National Institute of Health

Researchers provide genetic information on disease biomarkers to accelerate the development of therapeutics for a new strain of scrub typhus

Recent studies have reported the concerning development of a new, drug-resistant strain of scrub typhus, a fatal zoonotic disease spread by mite bites. Now, researchers from Korea have used genome-wide association studies to identify genetic biomarkers behind the disease’s progression. Their study revealed variations located on genes associated with susceptibility to this disease, as well as affected cell signaling pathways. These findings can be used to develop effective treatment measures against scrub typhus.

If left untreated, scrub typhus, which is spread by mite bites, has been reported to be fatal in 4–40% of cases.   Researchers from Korea used genome-wide association studies to determine genetic biomarkers behind the progression of scrub typhus. Their findings can be used to develop effective treatment measures against this fatal zoonotic disease.

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Zoonotic diseases—infectious diseases that spread from animals to humans—are a rapidly growing public health concern. COVID-19 is arguably today’s most familiar example of a possible zoonotic disease. However, it is imperative that other emerging zoonotic diseases are also kept in check to prevent them from ever reaching pandemic proportions. Scrub typhus is one such fatal zoonotic disease spread by mites and caused by the bacteria Orientia tsutsugamushi.

Since its discovery in the 1930s in Japan, scrub typhus has been steadily expanding due to global warming and globalization. When left untreated, the mortality of the disease reaches a median of 6%, but antibiotics such as doxycycline or azithromycin can bring this number down to 1.4%. However, recent studies have reported concerning findings about a new, antibiotic-resistant strain of this disease in Thailand. In light of this issue, novel antibiotics or therapeutics that can effectively treat scrub typhus are the need of the hour.

In a collaborative study published in the journal Cells, researchers from Jeonbuk National University and other institutes in Korea aimed to understand the molecular mechanisms behind the propagation of scrub typhus. Their study is based on findings from genome-wide association studies (GWAS), which are used identify genes that contribute to a disease. “GWAS is a high-throughput and convenient genetic method that can reveal the molecular mechanisms of a disease based on genome-wide comparisons between a diseased group and a healthy control group,” explains Professor Byung-Hoon Jeong. More specifically, these genetic comparisons allow researchers to identify consistent genetic variations (or ‘biomarkers’) between both groups. In turn, this provides leads to potential therapeutic targets, which are ultimately used to develop new drugs. This study was supported by a Korea Centers for Disease Control and Prevention (KCDC) grant (No. 2013-E71005-00, 2014-E71003-00).

The researchers initially obtained blood samples from 148 individuals, half of whom had scrub typhus at an early stage while the other half consisted of healthy individuals. The GWAS revealed eight genetic variations (called “single nucleotide polymorphisms”) on a group of genes related to susceptibility to the disease. Because the initial identification of these candidate genes did not explain much about the molecular mechanisms of scrub typhus, the researchers investigated which other genes interacted the most with them, as well as the cell signaling pathways they were involved in.

Using MIST (Molecular Interaction Search Tool)—a database of protein and gene interactions—the researchers identified 224 genes that interacted with the candidate genes of scrub typhus. These genes were then classified based on their cell signaling pathways using PANTHER, which is a web-based platform for analyzing gene function. Their analysis revealed a total of 62 signal pathways. Fifteen of these pathways that multiple candidate genes were involved in were responsible for vital cell functions, such as angiogenesis (the formation of new blood vessels) and apoptosis (programmed cell death). However, the signaling pathway with the most associated genes (31 genes) was the gonadotropin-releasing hormone pathway, which is responsible for producing the hormones testosterone in men and estrogen and progesterone in women.

This study constitutes a necessary first step in the development of effective treatment options for scrub typhus. “Our efforts will hopefully improve the understanding of the pathological mechanisms of scrub typhus. If an effective biomarker is verified based on our results, it may be possible to develop a much-needed therapeutic agent for this disease,” concludes Prof. Jeong. Furthermore, the study paves the way for further investigation into the relationship between susceptibility to scrub typhus and the gonadotropin-releasing hormone pathway.

Overall, this study’s findings certainly cement the importance of GWAS in breaking the chain of zoonotic diseases.

Reference

Authors                            Yong-Chan Kim ^1,2, Soriul Kim ³, Hee-Kwon Kim ⁴, Yi Lee ⁵ , Chol Shin ^3,6, Chang-Seop Lee ^7,8,* and Byung-Hoon Jeong ^1,2,*     

Title of original paper       Genome-Wide Association Study Identifies Eight Novel Loci for Susceptibility of Scrub Typhus  and Highlights Immune-Related

                                         Signaling Pathways in Its Pathogenesis

Journal                             Cells

DOI                                  10.3390/cells10030570

Affiliations                        1. Korea Zoonosis Research Institute, Jeonbuk National University, Korea

                                        2. Department of Bioactive Material Sciences, Jeonbuk National University, Korea

                                        3. Korea University, Korea

                                        4. Jeonbuk National University Medical School and Hospital, Korea

                                        5. Chungbuk National University, Korea

                                        6. Korea University Ansan Hospital, Korea

                                        7. Jeonbuk National University Medical School, Korea

                                        8. Jeonbuk National University Hospital, Korea

About National Institute of Health in Korea

The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.

Website: http://www.nih.go.kr/eng/

About Professor Byung-Hoon Jeong

Byung-Hoon Jeong is currently an Associate Professor at the Bioactive Material Sciences and Korea Zoonosis Research Institute, Jeonbuk National University. He obtained a Ph.D. degree from Kangwon National University in 2002. He has served as a Section Chief at the Ilsong Institute of Life Science, Hallym University, as well as a Member of the Editorial Board of the International Journal of Genomics. He is also the author or coauthor of more than 90 peer-reviewed research papers. His main research interests are in the diagnosis, genetic susceptibility makers, and pathogenic molecular mechanism of infectious diseases, including prion diseases.