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Background. Diarrhea causes enormous morbidity and mortality in developing countries, yet the relative importance of multiple potential enteropathogens has been difficult to ascertain. Methods. We performed a longitudinal cohort study from birth to 1 year of age in 147 infants in Dhaka, Bangladesh. Using multiplex polymerase chain reaction, we analyzed 420 episodes of diarrhea and 1385 monthly surveillance stool specimens for 32 enteropathogen gene targets. For each infant we examined enteropathogen quantities over time to ascribe each positive target as a probable or less-likely contributor to diarrhea. Results. Multiple enteropathogens were detected by the first month of life. Diarrhea was associated with a state of overall pathogen excess (mean number of enteropathogen gene targets (±SE), 5.6 ± 0.1 vs 4.3 ± 0.1 in surveillance stool specimens; P < .05). After a longitudinal, quantitative approach was applied to filter out less-likely contributors, each diarrheal episode still had an average of 3.3 probable or dominant targets. Enteroaggregative Escherichia coli, Campylobacter, enteropathogenic E. coli, rotavirus, and Entamoeba histolytica were the most frequent probable contributors to diarrhea. Rotavirus was enriched in moderate to severe diarrheal episodes. Conclusions. In this community-based study diarrhea seemed to be a multipathogen event and a state of enteropathogen excess above a high carriage baseline.

Conventional approaches to the diagnosis of infectious diarrhea must include several modalities to detect an array of potential viruses, bacteria, and parasites. We will provide a general overview of the wide range of diagnostic modalities available for enteropathogens, briefly discuss some of the limitations of conventional methods, and then focus on new molecular methods, including real-time PCR and next-generation sequencing. In particular, we will discuss quantitation of pathogen load with these techniques. We will then describe examples whereby novel diagnostics may help illuminate the etiology of infectious diarrhea, where they may not, and how they may benefit studies of immunity to enteric infections.

Leptin is an adipocytokine that links nutrition to immunity. Previous observation that a genetic polymorphism in the leptin receptor affected susceptibility to Entamoeba histolytica infection led to the hypothesis that leptin signaling has a protective role during intestinal amebic infection. In this study we show that mice lacking the functional leptin receptor developed devastating mucosal destruction after E. histolytica infection. Bone marrow chimera experiments demonstrated that leptin receptor expressed on hematopoietic cells was not sufficient to confer resistance. Similarly, peripheral knockout of the leptin receptor rendered animals susceptible, indicating that central expression of the leptin receptor was not sufficient to confer protection. The site of leptin action was localized to the gut via an intestinal epithelium-specific deletion of the leptin receptor, which rendered mice susceptible to infection and mucosal destruction by the parasite. Mutation of tyrosine 985 or 1138 in the intracellular domain of the leptin receptor, which mediates signaling through the SH2-containing tyrosine phosphatase/extracellular signal-regulated kinase (SHP2/ERK) and signal transducer and activator of transcription 3 (STAT3) pathways, respectively, demonstrated that both were important for mucosal protection. We conclude that leptin-mediated resistance to amebiasis is via its actions on intestinal epithelium rather than hematopoietic cells or the brain, and requires leptin receptor signaling through both the STAT3 and SHP2/ERK pathways.

Giardia lamblia is the most prevalent human intestinal protozoan worldwide, but only a minority of infections result in diarrhea. We tested here whether the 2 major G. lamblia genotypes, assemblages A and B, differ in their propensity to cause disease. To determine whether an association exists between infection with assemblage A or B and diarrhea, 2534 Bangladeshi patients were enrolled in a case-control study. A total of 322 Giardia infections were identified and assayed for genotype by real-time polymerase chain reaction. Higher odds ratios for diarrhea were observed for assemblage A and A2 infections, whereas higher parasite DNA loads and a higher overall prevalence were observed for assemblage B infections. Our findings indicate that genotypic differences in virulence and fecundity may help to explain why not every Giardia infection results in disease, but they need to be confirmed in other urban populations of the developing world

The mechanisms whereby certain mouse strains develop persistent intestinal infection with Entamoeba histolytica remain unclear. In this work, we characterized the kinetic pattern of cytokine responses during the course of natural infection in CBA mice and showed that intracecal amebic infection led to a rapid and sustained upregulation of Th2 (IL-4, IL-5, IL-13) and Th17 cytokine responses while Th1 cytokines, IL-12p35 and interferon (IFN)-γ, were suppressed. Depletion of IL-4 cleared infection by 14 days post-challenge, and this clearance correlated with and was mediated by IFN-γ. The protective role for IFN-γ was not strain-specific, as 129 background IFN-γR knockout mice exhibited a higher infection rate than their wild-type littermates. These studies indicate that IL-4 plays a critical pathogenic role in the persistence of E. histolytica infection through suppression of protective IFN-γ and provide a possible explanation for why certain humans spontaneously clear amebiasis while others progress to invasive disease.

Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in young infants in sub-Saharan Africa and to describe their antibiotics resistance profile. Between September 2016 and April 2018 we implemented an observational study in two rural sites in Burkina Faso and Tanzania enrolling young infants aged 0-59 days old with serious invasive infection. Blood samples underwent blood culture and molecular biology. In total 634 infants with clinical diagnosis of serious invasive infection were enrolled and 4.2% of the infants had a positive blood culture. The most frequent pathogens identified by blood culture were Klebsiella pneumonia and Staphylococcus aureus, followed by Escherichia coli. Gram-negative isolates were only partially susceptible to first line WHO recommended treatment for neonatal sepsis at community level. A total of 18.6% of the infants were PCR positive for at least one pathogen and Escherichia coli and Staphylococcus aureus were the most common bacteria detected. Among infants enrolled, 60/634 (9.5%) died. Positive blood culture but not positive PCR was associated with risk of death. For most deaths, no pathogen was identified either by blood culture or molecular testing, and hence a causal agent remained unclear. Mortality was associated with low body temperature, tachycardia, respiratory symptoms, convulsions, history of difficult feeding, movement only when stimulated or reduced level of consciousness, diarrhea and/or vomiting. While Klebsiella pneumonia and Staphylococcus aureus, as well as Escherichia coli were pathogens most frequently identified in infants with clinical suspicion of serious invasive infections, most cases remain without definite diagnosis, making more accurate diagnostic tools urgently needed. Antibiotics resistance to first line antibiotics is an increasing challenge even in rural Africa.

Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community—rather than the relatively rarer circumstances that lead to hospitalization—during the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings.

Resistance to the establishment of intestinal Entamoeba histolytica infection is dependent on the inbred mouse strain. In this work we used the inbred strains B6 (resistant), CBA (susceptible), B6CBAF 1 and a backcross of B6CBAF 1 to CBA to further examine the genetic basis of resistance. Mouse genotype was assessed with single nucleotide polymorphism and microsatellite markers and infection assessed by culture 9 days after intracecal E. histolytica challenge. The backcross population showed a male predisposition to culture positivity ( P <0.002). F1 genotype at two loci on chromosomes 1 and 2 exhibited suggestive linkage with resistance to infection ( P =0.0007 and 0.0200). Additional suggestive quantitative trait locus were observed on chromosomes 1, 9 and 13 for cecal parasite antigen load and histologic evidence of inflammation. Infection in C3H × B6 recombinant inbred mice supported the mapping data. Candidate B6 genes on chromosomes 1 and 2 were examined by microarray analysis of epithelial tissues from B6 vs CBA mice. This work shows a male predisposition to intestinal amebiasis and suggests that relatively few B6 loci can confer resistance in inbred mice. Future identification of regional candidate genes has implications for understanding the human variability to amebic infection.

Background. As the global polio eradication initiative prepares to cease use of oral polio vaccine (OPV) in 2020, there is increasing interest in understanding if oral vaccination provides non-specific immunity to other infections so that the consequences of this transition can be effectively planned for and mitigated. Methods. Data were collected from infants in an urban slum in Bangladesh (Mirpur, Dhaka) as part of the performance of rotavirus and oral polio vaccines in developing countries (PROVIDE) study. Following vaccination with trivalent oral polio vaccine (tOPV) at 6, 10, and 14 weeks, infants were randomly assigned to receive tOPV (n = 315) or inactivated polio vaccine (IPV) (n = 299) at 39 weeks. Episodes of diarrhea were documented through clinic visits and twice-weekly house visits through 52 weeks. In sum, 14 pathogens associated with diarrhea were analyzed with TaqMan Array Cards. Results. Although the proportion of children experiencing diarrhea was not different between the tOPV and IPV groups (P = .18), the number of days with diarrhea (P = .0037) and the number of separate diarrheal episodes (P = .054) trended lower in the OPV arm. Etiological analysis revealed that male tOPV recipients were less likely to have diarrhea of bacterial etiology (P = .0099) compared to male IPV recipients but equally likely to experience diarrhea due to viruses (P = .57) or protozoa (P = .14). Among the 6 bacterial enteric pathogens tested, only Campylobacter jejunil coli detection was significantly reduced in the OPV arm (P = .0048). Conclusions. Our results suggest that OPV may cause nonspecific reductions in mortality, as has been studied elsewhere, by reducing etiology-specific diarrheal burden. This is likely driven by reductions in bacterial diarrhea. Further study of nonspecific OPV effects before global cessation is supported. Clinical Trials Registration. NCT01375647.

Infection with Entamoeba histolytica can lead to amebic colitis and to complications including liver abscess. This review summarizes recent research on the pathogenesis and treatment of infection and the prospects for the development of a vaccine. A mucosal IgA response can produce partial, protective immunity to infection with E. histolytica . Diarrheal diseases continue to be major causes of morbidity and mortality in children in developing countries. For example, in Bangladesh 1 in 30 children dies of diarrhea or dysentery by his or her fifth birthday. 1 In developed countries the microorganisms that cause diarrheal disease remain of concern because of their potential use as bioterrorist agents. Bacillary dysentery is most commonly caused by microorganisms belonging to the genus shigella, whereas amebic dysentery is caused by the protozoan parasite Entamoeba histolytica . The annual number of shigella infections throughout the world is believed to be approximately 164 million. 2 Estimates of E. histolytica . . .