Research interest
1) Regulation of bacterial gene expression under infectious conditions
There are three systems by which bacteria adapt themselves to host environments through altering gene expression patterns. One is a two-component regulatory system to control signal transduction in bacteria. Another is by means of the promoter-recognizing subunit sigma of bacterial RNA polymerase that plays a major role in the selection of genes to be transcribed. The third consists of the complex of RNA chaperon proteins and small noncoding RNA facilitating their binding to target mRNA for the alteration of translation efficiency and stability. We examined the roles of these factors in bacterial adaptation to hosts using genetically tractable organisms, Escherichia coli and Staphylococcus aureus, as pathogens and Drosophila melanogaster, the immune system of which is conserved in humans as well as mammals as hosts.
1. The two-component regulatory system
We examined the transcriptional promoter strength of every genes coding sensor kinases and response regulators of E. coli in the host. Among these, we found a signaling system, consisting of EnvZ, a sensor kinase, and OmpR, a transcription factor, activated in the host and reduced bacterial virulence.
2. The sigma subunit of bacterial RNA polymerase
The DNA-dependent RNA polymerase of E. coli is a multisubunit holoenzyme and one of seven species of the promoter-recognizing subunit sigma. We found that the repertoire of the seven sigma subunits changed upon infection, and enhanced levels of sigma38 in the host induced expression of catalases for persistent infection.
3. RNA chaperone-non coding RNA complex
An RNA chaperone of E. coli called Hfq forms a complex with small noncoding RNA. We found that Hfq contributes to persistent infection of E. coli by maintaining the expression of sigma38, a type of sigma subunit in RNA polymerase.
2) Phagocytic elimination of bacteria and altered self
Phagocytes have a role in cellular innate immunity by eliminating microbes and altered-self cells. There are two evolutionarily conserved phagocytosis pathways in species ranging from nematodes to humans, including phagocytic receptors in phagocytes and their signaling molecules.
1. Phagocytic elimination of apoptotic cells
We found two phagocytic pathways with receptor Draper/MEGF-10 and Integrin alpha3-betanu/Integrin alpha3-beta5 (Drosophila/human) recognized both apoptotic and virus-infected cells. Their ligands are membrane lipid phosphatidylserine (PS) and PS-binding proteins.
2. Cell wall molecules of bacteria for interaction with host immunity
We found S. aureus provides cell wall components teichoic acid and peptidoglycan to ligands for phagocytic receptors and immune receptor Toll (flies) and Toll-like receptors (mammals).
3) The functions of pulmonary collectins
The surface of alveoli is covered with pulmonary surfactant, a mixture of lipids and proteins, which reduces surface tension to keep alveoli from collapsing. The surfactant contains two collectins called surfactant proteins A and D (SP-A and SP-D). These collectins play important roles in host defense in the lung. Furthermore, the collectins bind to host proteins and regulate their functions. The aim of our study is to clarify multiple functions of pulmonary collectins in host defense and homeostasis.
1. Innate immune functions
Pulmonary collectins are involved in the elimination of infectious pathogens in the innate immune system. We examined the roles of collectins in host defense against Legionella pneumophila, an intracellular pathogen. Also, we are interested in innate immune functions of collectins expressed in tissues other than the respiratory system.
The functions of pulmonary collectins are influenced by their structure. For instance, acrolein-modification disrupts structural and functional features of SP-A. Studies on structure-function relationships of collectins are ongoing.
2. Other functions
Recently, we found that SP-A interacts with human β-defensin 3 (hBD3), an antimicrobial peptide, and regulate its functions. SP-A attenuated chemoattractant activity and cytotoxicity of hBD3. Interestingly, SP-A did not affect antimicrobial activity of hBD3. More detailed studies are underway to apply SP-A as a regulatory molecule of hBD3 function.
Pulmonary collectins also affect the epidermal growth factor (EGF) signaling through interaction with the EGF receptor. Our data suggest that pulmonary collectins contribute to the suppression of lung cancer progression.