Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis

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

doi:10.1128/mbio.02068-22

Cited by 6 publications

(4 citation statements)

References 42 publications

(61 reference statements)

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“…Similar observations have been made in the fields of bacteriology and parasitology. Escherichia coli genotypes exhibit a spectrum of disease severity ranging from asymptomatic to severe, and parasite genotype explains 83% of the variation in mortality from visceral leishmaniasis [4][5][6]. Yet we know little about the impact of helminth genetic variation on disease severity.…”

Section: Introductionmentioning

confidence: 99%

Contribution of parasite and host genotype to immunopathology of schistosome infections

Jutzeler,

Le Clec’h,

Chevalier

et al. 2024

Preprint

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Background: The role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa, and viruses, but is poorly understood in parasitic helminths. The medically important blood fluke Schistosoma mansoni is an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes. Methods: We infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over an infection period of 12 weeks. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology), and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics. Results: We found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area, but not in granuloma size. Variation in organ weight was explained by egg burden and by intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokines (IFN-γ, TNF-α), eosinophil, lymphocyte, and monocyte counts. Conclusions: This study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotype impact immunopathology outcomes.

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Section: Introductionmentioning

confidence: 99%

Contribution of parasite and host genotype to immunopathology of schistosome infections

Jutzeler,

Le Clec’h,

Chevalier

et al. 2024

Preprint

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“…While most data suggests that parasite isolates from cutaneous and mucosal CL from the same patients are genetically very similar (11, 12), most of this work has relied on experimental characterisation of small numbers of parasite isolates taken from cases with differing clinical presentations. While whole-genome data from natural populations of many Leishmania species is now available (e.g (13–16)), there has been little work directly attempting to directly relate parasite genetic variation to clinical variation. One exception is a recent genome-wide association study that found some evidence that clinical outcome is linked to parasite genotype in L. infantum (16).…”

Section: Introductionmentioning

confidence: 99%

“…While whole-genome data from natural populations of many Leishmania species is now available (e.g (13–16)), there has been little work directly attempting to directly relate parasite genetic variation to clinical variation. One exception is a recent genome-wide association study that found some evidence that clinical outcome is linked to parasite genotype in L. infantum (16). Research on L. aethiopica is particularly neglected, and the only genomic data available for this species is from 19 historical isolates and some hybrid forms collected from cryopreserved culture collections (17).…”

Section: Introductionmentioning

confidence: 99%

Parasite genetic variation and systemic immune responses are not associated with different clinical presentations of cutaneous leishmaniasis caused by Leishmania aethiopica

Yizengaw,

Takele,

Franssen

et al. 2024

Preprint

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Cutaneous leishmaniasis (CL) is a neglected tropical skin disease, caused by the protozoan parasite Leishmania (L.). It is endemic to 90 countries and causes >200,000 new infections each year. In Ethiopia, CL is mainly caused by L. aethiopica and can present in different clinical forms: localised cutaneous leishmaniasis (LCL); mucocutaneous leishmaniasis (MCL), where the mucosa of the nose and/or the mouth are affected; and diffuse CL (DCL), characterised by non-ulcerating nodules. Persistent forms of LCL, as well as MCL and DCL, require treatment but are difficult to treat successfully and can lead to permanent disfigurement, social stigmatisation, and a mental health burden. The mechanisms behind the development of these different presentations of CL are not clearly understood, and both parasite and host factors could be involved. Here we analysed the whole genome sequence data for 48 clinical parasite isolates and show that parasites from CL cases with different presentations in a single Ethiopian setting are from the same genetic population. Furthermore, we did not identify any individual genetic variants significantly associated with disease presentation. We also measured plasma chemokine and cytokine levels of 129 CL patients presenting with different forms of CL. None of the cytokine or chemokine levels measured were significantly different between the different clinical presentations of CL. We also compared those with healthy nonendemic controls: our results show a chemokine but not a cytokine immune signature in patients with CL as compared to healthy nonendemic controls.

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“…Similar observations have been made in the fields of bacteriology and parasitology. Escherichia coli genotypes exhibit a spectrum of disease severity ranging from asymptomatic to severe [ 4 , 5 ], and parasite genotype explains 83% of the variation in mortality from visceral leishmaniasis [ 6 ]. Yet, we know little about the impact of helminth genetic variation on disease severity.…”

Section: Introductionmentioning

confidence: 99%

Contribution of parasite and host genotype to immunopathology of schistosome infections

Jutzeler,

Le Clec’h,

Chevalier

et al. 2024

Parasites Vectors

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Background The role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa and viruses but is poorly understood in parasitic helminths. The medically important blood fluke Schistosoma mansoni is an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes. Methods We infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over a 12-week infection period. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology) and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics. Results We found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area but not in granuloma size. Variation in organ weight was explained by egg burden and intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokine levels (IFN-γ, TNF-α), eosinophils, lymphocytes and monocyte counts. Conclusions This study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotypes impact immunopathology outcomes. Graphical Abstract

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Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis

Abstract: 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.

Cited by 6 publications

References 42 publications

Contribution of parasite and host genotype to immunopathology of schistosome infections

Contribution of parasite and host genotype to immunopathology of schistosome infections

Parasite genetic variation and systemic immune responses are not associated with different clinical presentations of cutaneous leishmaniasis caused by Leishmania aethiopica

Contribution of parasite and host genotype to immunopathology of schistosome infections

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