Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria.

Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.

Chloroquine treatment influences immunologicalmemory through the PD-1/PD-L1 pathway during the initiation of Plasmodium chabaudi infection.

Growing evidence describes the host immune response mechanism involved in malaria. Despite the spread of drug resistance, chloroquine (CQ) remains the main antimalarial drug in most countries in Latin America and Asia. Studies have indicated an immunomodulatory activity of CQ, however, the potential implications for CQ on immunological memory recognizing the malaria parasite are still being elucidated. Our study suggests that CQ treatment significantly delayed the initiation of parasitemia during infection of mice with the rodent malaria parasite, Plasmodium chabaudi (P.c.). Additionally, there was a decrease in T follicular helper cells (Tfh), CD4+ effector memory T cells, memory B cells (MBC), IgG2a memoryB cells, along with IgG2a plasma cells; while antibody production was not affected atthe observation time points. After PD-1 blockade and CQ treatment, no reductions in the numbers of CD4+ effector memory T cells, MBC, and IgG2a memoryB cells were observed compared with the P.c. group. Therefore, CQ might regulate immunological memory via the PD-1/PD-L1 signaling pathway. Compared with antibody secretion, the inhibition of CQ on immune memory cells was a more sensitive indicator.

Reliability and validity of the 15-item Chronic Oral Mucosal Disease Questionnaire in China: A short-form instrument to measure quality of life.

BACKGROUND: Chronic oral mucosal diseases have been a common problem, which affected individuals' health and social functions seriously. Although there has been a rigorous Chinese version of the Chronic Mucosal Diseases Questionnaire (COMDQ-26) to measure the quality of life of patients with chronic oral mucosal diseases, 26 items were so redundant to be a burden for patients. It was necessary to make a brief, practical, and easy-to-use tool in China. This study aimed to test the validity and reliability of the Chinese version of the short-form Chronic Mucosal Diseases Questionnaire (COMDQ-15). METHODS: A total of 165 respondents from a tertiary stomatological hospital were recruited in this study from July to December, 2020. Internal consistency, test-retest reliability, criterion validity, confirmatory factor analysis, and exploratory factor analysis were used to evaluate the reliability and validity of the Chinese version of Chronic Mucosal Diseases Questionnaire-15. RESULTS: The total Cronbach's α of 0.841 and subscale ranging from 0.736 to 0.965 revealed good internal consistency of the reliability. The intraclass correlation coefficients exceeded 0.80 indicated excellent test-retest reliability. Compared with the Oral Health Impact Profile-14, the criterion validity was 0.549. The confirmatory factor analysis results supported acceptable validity of the Chinese version of Chronic Mucosal Diseases Questionnaire-15, and the exploratory factor analysis demonstrated that the 15 items were classified into four domains, with a cumulative proportion of 71.52%. CONCLUSION: The Chinese version of Chronic Mucosal Diseases Questionnaire-15 is a brief and low-burden tool, and has been proved reliable and valid to assess the quality of life of patients with chronic oral mucosal diseases in China (the Chinese Clinical Trial Registry (no. ChiCTR2000031607).