# Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life

> **NIH NIH F30** · UNIVERSITY OF VIRGINIA · 2022 · $51,752

## Abstract

PROJECT SUMMARY
Cryptosporidia is a diarrheal pathogen with an important impact on global health. Overall, diarrheal disease is
estimated to be responsible for 10% of under 5-year old child mortality, and the recent Global Burden of
Diseases analysis of diarrheal mortality found that Cryptosporidia was second only to rotavirus as a cause of
death in children under five years old (5). Nitazoxanide, currently the only approved drug for Cryptosporidia
infection, is only moderately effective for treatment of immunocompetent patients. Furthermore, it is only
equivalent to placebo in severely immunocompromised patients. Clinical presentation of Cryptosporidia
infection is variable in severity; some patients experience severe diarrheal illness while some infections remain
subclinical. Although the cause for the wide spectrum of disease is poorly understood, several studies have
demonstrated long-term clinical implications of both asymptomatic and symptomatic infection. We performed a
genome-wide association study (GWAS) on infants in Bangladesh within the first year of life. We evaluated the
association between 6.5 million single nucleotide polymorphisms (SNPs) across the human genome and
symptomatic Cryptosporidia infection in three independent patient cohorts. This analysis revealed a highly
significant statistical association of multiple SNPs in the PRKCA gene and susceptibility to Cryptosporidia
diarrhea. Each copy of the risk allele increased the risk of contracting cryptosporidiosis by 2.4 times in the first
year of life. The most significant SNP in PRKCA is an eQTL in the GTex database, however, a definitive link
between PKCα and Cryptosporidia has not yet been established. The PKCα kinase is a primary regulator of
actin and during intracellular invasion, Cryptosporidia induces host cell actin remodeling. Further investigation
into how the PRKCA gene variation relates to PKCα function and susceptibility to Cryptosporidia infection will
provide insight into the pathogenesis of an important human pathogen to cause disease. We hypothesize that
host PKCα is required for Cryptosporidia invasion of intestinal epithelium through remodeling of actin
cytoskeleton. Based on this preliminary data, we aim to characterize (i) the role of PKCα in Cryptosporidia
invasion of the intestinal epithelium in vitro and in vivo (ii) define the impact of the SNPs on PRKCA expression
and downstream function, and (iii) identify if PRKCA expression mediates severity of disease in children. To
accomplish this, the research proposal includes active investigation of Cryptosporidia both in the field and at
the bench. Here, we propose bridging two approaches for scientific discovery by using molecular tools to
examine PRKCA and monitoring clinical outcomes in genotyped human children. The overarching goal of
these independent yet interacting aims will be the translational development of host PKCα as a potential
target to advance critically needed treatments for cryptosporidiosi...

## Key facts

- **NIH application ID:** 10436233
- **Project number:** 5F30DK124003-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Sayo Erick McCowin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436233

## Citation

> US National Institutes of Health, RePORTER application 10436233, Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life (5F30DK124003-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436233. Licensed CC0.

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