Biology subjects

Haque, R.

Publications and source records attributed to Haque, R..

At least 19 recordsLinked to original sources

bioRxiv2026

A cognitive representation in primary visual cortex modulated by vision

Primary visual cortex (V1) is a critical substrate for mammalian vision. Traditionally, visual inputs are thought to be the main drivers of V1 activity, with internal signals playing a modulatory role. Here we show that this relationship is inverted for a large fraction of V1 neurons. In rats completing a navigation task in darkness, these neurons encoded progress along physically distinct paths with a shared turn structure. Under illumination, visual stimuli gain-modulated this path-invariant activity rather than replacing it with stimulus-driven responses. Path-invariant V1 neurons were also preferentially coordinated with hippocampal ensembles during sharp-wave ripples, linking them to a brain-wide network involved in learning. These findings establish that an internal model of the world can serve as a primary driver of activity in sensory cortex.

neuroscience↗

bioRxiv2026

Unobserved Sequence Space Has Many Functional Proteins

The distribution of functional proteins across amino acid sequence space, and the proportion of functional space covered by existing proteins, remains unknown. Illuminating this distribution is integral to understanding protein evolution and advancing protein design. The recent explosion of AI/ML protein design tools presents an opportunity to explore protein sequence space distant from extant proteins, but these tools remain poorly validated. Here, we determine that portions of protein sequence space, despite being unobserved in nature, contains many functional proteins that cannot be predicted accurately in silico. We measure experimental fitness of highly diverse proteins across 3 families and assemble the largest known dataset of diverse, functionally labeled natural protein orthologs and new-to-nature proteins. For each family, we observe many functional, new-to-nature sequences with low amino acid identity to existing orthologs. Sequence-based scoring metrics, especially Potts models and protein language models, provide accurate but inconsistent and highly correlated function predictions. Empirical protein fitness landscapes are rugged, and predictions of function do not consistently capture either the local shape or global trends of the empirical fitness landscapes. Finally, we find extensive functional sequence space between existing proteins in each family, providing experimental support for the hypothesis that natural protein sequences explored by evolution represent a minuscule fraction of all possible functional sequences.

synthetic biology↗

bioRxiv2026

Gut Bacteria Prime Host Antibody Responses Against Ingested Dietary Fiber Glycans

Protein and glycan antigens synthesized by gut microbes stimulate circulating and secreted antibody production. Despite continuous exposure of hosts to the plant glycans that constitute dietary fiber, it remains unclear whether these foreign structures induce mucosal immune responses. We report that humans and mice generate antibodies specific for common glycans in plant foods. Oral exposure to individual fiber types induced T cell-independent, glycan-specific IgM and IgA. The induction of anti-fiber antibodies required colonization by particular microbes, since germ-free mice and mice harboring representatives of several bacterial phyla failed to respond. The OMM12 model community was sufficient to rescue antibody induction, and dietary fiber glycans were detected on the surfaces of OMM12 microbes, suggesting a route by which bacteria trigger anti-fiber immune responses. Our results reveal a direct impact of dietary fiber on the adaptive immune system with implications for host control of fiber breakdown by bacteria in the gut lumen.

immunology↗

bioRxiv2026

Screening of Potential Vaccine Candidate and Sera Based Diagnostic Markers from N-linked Surface Glycoproteins of Entamoeba histolytica

Pathogenesis inflicted by Entamoeba histolytica causes amoebic diarrhea and liver abscesses and is one of the leading causes of mortality from parasitic disease worldwide. Preventive therapeutics in the form of a vaccine could be highly effective at providing umbrella protection for a vulnerable community. In this study, a group of ten putative hypothetical surface N-linked glycoproteins was examined to assess their potential as vaccine candidates and/or diagnostic markers against amoebic intestinal colitis and liver abscesses. To evaluate the immunogenicity of putative surface glycoproteins, we used Entamoeba histolytica-infected patients sera from Bangladesh and then assessed the titer of antibody these glycoproteins elicited in patients by enzyme-linked immunosorbent assay (ELISA) and immunoblot. Based on this study, eight of ten surface glycoproteins were found immunogenic, as specific antibodies against these glycoproteins were detected in patients sera. Three of the immunogenic glycoproteins showed strong IgG antibody responses in both patients with intestinal amoebiasis and those with liver abscess. On the other hand, the other two glycoproteins showed the presence of specific serum antibodies exclusively in patients with amoebic liver abscesses, not in individuals with amoebic colitis. The remaining two glycoproteins showed more specific sera antibodies against ALA, but the preference was not very distinct. Immunolocalization with a specific antibody against the most immunogenic glycoproteins further confirmed their presence in the cell membrane. This differential immunogenicity of these glycoproteins in the two groups of patients qualifies them to become prospective sera-based diagnostic markers and also has the potential to become vaccine candidates for amoebiasis protection.

immunology↗

bioRxiv2026

Meta-learning is expressed through altered prefrontal cortical dynamics

Learning where and when rewards like food and water are available is essential for survival1,2. In the simplest cases where resource availability is stable, animals can learn reward contingencies by integrating outcomes across repeated samples of each possible action. In more natural settings, however, reward availability is governed by structured higher-order rules such as depletion and repletion over time. To adapt flexibly to such changing environments, optimal choices require meta-learning wherein animals learn how to learn from external feedback, ultimately enabling them to infer the underlying reward structure from abstract, generalizable rules rather than relying solely on recent outcomes3,4. The existence of meta-learning in animal behavior is well established3-8, yet the neural circuits and computations that implement it remain poorly understood9-11. Here we investigated meta-learning using a spatial foraging task in which rats acquired a depletion-repletion rule that regulated reward availability, and carried out longitudinal, high-density recordings from the medial prefrontal cortex (mPFC). We show that meta-learning engages specific, systematic changes in mPFC neural dynamics that embed the learned rule and thereby alter how the network learns action values from reward outcomes. These dynamics are based on mixed coding of task structure and value in individual mPFC neurons. At the population level, this coding organizes into low-dimensional dynamical motifs that generalize across task conditions. As meta-learning progresses, these motifs are reshaped to instantiate both rule-guided inference of future states before outcome delivery and rule-based value updating during the outcome period. These results indicate that meta-learning sculpts pre-existing prefrontal dynamics to support the acquisition of new, generalizable reward-learning strategies.

neuroscience↗

bioRxiv2025

Environmental and Maternal Imprints on Infant Gut Metabolic Programming

Early life is a critical period for immune and metabolic programming, but developmental patterns remain underexplored in populations from low- and middle-income countries. Here, we profiled the microbiome and metabolome of 55 Bangladeshi mother-infant dyads over the first six months of life. Importantly, we observed an increase in microbially-derived bile amidates and N-acyl lipids with age in conjunction with reads matching the bile salt hydrolase/transferase (bsh) gene. While microbial source tracking confirmed maternal fecal seeding, a substantial environmental contribution was also highlighted. Differences in infant fecal metabolic profiles were associated with delivery mode, maternal milk composition, household assets, and household-level water treatment. C-section delivery and untreated drinking water were linked to transient metabolic differences, including increases in bile amidates, N-acyl lipids, and other host-microbe co-metabolic products, including acylcarnitines. Multi-omics analysis revealed specific microbial-metabolite relationships, highlighting how early environmental and maternal living circumstances shape metabolic gut programming through the microbiome.

microbiology↗

bioRxiv2024

A Blueprint of Sex-Specific Neuronal Regulation in the C. elegans Nervous System at Single-Cell Resolution

Sex-specific behaviors are often attributed to differences in neuronal wiring and molecular composition, yet how genetic sex shapes the molecular architecture of the nervous system at the individual neuron level remains unclear. Here, we use single-cell RNA sequencing to profile the transcriptome of sex-shared neurons in adult Caenorhabditis elegans males and hermaphrodites. We uncover widespread molecular dimorphism across the nervous system, including in previously unrecognized neuron-types such as the touch receptors. Neuropeptides and signaling-related genes exhibit strong sex-biased expression, particularly in males, reinforcing the notion that neuropeptides are crucial for diversifying connectome outputs. Despite these differences, neurotransmitter identities remain largely conserved, indicating that functional dimorphism arises through modulatory, not identity-defining, changes. We show that sex-biased expression of neurotransmitter-related genes correlates with bias in outgoing synaptic connectivity and identify regulatory candidates for synaptic wiring, including both shared and sex-specific genes. This dataset provides a molecular framework for understanding how subtle regulatory differences tune conserved circuits to drive sex-specific behaviors.

neuroscience↗

bioRxiv2024

Examining the relationship between psychosocial adversity and inhibitory control: an fMRI study of children growing up in extreme poverty

Exposure to psychosocial adversity (PA) is associated with poor behavioral, physical, and mental health outcomes in adulthood. As these outcomes are related to alterations in developmental processes, growing evidence suggests that deficits in executive functions-inhibitory control in particular-may, in part, explain this relationship. However, literature examining the development of inhibitory control has been based on children in higher resource environments, and little is known how low resource settings might exacerbate the link between inhibitory control and health outcomes. In this context, we collected fMRI data during a Go/No-Go inhibitory control task and PA variables for 68 children 5 to 7 years of age living in Dhaka, Bangladesh, an area with a high prevalence of PA. The childrens mothers completed behavioral questionnaires to assess the childs PA and their own PA. Whole-brain activation underlying inhibitory control was examined using the No-Go versus Go contrast, and associations with PA variables were assessed using whole-brain regressions. Childhood neglect was associated with weaker activation in the right posterior cingulate, whereas greater family conflict, economic stress, and maternal PA factors were associated with greater activation in the left medial frontal gyrus, right superior and middle frontal gyri, and left cingulate gyrus. These data suggest that neural networks supporting inhibitory control processes may vary as a function of exposure to different types of PA, particularly between those related to threat and deprivation. Furthermore, increased activation in children with greater PA may serve as a compensatory mechanism, allowing them to maintain similar behavioral task performance.

neuroscience↗

bioRxiv2024

Regional specialization manifests in the reliability of neural population codes

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

neuroscience↗

bioRxiv2023

Modulation by NPYR underlies experience-dependent, sexually dimorphic learning

The evolutionary paths taken by each sex within a given species sometimes diverge, resulting in behavioral differences. Given their distinct needs, the mechanism by which each sex learns from a shared experience is still an open question. Here, we reveal sexual dimorphism in learning: C. elegans males do not learn to avoid the pathogenic bacteria PA14 as efficiently and rapidly as hermaphrodites. Notably, neuronal activity following pathogen exposure was dimorphic: hermaphrodites generate robust representations, while males, in line with their behavior, exhibit contrasting representations. Transcriptomic and behavioral analysis revealed that the neuropeptide receptor npr-5, an ortholog of the mammalian NPY receptor, regulates male learning by modulating neuronal activity. Furthermore, we show the dependency of the males decision-making on their sexual status and demonstrate the pivotal role of npr-5 as a modulator of incoming sensory cues. Taken together, we portray sex-specific plasticity in behavior toward a shared experience by modulating learning.

neuroscience↗

bioRxiv2023

Sex-Specific Developmental Gene Expression Atlas Unveils Dimorphic Gene Networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we created a comprehensive gene expression atlas for both sexes of the nematode Caenorhabditis elegans across development. By comparing the transcriptome of pure populations of hermaphrodites and males from early larval stages to adulthood, we discovered numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and GPCRs. We identified INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually-dimorphic roles in temperature sensation, survival in cold temperatures, resilience against high hydrogen peroxide levels, and dauer entry, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans, which will facilitate research into the genetic regulation of the sexual development of other organisms. Furthermore, it highlights conserved candidate genes that may underlie the sexually-dimorphic manifestation of different human diseases.

neuroscience↗

bioRxiv2021

Brain Morphometry and Chronic Inflammation in Bangladeshi Children Growing up in Extreme Poverty

Over three hundred million children live in environments of extreme poverty, and the biological and psychosocial hazards endemic to these environments often expose these children to infection, disease, and inflammatory responses. Chronic inflammation in early childhood has been associated with diminished cognitive outcomes, and despite this established relationship, the mechanisms explaining how inflammation affects brain development are not well known. Importantly, the prevalence of chronic inflammation in areas of extreme poverty raises the possibility that it may serve as a mechanism explaining the known relationship between low socioeconomic status (SES) and altered brain development. To examine these potential pathways, seventy-nine children growing up in an extremely poor, urban area of Bangladesh underwent MRI scanning at six years of age. Structural brain images were submitted to Mindboggle software, a Docker-compliant and high-reproducibility tool for regional estimations of volume, surface area, cortical thickness, sulcal depth, and mean curvature. C-reactive protein was assayed at eight time points between infancy and five years of age and the frequency with which children had elevated concentrations of inflammatory marker represented the measure of chronic inflammation. Childhood SES was measured with maternal education and income-to-needs (i.e., monthly household income divided by the number of household members). Chronic inflammation predicted volume in bilateral basal ganglia structures and mediated the link between maternal education and bilateral putamen volumes. These findings suggest that chronic inflammation is associated with brain morphometry in the basal ganglia, predominantly the putamen, and further offers inflammation as a potential mechanism linking SES to brain development.

neuroscience↗

bioRxiv2021

Nonsterile immunity to cryptosporidiosis in infants is associated with mucosal IgA against the sporozoite and protection from malnutrition

We conducted a longitudinal study of cryptosporidiosis from birth to three years of age in an urban slum of Dhaka Bangladesh. Fecal DNA was extracted from monthly surveillance samples and diarrheal stool samples collected from 392 infants from birth to three years. A pan-Cryptosporidium qPCR assay was used to identify sub-clinical and symptomatic cryptosporidiosis. Anthropometric measurements were collected quarterly to assess child nutritional status. 31% (121/392) of children experienced a single and 57% (222/392) multiple infections with Cryptosporidium. Repeat infections had a lower burden of parasites in the stool (Cq slope = -1.85; p<0.0001) and were more likely to be sub-clinical (Chi square test for trend; p=0.01). Repeat infections were associated with the development of growth faltering (Pearson correlation = -0.18; p=0.0004). High levels of fecal IgA antibodies against the Cryptosporidium Cp23 sporozoite protein at one year of life were associated with a delay in reinfection and amelioration of growth faltering through three years of life (HAZ IgA high responders -1.323 {+/-} 0.932 versus HAZ -1.731 {+/-} 0.984 p=0.0001). We concluded that nonsterile immunity to cryptosporidiosis in young children was associated with high levels of mucosal IgA anti-Cp23 and protection from diarrhea and growth faltering. Authors SummaryCryptosporidium is one of the top causes of diarrhea and growth faltering in Bangladesh infants. We discovered that a prior infection resulted in incomplete immunity that protected from diarrhea and growth faltering but not infection and was associated with mucosal IgA against a sporozoite surface protein Cp23. The most important implication of these findings is that a cryptosporidiosis vaccine may not need to achieve complete protection from infection to have a beneficial impact on child health.

microbiology↗

bioRxiv2021

Brain Morphometry and Diminished Physical Growth in Bangladeshi Children Growing up in Extreme Poverty: a Longitudinal Study

Diminished physical growth is a common marker of malnutrition and it affects approximately 200 million children worldwide. Despite its importance and prevalence, it is not clear whether diminished growth affects brain development and neurocognitive outcomes. Further, diminished growth is more common in areas of extreme poverty, raising the possibility that it may serve as a mechanism for previously shown links between poverty and brain development. To address these questions, 79 children growing up in an extremely poor, urban area of Bangladesh underwent MRI at 6 years. Structural brain images were submitted to Mindboggle software, a Docker-compliant and highly reproducible tool for tissue segmentation and regional estimations of volume, surface area, cortical thickness, travel depth, and mean curvature. Diminished growth predicted brain morphometry and mediated the link between poverty and brain morphometry most consistently for white matter and subcortical volumes. Meanwhile, brain volume in left pallidum and right ventral diencephalon mediated the relationship between diminished growth and full-scale IQ. These findings offer malnutrition as one possible mechanism by which poverty affects brain development and neurocognitive outcomes in areas of extreme poverty.

neuroscience↗

bioRxiv2020

Megasphaera in the stool microbiota is negatively associated with diarrheal cryptosporidiosis

BackgroundThe protozoan parasites in the Cryptosporidium genus cause both acute diarrheal disease and subclinical (i.e. non-diarrheal) disease. It is unclear if the microbiota can influence the manifestation of diarrhea during a Cryptosporidium infection. MethodsTo characterize the role of the gut microbiota in diarrheal cryptosporidiosis, the microbiome composition of both diarrheal and surveillance Cryptosporidium-positive fecal samples was evaluated using 16S rRNA gene sequencing. Additionally, the microbiome composition prior to infection was examined to test whether a preexisting microbiome profile could influence the Cryptosporidium infection phenotype. ResultsFecal microbiome composition was associated with diarrheal symptoms at two timepoints. Megasphaera was significantly less abundant in diarrheal samples when compared to subclinical samples at the time of Cryptosporidium detection (log2(fold change) = -4.3, p=10-10) and prior to infection (log2(fold change) = -2.0, p=10-4). Random forest classification also identified Megasphaera abundance in the pre- and post-exposure microbiota.as predictive of a subclinical infection. ConclusionsMicrobiome composition broadly, and specifically low Megasphaera abundance, was associated with diarrheal symptoms prior to and at the time of Cryptosporidium detection. This observation suggests that the gut microenvironment may play a role in determining the severity of a Cryptosporidium infection. SummaryMegasphaera abundance in the stool of Bangladeshi infants is associated with the development of diarrhea upon infection with the Cryptosporidium parasite.

microbiology↗

bioRxiv2020

The early evolution of oral poliovirus vaccine is shaped by strong positive selection and tight transmission bottlenecks

The evolution of circulating vaccine-derived polioviruses (cVDPV) from components of the live-attenuated oral poliovirus vaccine (OPV) presents a major challenge to global polio eradication. This process has largely been characterized by consensus sequencing of isolates collected from routine surveillance, and little is known about the early evolution of OPV within vaccinated hosts. These early events are critical steps in the progression of OPV to cVDPV. Here, we use whole genome, high depth of coverage sequencing to define the evolutionary trajectories of monovalent type 2 OPV in a cluster-randomized trial of polio vaccines in Matlab, Bangladesh. By sequencing 416 longitudinal samples from 219 mOPV2 recipients and 81 samples from 52 household contacts, we were able to examine the extent of convergent evolution in vaccine recipients and track the amount of viral diversity transmitted to new hosts. Using time-series data from a synchronized point of vaccine administration, we identify strong positive selection of reversion mutations at three known attenuating sites within two months post-vaccination. Beyond these three recognized "gate-keeper" mutations, we identify 19 mutations that exhibit significant parallelism across vaccine recipients, providing evidence for early positive selection not previously detected by phylogenetic inference. An analysis of shared genetic variants in samples from vaccinated individuals and their household contacts suggests a tight effective bottleneck during transmission. The absence of positively selected variants among household contacts across the cohort suggests that this tight bottleneck limits the transmission of these early adaptive mutations. Together, our results highlight the distinct evolutionary dynamics of live attenuated virus vaccines and have important implications for the success of novel OPV2 and other next generation approaches. SignificanceThe emergence of circulating vaccine-derived polioviruses (cVDPV) through evolution of the oral polio vaccine (OPV) poses a significant obstacle to global eradication. Understanding the genetic changes in OPV that occur as it evolves and transmits in populations is important for preventing future cVDPV outbreaks. Little is known about the early events in VDPV evolution and the selective forces that drive them. We used high depth-of-coverage genome sequencing to assess the within-host evolutionary dynamics of monovalent type 2 OPV in a vaccine trial in Matlab, Bangladesh. We leverage longitudinal sampling from vaccine recipients and household contacts to identify mutations that arise in parallel across individuals and estimate the size of the transmission bottleneck. We find evidence for strong positive selection on key sites in the capsid and the 5 noncoding region, many of which have not been previously identified. Our results also suggest that narrow transmission bottlenecks can constrain the spread of mutations selected within individuals. These results provide important insights into how OPV variants spread in populations and are highly relevant for ongoing poliovirus surveillance and the design of improved polio vaccines.

microbiology↗

bioRxiv2020

Insecticide resistance status of Aedes aegypti in Bangladesh

BackgroundArboviral diseases including dengue and chikungunya are major public health concern in Bangladesh, with unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is control of Aedes aegypti using pyrethroid insecticides. Although chemical control is long-practiced, no comprehensive analysis of Ae. aegypti susceptibility to insecticides has previously been conducted. This study aimed to determine the insecticide resistance status of Ae. aegypti in Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms. MethodsAedes eggs were collected using ovitraps from five districts across the country and in eight neighborhoods of the capital city Dhaka from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3-5-day old F0-F2 non-blood fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410. ResultsHigh levels of resistance to permethrin were detected in all Ae. aegypti populations, with mortality ranging from 0 - 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2X) doses of permethrin (5.1 - 44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency of kdr alleles varied across the Dhaka populations, and Leu410 was not detected in any of the tested populations. ConclusionsThe detection of widespread pyrethroid resistance and multiple mechanisms highlights the urgency for implementing alternate Ae. aegypti control strategies. In addition, implementing routine monitoring of insecticide resistance in Ae. aegypti in Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.

microbiology↗

bioRxiv2019

Genome-wide association study of cryptosporidiosis in infants implicates PRKCA

Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and Sub-Saharan Africa where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh: the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for height-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P=3.73x10-8), an intronic SNP and eQTL of PRKCA. Each additional risk allele conferred 2.4 times the odds of cryptosporidiosis in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. This article was submitted to an online preprint archive.(1)\n\nImportanceGlobally, one of the major causes of pediatric morbidity and mortality remains diarrhea. The initial symptoms of diarrhea can often lead to long term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase c alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

genetics↗