Novel Loci Controlling Parasite Load in Organs of Mice Infected With Leishmania major, Their Interactions and Sex Influence.

Tatyana Kobets,Marie Čepičková,Helena Havelková,Peter Demant,Marie Lipoldová,Yahya Sohrabi,Milena Svobodová,Valeriya Volkova

doi:10.3389/fimmu.2019.01083

Tatyana Kobets, Marie Čepičková + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2019.01083

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Abstract

Leishmaniasis is a serious health problem in many countries, and continues expanding to new geographic areas including Europe and USA. This disease, caused by parasites of Leishmania spp. and transmitted by phlebotomine sand flies, causes up to 1.3 million new cases each year and despite efforts toward its functional dissection and treatment it causes 20–50 thousands deaths annually. Dependence of susceptibility to leishmaniasis on sex and host's genes was observed in humans and in mouse models. Several laboratories defined in mice a number of Lmr (Leishmania major response) genetic loci that control functional and pathological components of the response to and outcome of L. major infection. However, the development of its most aggressive form, visceral leishmaniasis, which is lethal if untreated, is not yet understood. Visceral leishmaniasis is caused by infection and inflammation of internal organs. Therefore, we analyzed the genetics of parasite load, spread to internal organs, and ensuing visceral pathology. Using a new PCR-based method of quantification of parasites in tissues we describe a network-like set of interacting genetic loci that control parasite load in different organs. Quantification of Leishmania parasites in lymph nodes, spleen and liver from infected F2 hybrids between BALB/c and recombinant congenic strains CcS-9 and CcS-16 allowed us to map two novel parasite load controlling Leishmania major response loci, Lmr24 and Lmr27. We also detected parasite-controlling role of the previously described loci Lmr4, Lmr11, Lmr13, Lmr14, Lmr15, and Lmr25, and describe 8 genetic interactions between them. Lmr14, Lmr15, Lmr25, and Lmr27 controlled parasite load in liver and lymph nodes. In addition, Leishmania burden in lymph nodes but not liver was influenced by Lmr4 and Lmr24. In spleen, parasite load was controlled by Lmr11 and Lmr13. We detected a strong effect of sex on some of these genes. We also mapped additional genes controlling splenomegaly and hepatomegaly. This resulted in a systematized insight into genetic control of spread and load of Leishmania parasites and visceral pathology in the mammalian organism.

Highlights

Leishmaniasis is a neglected tropical disease, which belongs to the top health problems because it is endemic in 98 countries in Asia, Africa, the Americas, and the Mediterranean region [1,2,3] and is gradually expanding to new areas, including Central Europe and USA [2, 4,5,6,7,8,9]
The CcS-9 Strain: Two Novel Leishmania major response (Lmr) Loci, Multiple Interactions, and Sex Dependent Control of Parasite Load In F2 hybrids prepared from the parental strain BALB/c and the Recombinant congenic (RC) strain CcS-9, the analysis of parasite load in inguinal lymph nodes, spleen and liver followed by linkage analysis, revealed both main effect loci and interactions of genes located on chromosomes 2, 4, 5, 6, 11, and 17
Both in males and females, a homozygous STS allele (SS) at the Lmr14 linked to the marker D2Mit283 determined the highest parasite load in inguinal lymph nodes interacting with homozygous STS alleles (SS) of the Lmr25 linked to D5Mit143, and with the Lmr24 linked to D4Mit172 (Table 2)

Summary

Introduction

Leishmaniasis is a neglected tropical disease, which belongs to the top health problems because it is endemic in 98 countries in Asia, Africa, the Americas, and the Mediterranean region [1,2,3] and is gradually expanding to new areas, including Central Europe and USA [2, 4,5,6,7,8,9]. The disease occurs in cutaneous, mucocutaneous, and visceral forms [9]. It is caused by the protozoan intracellular parasite Leishmania transmitted by Phlebotomus spp. in the Old World and Lutzomyia spp. in the New World. The parasite can infect about 70 species of vertebrates, including humans [10,11,12,13]. Up to 1.3 million new cases occur annually: 300 000 are visceral and 1 million are cutaneous and mucocutaneous and about 20–50 thousands patients die [13]. In the infected mammalian organism, Leishmania parasites invade “professional phagocytes,” including monocytes, macrophages, and neutrophils and can reside in dendritic cells (DC) [16], immature myeloid precursor cells, hepatocytes, and fibroblasts; the parasite can enter sialoadhesin-positive stromal macrophages [17]

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