Biology subjects

Petri, W.

Publications and source records attributed to Petri, W..

7 recordsLinked to original sources

bioRxiv2025

Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands

Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While TLR5 signaling has previously been implicated in promoting myeloid cell recruitment to the ovarian TME, the upstream source of ligand and its systemic effects on hematopoiesis remain poorly understood(1,2). Here, we show that ovarian cancer disrupts gut barrier integrity, leading to systemic translocation of TLR5 ligands into the peritoneum, blood, and bone marrow. This translocation correlates with enhanced expansion of myeloid progenitors in the bone marrow of wild-type (WT) but not TLR5-deficient (TLR5 KO) mice, leading to enhanced accumulation of monocytes into the tumor microenvironment. Pharmacologic blockade of TLR5 in tumor-bearing mice alters the composition of tumor-associated myeloid populations, increasing the frequency of monocytes and CCR2-expressing macrophages In the bone marrow of tumor-bearing WT mice. In the bone marrow, blockade of TLR5 signaling led to expansion of granulocyte-monocyte progenitors (GMPs), a phenotype recapitulated in a competitive chimera model. In vitro, stimulation of WT bone marrow cells with purified TLR5 ligands led to enhanced colony formation and skewed differentiation toward granulocyte-macrophage lineages. These data reveal that chronic TLR5 signaling, driven by tumor-induced gut leakage, promotes expansion of myeloid cells within the bone marrow and is a host-intrinsic mechanism driving accumulation of immature monocytes and macrophages into the tumor microenvironment.

immunology↗

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

Clostridioides difficile binary toxin binding component (CDTb) increases virulence in a hamster model

Clostridioides difficile is the leading cause of hospital-acquired gastrointestinal infection, in part due to the existence of binary toxin (CDT)-expressing hypervirulent strains. We have previously shown that CDT interacts with the TLR2/6 heterodimer to induce inflammation, and in this study we further explore this interaction as well as the contribution of the separate components of CDT, CDTa and CDTb. We found that the binding component, CDTb, is capable of inducing inflammation. Additionally, complementation of a CDT-deficient C. difficile strain with CDTb alone restored virulence in a hamster model of C. difficile infection. Overall, this study demonstrates that the binding component of C. difficile binary toxin contributes to virulence during infection.

microbiology↗

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

Clostridium difficile binary toxin (CDT) is recognized by the TLR2/6 heterodimer to induce an NF-κB response

Clostridioides difficile infection (CDI) represents a significant burden on the health care system, one that is exacerbated by the emergence of binary toxin (CDT)-producing hypervirulent C. difficile strains. Previous work from our lab has shown that TLR2 recognizes CDT to induce inflammation. Here we explore the interactions of CDT with TLR2 and the impact on host immunity during CDI. We found that the TLR2/6 heterodimer, not TLR2/1, is responsible for CDT recognition, and that gene pathways including NF-{kappa}B and MAPK downstream of TLR2/6 are upregulated in mice with intact TLR2/6 signaling during CDI.

immunology↗

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↗