Abstract
Backgroundgenetic susceptibility to infection is mediated by numerous host factors, including the highly diverse, classical human leukocyte antigen (HLA) genes, which are critical genetic determinants of immunity. We systematically evaluated the effect of HLA alleles and haplotypes on susceptibility to 12 common enteric infections in children during the first year of life in an urban slum of Dhaka, Bangladesh.Methodsa birth cohort of 601 Bangladeshi infants was prospectively monitored for diarrhoeal disease. Each diarrhoeal stool sample was analyzed for enteric pathogens by multiplex TaqMan Array Card (TAC). High resolution genotyping of HLA class I (A and B) and II (DRB1, DQA1, and DQB1) genes was performed by next-generation sequencing. We compared the frequency of HLA alleles and haplotypes between infected and uninfected children.Findingswe identified six individual allele associations and one five-locus haplotype association. One allele was associated with protection: A*24:02 – EAEC. Five alleles were associated with increased risk: A*24:17 – typical EPEC, B*15:01 – astrovirus, B*38:02 – astrovirus, B*38:02 – Cryptosporidium and DQA1*01:01 – Cryptosporidium. A single five-locus haplotype was associated with protection: A*11:01~B*15:02~DRB1*12:02~DQA1*06:01~DQB1*03:01– adenovirus 40/41.Interpretationour findings suggest a role for HLA in susceptibility to early enteric infection for five pathogens. Understanding the genetic contribution of HLA in susceptibility has important implications in vaccine design and understanding regional differences in incidence of enteric infection.Fundingthis research was supported by the National Institute of Health (NIH) and the Bill and Melinda Gates Foundation.
Highlights
Enteric infection and diarrhoeal disease have an adverse impact on early childhood development in low-and middle-income countries [1]
human leukocyte antigen (HLA) classes I and II alleles associated with resistance or susceptibility to specific enteric pathogens
For analysis of HLA and susceptibility to rotavirus infection only, we performed the analysis on 300 rotavirus unvaccinated infants
Summary
Enteric infection and diarrhoeal disease have an adverse impact on early childhood development in low-and middle-income countries [1]. Previous work has reported a wide range of pathogens associated with moderate-to-severe diarrhoea in infants and young children living in low-resource settings. Even in the absence of mortality, long-term health deficits are attributed to diarrhoeal disease during early life. This study builds on our previous findings reporting an association between pathogen-specific diarrhoea in early life and decreased long-term growth and cognitive development. These results further support a genetic role for HLA in susceptibility to infection. The data reported here provides insight on potential pathogenic epitopes that lead to a protective or deleterious immune response These findings have implications for vaccine design and much-needed therapeutics for pediatric diarrhoeal disease
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