Special Feature: New Paradigms in Host-Pathogen Interaction
There are increasing threats with a variety of virulent pathogens causing emerging, and re-emerging infectious diseases worldwide. Understanding the host defensive mechanisms and pathogenic strategies is essential for identifying novel strategies to combat and restrain the spread of infection. Recently, paradigms are shifting in terms of host-microbial interaction. The traditional concepts of host-pathogen interaction are being expanded into new insights on various areas including preclinical and clinical application to non-infectious diseases. In this special issue of host-pathogen interaction, we invited seven review articles highlighting the recent advances in host immune protective mechanisms and microbial pathogenesis during viral, mycobacterial, and parasitic infections, and the importance of gut microbiota in human health and diseases. This issue also covers the recent trial of microbial utilization for anticancer strategies. We hope that the basic and applied research in the host-pathogen interaction will promote intensive discussion and networking in the community.
Microbes living in the gut and mouth have been implicated in the development of rheumatoid arthritis (RA) and treatments that promote the growth of healthier bacterial communities may help weaken this autoimmune disease. Yuichi Maeda and Kiyoshi Takeda from Osaka University, Japan, review data from mice and humans linking RA to altered microbial compositions in the gut. They focus on a particular bacterium called Prevotella copri, which is found at much higher numbers in the gastrointestinal tracts of people with newly diagnosed RA than in those without the disease. Certain mouth-dwelling bacteria may also help exacerbate RA through the induction of antibodies directed against the host. The exact molecular mechanism by which gut and oral microbes contribute to RA remains unclear.
Therapies that promote intracellular digestion of microbes could prove a valuable addition to antibiotic weapons against tuberculosis. Mycobacterium tuberculosis (Mtb) establishes itself within immune cells, and employs a variety of tricks to protect itself as it sickens its host. Researchers led by Eun-Kyeong Jo at Chungnam National University, Daejeon, South Korea, have reviewed efforts to defeat this pathogen by jump-starting a cellular ‘recycling’ pathway called autophagy. Autophagy helps cells break down both biomolecules aggregates and potential invaders, but Mtb can elude such digestion. Jo and colleagues highlight antimycobacterial agents that can potentially render Mtb vulnerable to autophagy, as well as promising cellular targets that may allow researchers to access this process. For example, evidence suggests that agents that activate a regulatory protein such as ERRα or PPARα could stimulate cellular degradation of Mtb.
Live tumor-targeting bacteria can selectively induce cancer regression and, with the help of genetic engineering, be made safe and effective vehicles for delivering drugs to tumor cells. In a review article, Jung-Joon Min and colleagues from Chonnam National University Medical School in Hwasun, South Korea, discuss the clinical history of using natural or engineered bacterial strains to suppress cancer growth. Because bacteria such as Salmonella and Listeria preferentially home in on tumors or their surrounding microenvironments, researchers have harnessed these microbial agents to attack cancer cells without causing collateral damage to normal tissues. Bioengineers have also armed bacteria with stronger tumor-sensing and more targeted drug delivery capabilities, and improved control of off-target toxicities. An increasing number of therapeutic bacterial strains are now entering clinical testing, promising to enhance the efficacy of more conventional anticancer treatments.
Viruses escape the body’s immune surveillance mechanisms by manipulating and subverting key intracellular sensors of viral RNA or DNA. In a review article, Jong-Soo Lee and colleagues from Chungnam National University in Daejeon, South Korea, discuss the strategies used by viral pathogens to avoid detection by immune receptors or to block activation of these receptors and the associated signaling molecules, thus preventing expression of antiviral genes. These strategies include modifying viral nucleic acids or making them inaccessible, and interference with sensor proteins, either though degradation, altered processing or relocalization within the cell. The authors summarize rapid advances in scientists’ understanding of sensor-mediated antiviral responses at the molecular level, and highlight how that knowledge could help guide the development of novel vaccines and antiviral agents.
Immune cells that are non-specifically activated during infection can offer protection, but may also inflict collateral damage on infected patients. T cells normally mount an antigen-specific immune response, but certain T cells can become stimulated during viral infection without selective activation by a particular antigen. Tae-Shin Kim and Eui-Cheol Shin at KAIST in Daejon, South Korea, have reviewed current insights into this ‘bystander activation’ phenomenon. They explore how the immune response to viruses such as influenza and hepatitis A produces molecular signals that induce bystander activation of ‘killer’ T cells. In some scenarios, this leads to stronger immune protection, but these cells can also damage host tissues, or contribute to disease progression. Modulating this nonspecific response could prove valuable in managing the severity of viral disease.
In response to microbial infections a protein sensor named stimulator of interferon genes (STING) initiates the production of small defensive proteins called interferons. This is an early and ‘innate’ immune response, that is, one not targeted at specific invaders. Jeonghyun Ahn and Glen Barber at the University of Miami, USA, review the relevance of STING signaling in defense against infection, including consideration of microbial activities that can help the microbes evade this immune response. STING signaling is initiated by the presence of fragments of microbial genetic material called cyclic dinucleotides. These can be derived via cyclic GMP-AMP synthase (cGAS) from the DNA of invading viruses, bacteria or larger parasites such as single-cell protozoans. Discoveries revealing the significance and mechanism of our STING signaling system could lead to new strategies for combating infections, using either drugs or vaccines.
Researchers are extensively studying immune responses to the single-celled parasite Toxoplasma gondii, which infects around one-third of humans, often harmlessly, but can cause life-threatening toxoplasmosis infections in patients with weakened immune systems. Masahiro Yamamoto and Miwa Sasai at Osaka University in Japan review recent advances in understanding the interactions between the immune system and the parasite. They consider non-specific ‘innate’ immune responses and also the ‘acquired’ responses that target specific parts of the parasite, referred to as antigens. Methods that selectively switch off genes in mice are revealing details presumed to also be relevant for humans. Significant molecules, molecular signaling pathways and immune-regulating processes are being identified. Recent studies suggest cell-autonomous immunity, the ability of host cells to defend themselves against attack, plays a significant role in fighting Toxoplasma gondii infection.