Laboratory of Microbial Informatics

1. Key Members

2. Background and Objectives

In recent years, infectious diseases caused by drug-resistant bacteria have become a serious global health threat. It is estimated that approximately 4.95 million people worldwide died in 2019 from diseases related to antimicrobial resistance (AMR). Since drug-resistant bacteria have historically emerged within a few years of the introduction of new antimicrobial agents, there is an urgent need to develop not only novel antimicrobial drugs but also vaccines and innovative treatment strategies.

Our research focuses on elucidating the mechanisms by which pathogenic bacteria cause infections. Understanding these mechanisms enables the identification of molecular targets for drug development, ultimately contributing to the creation of effective prevention and treatment methods.

In addition to investigating pathogenic bacteria, we analyze the human microbiota. By comparing the composition and genetic profiles of bacterial communities from diverse populations, we aim to identify factors within the microbiota that promote health or contribute to disease progression.

3.Overview of our research

Ⅰ Pneumococcal infection

Streptococcus pneumoniae (pneumococcus) is one of the pathogenic bacteria of greatest concern due to its increasing antibiotic resistance. Our research investigates the mechanisms underlying the progression of pneumococcal infections from both bacterial and host perspectives.

On the bacterial side, we conduct pangenome-wide association studies (pan-GWAS) to identify bacterial genes correlated with disease severity. We further analyze the roles of these disease-associated bacterial factors through molecular biology experiments, aiming to clarify how they contribute to pathogenesis.

On the host side, we focused on aging and host immunity. S. pneumoniae is the leading cause of pneumonia and is isolated from approximately half of elderly patients with severe pneumonia. In Japan, 98% of pneumonia-related deaths occur in individuals aged 65 years and older, highlighting advanced age as a significant risk factor for severe disease. To elucidate age-related changes in immune responses, we compare immune responses between young and elderly hosts using advanced techniques such as single-cell analysis and spatial transcriptomics.

Ⅱ Streptococcal toxic shock syndrome

Streptococcal toxic shock syndrome (STSS) is a serious infection caused by β-hemolytic streptococci, characterized by shock symptoms associated with hepatic failure, renal failure, disseminated intravascular coagulation (DIC), and necrotizing fasciitis. Although rare, STSS can occur in anyone and has a high mortality rate of 30–40%. Despite the severity, many aspects of its pathogenesis remain unclear.

In the well-studied M1 serotype of S. pyogenes, mutations in the CovR/S two-component regulatory system—which controls bacterial gene expression—can alter the expression patterns of virulence factors, leading to invasive disease manifestations (Cole J.N. et al., Nat. Rev. Microbiol. 2011). However, STSS can also occur in strains lacking such mutations, suggesting that unidentified pathogenic mechanisms may exist.

To investigate these mechanisms, we compared the whole-genome sequences of strains isolated from STSS and non-STSS cases and conducted pan-GWAS. Our results indicate that there is no specific lineage exclusive to STSS strains; instead, mutations accumulated during the infection process may sporadically trigger the development of STSS. Furthermore, we identified multiple bacterial mutations associated with STSS beyond the previously known CovR/S alterations.

Currently, we are working to elucidate the detailed mechanisms by which these mutations contribute to disease severity. Leveraging the insights gained from this research, we aim to develop novel preventive and therapeutic agents for STSS.

Ⅲ Microbiome analysis

Healthy individuals coexist with a wide variety of microorganisms inhabiting various body sites, including the skin, oral cavity, and gut. These microbial communities, known as the resident microbiota, play a significant role in promoting health and contributing to disease development through the balance of their composition. However, many bacterial species within the microbiota remain poorly understood due to their inability to be cultured using conventional methods.

Our research aims to elucidate the detailed composition and functions of the microbiota through approaches such as metagenomic analysis and bacterial single-cell analysis. In parallel, we explore valuable genetic resources harbored within these microbial communities.

Notably, certain pathogenic bacteria have been shown to utilize related commensal bacteria as external genetic reservoirs (Kilian M. et al., mBio 2019; Nahm M.H. et al., J. Infect. Dis. 2020). Understanding the prevalence of antimicrobial resistance (AMR) genes within the resident microbiota and the extent to which these genes can be transferred across species boundaries is critical for preventing the spread of resistance genes.