The artemisinin (ART), discovered in China, has been widely used against malaria in China over the last 30 years. Understanding the emergence and origin of ART resistance in China is therefore of great interest. We analyzed 111 culture-adapted isolates of P. falciparum from China-Myanmar (CM) border for their susceptibility to dihydroartemisinin using the ring stage survival assay (RSA_0−3h) and genotyped their K13 genes. Of the isolates, 59 had a wild type of the K13 marker and a median ring survival rate of 0.26% (P₉₅ = 1.005%). Among the remaining isolates harboring single mutations in the K13 marker, 26 survived at >P₉₅(median survival rate = 2.95%). Further, we genotyped the K13 gene of 693 isolates collected from different regions in China and China-Myanmar/Thai-Cambodia/Thai-Myanmar (CM/TC/TM) borders, 308 (44.4%) had K13 mutations and marked differences in the patterns of K13 mutations were observed between the CM and the TC/TM borders. A network diagram showed that majority of the K13 mutant alleles from the CM border clustered together including those harboring the high resistant-associated R539T mutations. The resistant parasites carrying distinct halplotypes suggested the multiple indigenous origins of the resistant alleles, which highlight the importance of surveillance of resistance in all malaria endemic areas where ART has been introduced.

Schistosomiasis is a chronic disease caused by the parasite of the Schistosoma genus and is characterized by egg-induced hepatic granulomas and fibrosis. Macrophages play a central role in schistosomiasis with several studies highlighting their differentiation into M2 cells involved in the survival of infected mice through limitation of immunopathology. However, little is known regarding the mechanisms of regulating macrophage differentiation. Here, we showed that the early stage of infection by Schistosoma japonicum induced expression of type 1T-helper-cell (Th1) cytokine, interferon-γ (IFN-γ), leading to increase in M1 cells. However, the presence of liver-trapped eggs induced the expression of Th2 cytokines including interleukin-4 (IL-4), IL-10, and IL-13 that upregulated the transcription of miR-146b by activating signal transducer and activator of transcription 3/6 (STAT3/6) that bind to the promoter of the pre-miR-146b gene. We found that the miR-146a/b was significantly upregulated in macrophages during the progression of hepatic schistosomiasis. The elevated miR-146a/b inhibited the IFN-γ-induced differentiation of macrophages to M1 cells through targeting STAT1. Our data indicate the protective roles of miR-146a/b in hepatic schistosomiasis through regulating the differentiation of macrophages into M2 cells.

Significance: Hepatic fibrosis is the final common pathological outcome of many chronic liver diseases and occurs when hepatic stellate cells (HSCs) are activated to become fibrogenic myofibroblasts. To date, there are still no approved antifibrotic therapies. Accumulating evidence suggests that targeting the deregulated miRNAs could mitigate disease outcomes. In this study, using a well-studied model of human schistosomiasis, we show that elevated miR-351 promotes the activation of HSCs after infection by targeting the vitamin D receptor, and inhibition of miR-351 in the liver mediated by rAAV8 protects the host from lethal infection by alleviating hepatic fibrosis. This study provides insights into the mechanisms that result in schistosomiasis-related hepatic fibrosis and targets of intervention for schistosomiasis and other fibrotic diseases.

Tuberculosis (TB) remains a serious public health threat around the world. An effective vaccine is urgently required for cost-effective, long-term control of TB. However, the only licensed vaccine Bacillus Calmette-Guerin (BCG) is limited to prevent TB for its highly variable efficacy. Substantial progress has been made in research and development (R&D) of TB vaccines in the past decades, and a dozen vaccine candidates, including live attenuated mycobacterial vaccines, killed mycobacterial vaccines, adjuvanted subunit vaccines, viral vector vaccines, and messenger RNA (mRNA) vaccines were developed in clinical trials to date. Nevertheless, many challenges to the successful authorization for the use and deployment of an effective tuberculosis vaccine remain. Therefore, it is still necessary and urgent to continue exploring new vaccine construction approaches. Virus-like particles (VLPs) present excellent prospects in the field of vaccine development because of their helpful immunological features such as being safe templates without containing viral nucleic acid, repetitive surface geometry, conformational epitopes similar to natural viruses, and enhancing both innate and adaptive immune responses. The marketization process of VLP vaccines has never stopped despite VLP vaccines face several shortcomings such as their complex and slow development process and high production cost, and several VLP-based vaccines, including vaccines against Human papillomavirus (HPV), Hepatitis B Virus (HBV) and malaria, are successfully licensed for use at the market. In this review, we provide an update on the current progress regarding the development of TB vaccines in clinical trials and seek to give an overview of VLP-based TB vaccine candidates.

Schistosomiasis remains a serious parasitic disease, which is characterized by granulomatous inflammation and hepatic fibrosis. MicroRNAs derived from parasites can regulate host genes and cell phenotype. Here, we showed that a miRNA derived from S. japonicum (Sja-miR-1) exists in the hepatic stellate cells (HSCs) of mice infected with the parasite and up-regulates the expression of collagens and α-SMA by targeting secreted frizzled-related protein 1 (SFRP1). A vector-mediated delivery of Sja-miR-1 into naive mice led to hepatic fibrogenesis in the mice. Accordingly, inhibition of Sja-miR-1 in the infected mice led to reduction of the parasite-induced hepatic fibrosis. The mechanism behind the Sja-miR-1-mediated activation of HSC could be through targeting SFRP1 to regulate the Wnt/β-catenin pathway. These findings reveal that parasite-derived small non-coding RNAs are implicated in cross-species regulation of host pathological process and persistent inhibition of Sja-miR-1 may provide a therapeutic potential for the parasite diseases.

Mutations in the Plasmodium falciparum k13 gene are associated with artemisinin (ART) resistance. However, it is unclear whether the F446I mutation, the most prevalent allele at the China–Myanmar border and north of Myanmar, is associated with ART resistance. Therefore, the aim of this study was to investigate the role of this mutation in ART resistance by generating transgenic parasites expressing the F446I mutant allele. The transgenic parasites carrying the F446I or C580Y mutation in both 3D7 and FCC1/HN isolates were generated by single crossing-over recombination and verified using PCR and gene sequencing. The ring-stage survival assay of 0–3 h (RSA0–3 h) was used to evaluate ART susceptibility of the transgenic parasites in vitro. Four transgenic parasite lines named 3D7F446I mut, 3D7C580Y mut, FCC1/HNF446I mut and FCC1/HNC580Y mut were successfully generated. These parasite lines showed no changes in the expression level of k13 when compared with their parent parasite isolates. However, introduction of the F446I mutation in k13 of the 3D7 and FCC1/HN isolates led to elevated ring survival rates detected using RSA0–3 h when subjected to both 700 and 20 nM concentrations of dihydroartemisinin. The survival rates were similar to those detected in the parasite lines with the C580Y mutation. Insertion of the F446I mutation in k13 led to increased ring survival, suggesting that this mutation may be associated with ART resistance and could be used as a molecular marker for monitoring ART-resistant parasites. The results also highlights the importance of surveillance of F446I mutants for containing the resistant parasite.