Phagocytosis is an essential mechanism in innate immune defense, and in maintaining homeostasis to eliminate apoptotic cells or microbes, such as Mycobacterium tuberculosis, Salmonella enterica, Streptococcus pyogenes and Legionella pneumophila. After internalizing microbial pathogens via phagocytosis, phagosomes undergo a series of ‘maturation’ steps, to form an increasingly acidified compartment and subsequently fuse with the lysosome to develop into phagolysosomes and effectively eliminate the invading pathogens. Through this mechanism, phagocytes, including macrophages, neutrophils and dendritic cells, are involved in the processing of microbial pathogens and antigen presentation to T cells to initiate adaptive immune responses. Therefore, phagocytosis plays a role in the bridge between innate and adaptive immunity. However, intracellular bacteria have evolved diverse strategies to survive and replicate within hosts. In this review, we describe the sequential stages in the phagocytosis process. We also discuss the immune evasion strategies used by pathogens to regulate phagosome maturation during intracellular bacterial infection, and indicate that these might be used for the development of potential therapeutic strategies for infectious diseases.

Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action.

The treatment of tumors requires the induction of cell death. Radiotherapy, chemotherapy, and immunotherapy are administered to kill cancer cells; however, some cancer cells are resistant to these therapies. Therefore, effective treatments require various strategies for the induction of cell death. Regulated cell death (RCD) is systematically controlled by intracellular signaling proteins. Apoptosis and autophagy are types of RCD that are morphologically different from necrosis, while necroptosis, pyroptosis, and ferroptosis are morphologically similar to necrosis. Unlike necrosis, regulated necrotic cell death (RNCD) is caused by disruption of the plasma membrane under the control of specific proteins and induces tissue inflammation. Various types of RNCD, such as necroptosis, pyroptosis, and ferroptosis, have been used as therapeutic strategies against various tumor types. In this review, the mechanisms of necroptosis, pyroptosis, and ferroptosis are described in detail, and a potential effective treatment strategy to increase the anticancer effects on apoptosis- or autophagy-resistant tumor types through the induction of RNCD is suggested.

Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

Hyo-Ji Lee, Wan-Gi Hong, Yunseo Woo, Jae-Hee Ahn, Hyun-Jeong Ko, Hyeran Kim, Sungjin Moon, Tae-Wook Hahn, Young Mee Jung, Dong-Keun Song, and Yu-Jin Jung. Mol. Cells -0001;0:. https://doi.org/10.14348/molcells.2020.0030

The Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative Gram-negative bacterium that causes acute gastroenteritis and food poisoning. S. Typhimurium can survive within macrophages that are able to initiate the innate immune response after recognizing bacteria via various pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs). In this study, we investigated the effects and molecular mechanisms by which agonists of endosomal TLRs—especially TLR3—contribute to controlling S. Typhimurium infection in murine macrophages. Treatment with polyinosinic:polycytidylic acid (poly(I:C))—an agonist of TLR3—significantly suppressed intracellular bacterial growth by promoting intracellular ROS production in S. Typhimurium-infected cells. Pretreatment with diphenyleneiodonium (DPI)—an NADPH oxidase inhibitor—reduced phosphorylated MEK1/2 levels and restored intracellular bacterial growth in poly(I:C)-treated cells during S. Typhimurium infection. Nitric oxide (NO) production increased through the NF-κB-mediated signaling pathway in poly(I:C)-treated cells during S. Typhimurium infection. Intracellular microtubule-associated protein 1A/1B-light chain 3 (LC3) levels were increased in poly(I:C)-treated cells; however, they were decreased in cells pretreated with 3-methyladenine (3-MA)—a commonly used inhibitor of autophagy. These results suggest that poly(I:C) induces autophagy and enhances ROS production via MEK1/2-mediated signaling to suppress intracellular bacterial growth in S. Typhimurium-infected murine macrophages, and that a TLR3 agonist could be developed as an immune enhancer to protect against S. Typhimurium infection.