Abstract
Immunopathologies caused by Leishmania cause severe human morbidity and mortality. This protozoan parasite invades and persists inside host cells, resulting in disease development. Leishmania modifies the epigenomic status of the host cells, thus probably averting the host cell defense mechanism. To accomplish this, Leishmania may change the host cell chromatin structure. However, the mechanism by which the parasite changes the host cell chromatin has not been characterized. In the present study, we found that ectopically produced Leishmania histone H3, LmaH3, which mimics the secreted LmaH3 in infected cells, is incorporated into chromatin in human cells. A crystallographic analysis revealed that LmaH3 forms nucleosomes with human histones H2A, H2B and H4. We found that LmaH3 was less stably incorporated into the nucleosome, as compared to human H3.1. Consistently, we observed that LmaH3–H4 association was remarkably weakened. Mutational analyses revealed that the specific LmaH3 Trp35, Gln57 and Met98 residues, which correspond to the H3.1 Tyr41, Arg63 and Phe104 residues, might be responsible for the instability of the LmaH3 nucleosome. Nucleosomes containing LmaH3 resisted the Mg2+-mediated compaction of the chromatin fiber. These distinct physical characteristics of LmaH3 support the possibility that histones secreted by parasites during infection may modulate the host chromatin structure.
Highlights
Parasites of the genus Leishmania are the causative agents of the immunopathologies known as leishmaniasis
These results indicated that Leishmania major histone H3 (LmaH3) has the potential to be incorporated into the host cell chromatin
We found that the Leishmania histone H3, LmaH3, is incorporated into human chromatin in vivo (Figure 1), and formed nucleosomes with human histones in vitro (Figures 2 and 3), Leishmania histone incorporation into infected cells has not been investigated
Summary
Parasites of the genus Leishmania are the causative agents of the immunopathologies known as leishmaniasis. Depending on the parasite species, the clinical manifestations of this disease range largely from self-healing ulcerative skin lesions to disseminated visceral infections that are often fatal (for a recent review, see 1). There are no vaccines available and the current anti-leishmanial treatments are quite limited due to their toxicity and cost, and their continuous use is threatened by the rise of drug-resistant parasites [1,2]. A better understanding of the biology of the host-Leishmania interaction would facilitate the discovery of novel targets for anti-leishmanial chemotherapy. Transmission of Leishmania to the mammalian host occurs during a blood meal by infected sand flies. Leishmania differentiates and proliferates inside macrophages, and has established efficient strategies to alter the host innate immune response, favoring its survival [3–5]
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