Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis

Cooper Alastair Grace, Kátia Silene Sousa Carvalho, Mayara Ingrid Sousa Lima, Vladimir Costa Silva, João Luís Reis-Cunha, Matthew J. Brune, Sarah Forrester, Conceição de Maria Pedrozo, Silva de Azevedo, Dorcas Lamounier Costa, Doug Speed, Jeremy C. Mottram, Daniel C. Jeffares*, Carlos H.N. Costa

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Visceral leishmaniasis (VL) is a potentially fatal disease caused mainly by Leishmania infantum in South America and Leishmania donovani in Asia and Africa. Disease outcomes have been associated with patient genotype, nutrition, age, sex, comorbidities, and coinfections. In this study, we examine the effects of parasite genetic variation on VL disease severity in Brazil. We collected and sequenced the genomes of 109 L. infantum isolates from patients in northeastern Brazil and retrieved matching patient clinical data from medical records, including mortality, sex, HIV coinfection, and laboratory data (creatinine, hemoglobin, and leukocyte and platelet counts). We identified genetic differences between parasite isolates, including single nucleotide polymorphisms (SNPs), small insertions/deletions (indels), and variations in genic, intergenic, and chromosome copy numbers (copy number variants [CNVs]). To describe associations between the parasite genotypes and clinical outcomes, we applied quantitative genetics methods of heritability and genome-wide association studies (GWAS), treating clinical outcomes as traits that may be influenced by parasite genotype. Multiple aspects of the genetic analysis indicate that parasite genotype affects clinical outcomes. We estimate that parasite genotype explains 83% chance of mortality (narrow-sense heritability [ h 2] = 0.83 ± 0.17) and has a significant relationship with patient sex ( h 2 = 0.60 ± 0.27). Impacts of parasite genotype on other clinical traits are lower ( h 2 ≤ 0.34). GWAS analysis identified multiple parasite genetic loci that were significantly associated with clinical outcomes; 17 CNVs were significantly associated with mortality, two with creatinine, and one with bacterial coinfection, jaundice, and HIV coinfection, and two SNPs/indels and six CNVs were associated with age, jaundice, HIV and bacterial coinfections, creatinine, and/or bleeding sites. Parasite genotype is an important factor in VL disease severity in Brazil. Our analysis indicates that specific genetic differences between parasites act as virulence factors, enhancing risks of severe disease and mortality. More detailed understanding of these virulence factors could be exploited for novel therapies. IMPORTANCE Multiple factors contribute to the risk of mortality from visceral leishmaniasis (VL), including, patient genotype, comorbidities, and nutrition. Many of these factors are influenced by socioeconomic biases. Our work suggests that the virulence of the infecting parasite is an important risk factor for mortality. We pinpoint some specific genomic markers that are associated with mortality, which can lead to a greater understanding of the molecular mechanisms that cause severe VL disease, to the identification of genetic markers for virulent parasites, and to the development of drug and vaccine therapies.

Original languageEnglish
Pages (from-to)e0206822
Number of pages13
JournalMBio
Volume13
Issue number6
Early online date12 Oct 2022
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
We thank the Brazilian Legislators that provided funds for the Ministry of Health destined for this study. C.A.G. was supported by MRC Newton as a component of the UK: Brazil Joint Centre Partnership in Leishmaniasis to J.C.M. (MR/S019472/1). J.L.R.-C. and D.C.J. are supported by a MRC New Investigator Research Grant to D.C.J. (MR/T016019/1). S.F. was supported by a Wellcome Trust Seed Award in Science to D.C.J. (208965/Z/17/Z). M.I.S.L. and C.d.M.P.e.S.d.A. are supported by Coordination for the Improvement of Higher Education Personnel (CAPES; Finance Code 001 and PROCAD-Amazônia 001-21/2018) and Foundation for Research and Scientific and Technological Development of Maranhão (FAPEMA). C.H.N.C. was supported by the National Council of Scientific and Technological Development (CNPq). The Brazilian Ministry of Education supported this research.

Publisher Copyright:
Copyright © 2022 Grace et al.

Keywords

  • Brazil
  • genetic diversity
  • Leishmania infantum
  • mortality
  • quantitative genetics
  • virulence factors
  • visceral leishmaniasis

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