A Systematic Review of Apicomplexa Looking into Epigenetic Pathways and the Opportunity for Novel Therapies

Abstract

Interest in host epigenetic changes during apicomplexan infections increased in the last decade, mainly due to the emergence of new therapies directed to these alterations. This review aims to carry out a bibliometric analysis of the publications related to host epigenetic changes during apicomplexan infections and to summarize the main studied pathways in this context, pointing out those that represent putative drug targets. We used four databases for the article search. After screening, 116 studies were included. The bibliometric analysis revealed that the USA and China had the highest number of relevant publications. The evaluation of the selected studies revealed that Toxoplasma gondii was considered in most of the studies, non-coding RNA was the most frequently reported epigenetic event, and host defense was the most explored pathway. These findings were reinforced by an analysis of the co-occurrence of keywords. Even though we present putative targets for repurposing epidrugs and ncRNA-based drugs in apicomplexan infections, we understand that more detailed knowledge of the hosts' epigenetic pathways is still needed before establishing a definitive drug target.

Keywords: Cryptosporidium parvum; DNA methylation; Toxoplasma gondii; epidrugs; histone modification; malaria; miRNA; non-coding RNA; parasite infection; protist.

Figure 1

Flow chart of returned results from the present database search.

Figure 2

Map of the distribution of publications by country. The color intensity varies according to the number of publications.

Figure 3

Co-occurrence network by country. The cluster (different colors) is formed by the frequency of the country’s names co-occurring, as the node size is proportional to the number of pub-lished articles. The blue cluster displays the countries most cooperated with Germany (Saudi Arabia, Egypt, Denmark, Brazil, and the Netherlands – node not labeled). The green cluster is composed of countries that most collaborated with France, and in the yellow cluster, the collaborations with Australia. In the red cluster, it is displayed the countries that cooperated with USA and China. The line thickness is proportional to the number of articles published in collaboration between countries.

Figure 4

Co-occurrence network by keyword segregated according to their occurrence in colored clusters (red: words related to T. gondii; blue: C. parvum; yellow: Plasmodium spp.). The node size is proportional to the word occurrence among the studies. Linked nodes represent the co-occurrence of the keyword in articles.

Figure 5

Modulation of IFNGγ response genes in macrophages upon T. gondii infection (A) and in infected macrophage treated with HDACi (B). (A) T. gondii tachyzoite replicates in the parasitophorous vacuole (PV), releasing the T. gondii inhibitor of STAT1 transcriptional activity (TgIST) (pink), which is translocated to the nucleus. TgIST sequesters STAT1 and recruits the Mi2/NurD complex to the promoter of IFNγ response genes, remodeling the chromatin to a repressive state, thus silencing the gene. (B) The HDACi inhibits the action of the histone deacetylase (HDAC) present in the Mi2/NurD complex. The inhibition of HDAC prevents the histone deacetylation and leads to an open chromatin state, restoring the Ciita gene expression (an IFNγ response gene).

Figure 6

Epigenetic regulation of CCNB gene in BeWo cells upon Toxoplasma gondii infection and the mechanism of inhibition by putative drug targets. T. gondii secretes the effector Ropthry 16 (ROP16) in the cytoplasm of the infected cell that phosphorylates the ubiquitin-like containing PHD and RING finger domain (UHRF1) that translocates to the nucleus. The UHRF1 recruits the histone deacetylase (HDAC), histone methyltransferase (HMT), and DNA methyltransferase (DNMT) enzymes to the CCNB promoter, silencing its transcription and arresting the cell cycle in the G2 phase. We hypothesize that treatment with histone deacetylase inhibitor (HDACi), histone methyltransferase inhibitor (HMTi), or DNA methyltransferase inhibitor (DNMTi) can prevent histone H3 deacetylation, H3K9 methylation, and DNA methylation, respectively. It would restore the cyclin B expression and the continuity of the cell cycle.