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Giardiasis is an intestinal infection that affects more than two hundred million people annually worldwide; it is caused by the flagellated protozoan Giardia duodenalis. In tropical countries and in low or middle-income settings, like Brazil, its prevalence can be high. There is currently no systematic review on the presence of G. duodenalis in patients, animals or water sources in Brazil. This systematic review was performed according to recommendations established by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). As databases for our searches, we have used PubMed, Embase, Scopus and the Brazilian database SciELO using the keywords «Giardia*» and «Brazil». This systematic review identified research studies related to G. duodenalis in water, giardiasis in animals, prevalence of giardiasis across Brazilian regions, genotyping of strains isolated in humans, and giardiasis in indigenous populations. We also propose a network of G. duodenalis transmission in Brazil based on genotypes analyses. This is the first time within the last twenty years that a review is being published on the occurrence of G. duodenalis in Brazil, addressing relevant issues such as prevalence, molecular epidemiology and analytical methods for parasite detection.

Parasitic diseases cause significant morbidity and mortality in the developing and underdeveloped countries. No efficacious vaccines are available against most parasitic diseases and there is a critical need for developing novel vaccine strategies for care. IL-21 is a pleiotropic cytokine whose functions in protection and immunopathology during parasitic diseases have been explored in limited ways. IL-21 and its cognate receptor, IL-21R, are highly expressed in parasitized organs of infected humans as well in murine models of the human parasitic diseases. Prior studies have indicated the ability of the IL-21/IL-21R signaling axis to regulate the effector functions (e.g., cytokine production) of T cell subsets by enhancing the expression of T-bet and STAT4 in human T cells, resulting in an augmented production of IFN-γ. Mice deficient for either IL-21 ( ) or IL-21R ( ) showed significantly reduced inflammatory responses following parasitic infections as compared with their WT counterparts. Targeting the IL-21/IL-21R signaling axis may provide a novel approach for the development of new therapeutic agents for the prevention of parasite-induced immunopathology and tissue destruction.

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia- associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia -mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors. Giardia lamblia intestinal infection is independently associated with faltering linear growth in children in low-middle income countries, yet the mechanistic pathway has not been clearly identified. Authors utilise the MAL-ED cohort, and a gnotobiotic murine model, to explain Giardia -induced effects on childhood growth.

Bluetongue (BT) is a vector-borne disease affecting wild and domestic ruminants in many parts of the world. Although bluetongue virus (BTV) is widespread in ungulates in Africa, available epidemiological information on BT in this continent is limited. This systematic review and meta-analysis aimed to estimate the seroprevalence of BTV and summarize information on associated risk factors in domestic ruminants and camels in Africa. Systematic searches were conducted from the inception of the database to November 2022 on PubMed/MEDLINE, ScienceDirect, Web of Science, and Google/Google Scholar. Forty-four eligible publications were identified, published in the range from 1973 to 2020, and statistically analyzed. The pooled overall seroprevalence of BTV was 45.02% (95% confidence interval [CI]: 36.00-54.00%). The pooled seroprevalence was 49.70% (95% CI: 34.50-65.00%) in cattle, 47.00% (95% CI: 29.90-64.50%) in goats, 40.80% (95% CI: 19.60-63.90%) in camels, and 36.30% (95% CI: 29.00-44.90%) in sheep. The pooled seroprevalence decreased after 1990 and increased again after 2010. The highest pooled overall seroprevalence was found in the southeastern region, and the highest pooled overall seroprevalence was obtained by Competitive Enzyme-Linked Immunosorbent Assay. Finally, the seroprevalence in females (53.30%, 95% CI: 34.80-71.00%) was significantly higher than in males (28.10%, 95% CI: 17.40-40.30%) (p < 0.05). We showed that antibodies against BTV were common in African ruminants and camels. Monitoring the seroprevalence of BTV, as well as systematic and continuous surveillance of the Culicoides population, are encouraged to prevent and control the spread of BT.

Background The mechanisms underlying the clinical outcome disparity during human infection with Giardia duodenalis are still unclear. In recent years, evidence has pointed to the roles of host factors as well as parasite’s genetic heterogeneity as major contributing factors in the development of symptomatic human giardiasis. However, it remains contested as to how only a small fraction of individuals infected with G. duodenalis develop clinical gastrointestinal manifestations, whereas the majority of infected individuals remain asymptomatic. Here, we demonstrate that diversity in the fecal microbiome correlates with the clinical outcome of human giardiasis. Methods The genetic heterogeneity of G. duodenalis clinical isolates from human subjects with asymptomatic and symptomatic giardiasis was determined using a multilocus analysis approach. We also assessed the genetic proximity of G. duodenalis isolates by constructing phylogenetic trees using the maximum likelihood. Total genomic DNA (gDNA) from fecal specimens was utilized to construct DNA libraries, followed by performing paired-end sequencing using the HiSeq X platform. The Kraken2-generated, filtered FASTQ files were assigned to microbial metabolic pathways and functions using HUMAnN 3.04 and the UniRef90 diamond annotated full reference database (version 201901b). Results from HUMAnN for each sample were evaluated for differences among the biological groups using the Kruskal–Wallis non-parametric test with a post hoc Dunn test. Results We found that a total of 8/11 (72.73%) human subjects were infected with assemblage A (sub-assemblage AII) of G. duodenalis , whereas 3/11 (27.27%) human subjects in the current study were infected with assemblage B of the parasite. We also found that the parasite’s genetic diversity was not associated with the clinical outcome of the infection. Further phylogenetic analysis based on the tpi and gdh loci indicated that those clinical isolates belonging to assemblage A of G. duodenalis subjects clustered compactly together in a monophyletic clade despite being isolated from human subjects with asymptomatic and symptomatic human giardiasis. Using a metagenomic shotgun sequencing approach, we observed that infected individuals with asymptomatic and symptomatic giardiasis represented distinctive microbial diversity profiles, and that both were distinguishable from the profiles of healthy volunteers. Conclusions These findings identify a potential association between host microbiome disparity with the development of clinical disease during human giardiasis, and may provide insights into the mechanisms by which the parasite induces pathological changes in the gut. These observations may also lead to the development of novel selective therapeutic targets for preventing human enteric microbial infections. Graphical Abstract

About the Authors: Camila H. Coelho Affiliations Department of Biology, Georgetown University, Washington, DC, United States of America, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America Steven M. Singer * E-mail: steven.singer@georgetown.edu Affiliation: Department of Biology, Georgetown University, Washington, DC, United States of America ORCID logo http://orcid.org/0000-0001-5719-7535 Citation: Coelho CH, Singer SM (2018) Recent advances in the Giardia–host relationship reveal danger lurking behind the smile. In addition to ADI and OCT, Ma’ayeh and colleagues report that both GS and WB release 13 different cathepsin B proteases, and Ortega-Pierres and colleagues [15] have recently demonstrated that a specific Giardia protease from the WB strain (named by the authors as giardiapain-1) can induce apoptosis in rat intestinal epithelial cells (IEC-6) and Madin Darby Canine Kidney (MDCK) epithelial cells and degrade proteins at tight junctions. [...]the small intestine is home to a robust microbiota, and several studies suggest that interactions among Giardia, the host, and these additional microbes all contribute to the eventual outcome of Giardia infection [19, 20]. Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia.

Metronidazole is the most commonly used drug for the treatment of giardiasis in humans. In spite of its therapeutic efficacy for giardiasis, low patient compliance, especially in children, side effects, and the emergence of metronidazole-resistant strains may restrict its use. Albendazole has been used to treat Giardia duodenalis infections in recent years. However, efficacy studies in vivo and in vitro have produced diverse results as to its effectiveness. A moderately benign side effect profile, combined with established efficacy against many helminths, renders it promising for treatment of giardiasis in humans. We performed a search in the PubMed, Scopus, EMBASE, the ISI Web of Science, LILIACS, and Cochrane Controlled Trials Register for trials published before February 2010 as well as in references of relevant research and review articles. Eight randomized clinical trials (including 900 patients) comparing the effectiveness of albendazole with that of metronidazole were included in meta-analysis. After extracting and validating the data, the pooled risk ratio (RR) was calculated using an inverse-variance random-effects model. Albendazole was found to be equally as effective as metronidazole in the treatment of giardiasis in humans (RR 0.97; 95% CI, 0.93, 1.01). In addition, safety analysis suggested that patients treated with albendazole had a lower risk of adverse effects compared with those who received metronidazole (RR 0.36; 95% CI, 0.10, 1.34), but limitations of the sample size precluded a definite conclusion. The effectiveness of albendazole, when given as a single dose of 400 mg/day for 5 days, was comparable to that of metronidazole. Patients treated with albendazole tended to have fewer side effects compared with those who took metronidazole. Given the safety, effectiveness, and low costs of albendazole, this drug could be potentially used as an alternative and/or a replacement for the existing metronidazole therapy protocols in the treatment of giardiasis in humans.

The immune system has numerous mechanisms that it can use to combat pathogens and eliminate infections. Nevertheless, studies of immune responses often focus on single pathways required for protective responses. We applied microarray analysis of RNA in order to investigate the types of immune responses produced against infection with the intestinal pathogen Giardia duodenalis . Infection with G. duodenalis is one of the most common causes of diarrheal disease in the world. While several potential antiparasitic effector mechanisms, including complement lysis, nitric oxide (NO), and α-defensin peptides, have been shown to inhibit parasite growth or kill Giardia in vitro , studies in vivo have thus far shown clear roles only for antibody and mast cell responses in parasite control. A total of 96 transcripts were identified as being upregulated or repressed more than 2-fold in the small intestine 10 days following infection. Microarray data were validated using quantitative PCR. The most abundant category of transcripts was antibody genes, while the most highly induced transcripts were all mast cell proteases. Among the other induced transcripts was matrix metalloprotease 7 (Mmp7), the protease responsible for production of mature α-defensins in mice. While infections in Mmp7-deficient mice showed only a small increase in parasite numbers, combined genetic deletion of Mmp7 and inducible nitric oxide synthase (iNOS, Nos2) or pharmacological blockade of iNOS in Mmp7-deficient mice resulted in significant increases in parasite loads following infection. Thus, α-defensins and NO are redundant mechanisms for control of Giardia infections in vivo . IMPORTANCE The immune system has multiple weapons which it uses to help control infections. Many infections result in activation of several of these response mechanisms, but it is not always clear which responses actually contribute to control of the pathogen and which are bystander effects. This study used the intestinal parasite Giardia duodenalis to examine the redundancy in immune responses during infections in mice. Our results showed that at least four distinct mechanisms are activated following infections. Furthermore, by blocking two pathways at the same time, we showed that both mechanisms contribute to control of the infection, whereas blocking single responses showed no or minimal effect in these cases. The immune system has multiple weapons which it uses to help control infections. Many infections result in activation of several of these response mechanisms, but it is not always clear which responses actually contribute to control of the pathogen and which are bystander effects. This study used the intestinal parasite Giardia duodenalis to examine the redundancy in immune responses during infections in mice. Our results showed that at least four distinct mechanisms are activated following infections. Furthermore, by blocking two pathways at the same time, we showed that both mechanisms contribute to control of the infection, whereas blocking single responses showed no or minimal effect in these cases.

The zoonotic potential of giardiasis, as proposed by WHO since the late 70's, has been largely confirmed in this century. The genetic assemblages A and B of Giardia duodenalis are frequently isolated from human and canine hosts. Most of the assemblage A strains are not infective to adult mice, which can limit the range of studies regarding to biology of G. duodenalis, including virulence factors and the interaction with host immune system. This study aimed to determine the infectivity in mice of an assemblage A Giardia duodenalis strain (BHFC1) isolated from a dog and to classify the strain in sub-assemblages (AI, AII, AIII) through the phylogenetic analysis of beta-giardin (bg), triose phosphate isomerase (tpi) and glutamate dehydrogenase (gdh) genes. In addition, the proteomic profile of soluble and insoluble protein fractions of trophozoites was analyzed by 2D-electrophoresis. Accordingly, trophozoites of BHFC1 were highly infective to Swiss mice. The phylogenetic analysis of tpi and gdh revealed that BHFC1 clustered to sub-assemblage AI. The proteomic map of soluble and insoluble protein fractions led to the identification of 187 proteins of G. duodenalis, 27 of them corresponding to hypothetical proteins. Considering both soluble and soluble fractions, the vast majority of the identified proteins (n = 82) were classified as metabolic proteins, mainly associated with carbon and lipid metabolism, including 53 proteins with catalytic activity. Some of the identified proteins correspond to antigens while others can be correlated with virulence. Besides a significant complementation to the proteomic data of G. duodenalis, these data provide an important source of information for future studies on various aspects of the biology of this parasite, such as virulence factors and host and pathogen interactions.