulate their hosts' behavioral and cellular rhythms. Lastly, parasites themselves were in some cases shown to possess their own circadian clock mechanisms, which can influence their capacity to infect their hosts. A better knowledge of the circadian regulation of host-parasite interactions will help in designing new preventive and therapeutic strategies for parasitic diseases.

What's eating you? Ixodes tick and related diseases, part 1: life cycle, local reactions, and lyme disease.

The Ixodes tick is an important arthropod vector in the transmission of human disease. This 3-part review highlights the biology of the Ixodes tick and manifestations of related diseases. Part 1 addresses the Ixodes tick biology and life cycle; local reactions; and Lyme disease, the most prevalent of associated diseases. Part 2 will address human granulocytic anaplasmosis, babesiosis, Powassan virus infection, Borrelia miyamotoi disease, tick-borne encephalitis, and tick paralysis. Part 3 will address coinfection with multiple pathogens as well as methods of tick-bite prevention and tick removal.

The roles of galectins in parasitic infections.

Galectins is a family of multifunctional lectins. Fifteen galectins have been identified from a variety of cells and tissues of vertebrates and invertebrates. Galectins have been shown to play pivotal roles in host-pathogen interaction such as adhesion of pathogens to host cells and activation of host innate and adaptive immunity. In recent years, the roles of galectins during parasite infections have gained increasing attention. Galectins produced by different hosts can act as pattern recognition receptors detecting conserved pathogen-associated molecular patterns of parasites, while galectins produced by parasites can modulate host responses. This review summarizes some recent studies on the roles of galectins produced by parasitic protozoa, nematodes, and trematodes and their hosts. Understanding the roles of galectins in host-parasite interactions may provide targets for immune intervention and therapies of parasitic infections.

Response to comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation".

According to the literature review, CO2 insufflation on parasitic myoma implantation is not well studied, and we concur that our study is related to "Morcellation-induced parasitic myomas." We did not compare CO2 insufflation to non-insufflation in our study. The reason is the efficacy of gasless laparoscopic myomectomy and morcellation is not well established and this modality is seldom performed. Moreover, the effects of pneumoperitoneum on mesothelial cells and the role of the entire peritoneal cavity as a cofactor in adhesion formation have become well established, the role of CO2 insufflation in the establishment of parasitic myomas has not yet been studied. As such, more in-depth and well-designed studies for the role of CO2 insufflation are needed.

Cancer and life-history traits: lessons from host-parasite interactions.

Despite important differences between infectious diseases and cancers, tumour development (neoplasia) can nonetheless be closely compared to infectious disease because of the similarity of their effects on the body. On this basis, we predict that many of the life-history (LH) responses observed in the context of host-parasite interactions should also be relevant in the context of cancer. Parasites are thought to affect LH traits of their hosts because of strong selective pressures like direct and indirect mortality effects favouring, for example, early maturation and reproduction. Cancer can similarly also affect LH traits by imposing direct costs and/or indirectly by triggering plastic adjustments and evolutionary responses. Here, we discuss how and why a LH focus is a potentially productive but under-exploited research direction for cancer research, by focusing our attention on similarities between infectious disease and cancer with respect to their effects on LH traits and their evolution. We raise the possibility that LH adjustments can occur in response to cancer via maternal/paternal effects and that these changes can be heritable to (adaptively) modify the LH traits of their offspring. We conclude that LH adjustments can potentially influence the transgenerational persistence of inherited oncogenic mutations in populations.

Plasmin in Parasitic Chronic Infections: Friend or Foe?

Plasmin is the final product of the fibrinolytic system, the physiological mechanism responsible for dissolving fibrin clots. Its broad-range proteolytic activity implies that interaction with fibrinolysis and recruitment of plasmin by blood and tissue parasites is an important mechanism that mediates the invasion and establishment of this kind of pathogen in the hosts. However, recent studies have linked an excess of plasmin generated by this interaction with serious pathological events at the vascular level, including the proliferation and migration of arterial wall cells, inflammation, and degradation of the extracellular matrix. Therefore, we present data that support the need to reconsider the role of plasmin, as well as its benefits or drawbacks, in the context of host-parasite relations.

Situación de la hidatidosis humana en la provincia de Santiago del Estero, República Argentina

La Hidatidosis Humana es una enfermedad grave, de evolución crónica, causadda por el estadio larval del echinococcus granulosus que en su ciclo biológico convierte al ser humano en un huésped intermediario, causando estragos en la salud de quien la padecen por las secuelas orgánicas y psicológicas ocasionadas por la implantación del tumores originados por dicho parásito, en diversos órganos de la economía.

Human Hydatidosis is a serious disease of chronic evolution caused by the larval stage of the Echinococcosis Granulosis. During its biological cycle it turns the human being into an intermediate host. It still causes havoc to the health of those who suffer from it because of the organic and psychological sequels caused by the implantation of tumors originate by such parasite.

Epaulet size and current condition in red-winged blackbirds: examining a semistatic signal, testosterone, immune function, and parasites.

Some sexually selected signals are thought to convey information about the current condition and genetic/epigenetic quality of the individual signaling, including the ability to resist parasites. However, it is unclear whether semistatic sexual signals that develop periodically and remain stable over protracted periods, such as avian breeding plumage, can relate to measures of current condition and health. We examined a semistatic signal (wing epaulet size) in male red-winged blackbirds (Agelaius phoeniceus) during the breeding season and looked for relationships between this trait and circulating testosterone (T), hematocrit, bacteria-killing ability (BKA) of the blood, and the infection status, richness, and abundance of four functional categories of parasite. We found that epaulet size was positively related to circulating levels of T and ectoparasite infections. We found no relationships between T and parasite infections. In adult males there was a negative relationship between T and BKA, whereas in yearling males there was no relationship. We found no evidence for a general reduction in immunocompetence in males with larger epaulets but rather an increase in susceptibility to specific types of parasites. Our results suggest that semistatic signals can be linked to measures of current condition, and we postulate that these relationships are modulated via activity levels related to breeding-season activities.

Health-related quality of life among school children with parasitic infections: findings from a national cross-sectional survey in Côte d'Ivoire.

BACKGROUND: Parasitic infections are still of considerable public health relevance, notably among children in low- and middle-income countries. Measures to assess the magnitude of ill-health in infected individuals, however, are debated and patient-based proxies through generic health-related quality of life (HrQoL) instruments are among the proposed strategies. Disability estimates based on HrQoL are still scarce and conflicting, and hence, there is a need to strengthen the current evidence-base. METHODOLOGY: Between November 2011 and February 2012, a national school-based cross-sectional survey was conducted in Côte d'Ivoire. Children underwent parasitological and clinical examination to assess infection status with Plasmodium and helminth species and clinical parameters, and responded to a questionnaire interview incorporating sociodemographic characteristics, self-reported morbidity, and HrQoL. Validity analysis of the HrQoL instrument was performed, assessing floor and ceiling effects, internal consistency, and correlation with morbidity scores. Multivariate regression models were applied to identify significant associations between HrQoL and children's parasitic infection and clinical status. PRINCIPAL FINDINGS: Parasitological examination of 4,848 children aged 5-16 years revealed Plasmodium spp., hookworm, Schistosoma haematobium, Schistosoma mansoni, Ascaris lumbricoides, and Trichuris trichiura prevalences of 75.0%, 17.2%, 5.7%, 3.7%, 1.8%, and 1.3%, respectively. Anemic children showed a significant 1-point reduction in self-rated HrQoL on a scale from 0 to 100, whereas no significant negative association between HrQoL and parasite infection was observed. The 12-item HrQoL questionnaire proofed useful, as floor and ceiling effects were negligible, internally consistent (Cronbach's alpha = 0.71), and valid, as revealed by significant negative correlations and associations with children's self-reported and clinically assessed morbidity. CONCLUSIONS/SIGNIFICANCE: Our results suggest that HrQoL tools are not sufficiently sensitive to assess subtle morbidities due to parasitic infection in Ivorian school-aged children. However, more advanced morbid sequelae (e.g., anemia), were measurable by the instrument's health construct. Further investigations on health impacts of parasitic infection among school-aged children and refinement of generic HrQoL questionnaires are warranted.

Diagnóstico parasitológico e molecular de enteroparasitos entre crianças residentes e funcionários de uma institução beneficente para menores no município de Niterói-RJ, Brasil / Parasitological and molecular diagnosis of enteroparasites among resident children and employees of a child care institution at Niterói city, RJ, Brazil

Os enteroparasitos são causa importante de agravos à saúde humana e podem interferir de forma significativa no desenvolvimento infantil. Embora as formas de transmissão sejam bemdocumentadas, a desinformação e as precárias condições socioeconômicas de alguns segmentos da população ainda são fatores que contribuem para a manutenção de parasitos no País, viabilizando a transmissão. Este estudo foi realizado entre crianças residentes e funcionários de uma instituiçãofilantrópica religiosa, situada na cidade de Niterói, Rio de Janeiro, consistindo em um ciclo de palestras educativas, seguido da coleta de amostras fecais para diagnóstico coproparasitológico.Foram coletadas 68 amostras fecais frescas e encontrados enteroparasitos em 41 delas (60 por cento),sendo o Blastocystis hominis o parasito mais prevalente (44 por cento). Adicionalmente, sete amostrasforam positivas para o complexo Entamoeba histolytica/E. dispar, sendo uma confirmada como E. histolytica pelo ELISA para pesquisa de coproantígeno. Em 37 amostras de fezes foi pesquisadaa presença de E. histolytica e E. dispar pela técnica de Nested-PCR. Entre essas, 12 (32 por cento) amplificaram um fragmento de 195 pb quando utilizados primers específicos para E. dispar, não havendo amplificação de qualquer produto com os primers de E. histolytica. Estudo feito no entornoda instituição revelou acúmulo de lixo e a presença de saídas de esgoto no peridomicílio, as quais desembocavam nas proximidades da área de lazer das crianças. É possível que esses pontos sejam responsáveis pela contaminação do solo e mesmo incriminados como uma das possíveis fontes deinfestação para as crianças.

Intestinal parasites are important agents of human diseases, besides being responsible for impairingchildhood development. Although transmission is well known, lack of information and precarioussocial and economic conditions are risk factors that allow maintenance of parasite cycles, favoringtransmission. This study was carried out among resident children and employees of a Catholic Institution, located in Niterói, Rio de Janeiro, and consisted of delivering lectures and collectingfresh stool samples, which were processed through the Willis and Hoffman, Pons and Janermethods. Enteroparasites were found in 41 samples (60 percent) and Blastocystis hominis was the mostprevalent (44 percent). Additionally, in seven samples where microscopic examination was positive forthe E. histolytica/E. dispar complex an ELISA was employed to detect E. histolytica and only onereacted positively in the immunoassay. In 37 samples a Nested-PCR was carried out for detectionof E. histolytica and E. dispar and in 12 samples (32 percent) a product with 195 bp was observed usingE. dispar primers, while there was no amplification product with E. histolytica specific primers. As the Institution has a good pattern of hygiene not related with the results, a superficial analysis of its peripheral area was carried out and showed lots of garbage in the neighborhood and sewage outflowinto the play area of the Institution. We concluded that these points may be responsible for the soil contamination and could be incriminated as one of the sources of infection in the children.

The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.

The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.