Parasite genotype is a major predictor of mortality from visceral leishmaniasis
Authors: Grace Cooper Alastair , Sousa Carvalho Kátia Silene , Sousa Lima Mayara Ingrid , Silva Vladimir Costa , Reis-Cunha João Luís , Brune Matthew J. , Forrester Sarah , Pedrozo e Silva de Azevedo Conceição de Maria , Costa Dorcas Lamounier , Speed Doug , Mottram Jeremy C. , Jeffares Daniel C. , Costa Carlos H.N. 
Published: August 2022

Abstract/SummaryBackgroundVisceral leishmaniasis (VL) is a potentially fatal disease mainly caused by Leishmania infantum in South America and L. donovani in Asia and Africa. Disease outcomes have been associated with patient genotype, nutrition, age, sex, comorbidities, and co-infections. In this study, we examine the effects of parasite genetic variation on VL disease severity in Brazil.MethodsWe collected and sequenced the genomes of 109 L. infantum isolates from patients in northeast Brazil and retrieved matching patient clinical data from medical records, including mortality, sex, HIV co-infection and laboratory data (creatinine, haemoglobin, 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.FindingsMultiple 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, h2 = 0·83±0·17), and has a significant relationship with patient sex (h2 = 0·60±0·27). Impacts of parasite genotype on other clinical traits are lower (h2 ≤0·34). GWAS analysis identified multiple parasite genetic loci that were significantly associated with clinical outcomes; 17 CNVs that were significantly associated with mortality, two with creatinine and one with bacterial co-infection, jaundice and HIV co-infection; and two SNPs/indels and six CNVs that associate with age, jaundice, HIV and bacterial co-infections, creatinine, and/or bleeding sites.InterpretationParasite 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.Author SummaryMultiple factors contribute to the risk of mortality from visceral leishmaniasis (VL), including, patient genotype, comorbidities, and nutrition. Many of these factors will be influenced by socio-economic biases 1. 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 genetic markers for virulent parasites and to the development of drug and vaccine therapies.