C-Jun N-terminal kinases (JNKs) are among the most crucial mitogen-activated protein kinases (MAPKs) and regulate various cellular processes, including cell proliferation, apoptosis, autophagy, and inflammation. Microbes heavily rely on cellular signaling pathways for their effective replication; hence, JNKs may play important roles in infectious diseases. In this review, we describe the basic signaling properties of MAPKs and JNKs in apoptosis, autophagy, and inflammasome activation. Furthermore, we discuss the roles of JNKs in various infectious diseases induced by viruses, bacteria, fungi, and parasites, as well as their potential to serve as targets for the development of therapeutic agents for infectious diseases. We expect this review to expand our understanding of the JNK signaling pathway’s role in infectious diseases and provide important clues for the prevention and treatment of infectious diseases.

With the increasing bacterial resistance to traditional antibiotics, there is an urgent need for the development of alternative drugs or adjuvants of antibiotics to enhance antibacterial efficiency. The combination of antimicrobial peptides (AMPs) and traditional antibiotics is a potential alternative to enhance antibacterial efficiency. In this study, we investigated the synergistic bactericidal effect of AMPs, including chicken (CATH-1,−2,−3, and -B1), mice (CRAMP), and porcine (PMAP-36 and PR-39) in combination with conventional antibiotics containing ampicillin, tetracycline, gentamicin, and erythromycin against Staphylococcus aureus, Salmonella enteritidis, and Escherichia coli. The results showed that the minimum bactericidal concentration (MBC) of CATH-1,−3 and PMAP-36 was lower than 10 μM, indicating that these three AMPs had good bacterial activity against S. aureus, S. enteritidis, and E. coli. Then, the synergistic antibacterial activity of AMPs and antibiotics combination was determined by the fractional bactericidal concentration index (FBCI). The results showed that the FBCI of AMPs (CATH-1,−3 and PMAP-36) and erythromycin was lower than 0.5 against bacterial pathogens, demonstrating that they had a synergistic bactericidal effect. Furthermore, the time-killing kinetics of AMPs (CATH-1,−3 and PMAP-36) in combination with erythromycin showed that they had a continuous killing effect on bacteria within 3 h. Notably, the combination showed lower hemolytic activity and cytotoxicity to mammal cells compared to erythromycin and peptide alone treatment. In addition, the antibacterial mechanism of CATH-1 and erythromycin combination against E. coli was studied. The results of the scanning electron microscope showed that CATH-1 enhanced the antibacterial activity of erythromycin by increasing the permeability of bacterial cell membrane. Moreover, the results of bacterial migration movement showed that the combination of CATH-1 and erythromycin significantly inhibits the migration of E. coli. Finally, drug resistance analysis was performed and the results showed that CATH-1 delayed the emergence of E. coli resistance to erythromycin. In conclusion, the combination of CATH-1 and erythromycin has synergistic antibacterial activity and reduces the emergence of bacterial drug resistance. Our study provides valuable information to develop AMPs as potential substitutes or adjuvants for traditional antibiotics.

Staphylococcus aureus is a Gram-positive opportunistic pathogen which causes infections in a variety of vertebrates. Virulence factors are the main pathogenesis of S. aureus as a pathogen, which induce the host’s innate and adaptive immune responses. Toxic shock syndrome toxin 1 (TSST-1) is one of the most important virulence factors of S. aureus. However, the role of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) in TSST-1-induced innate immune response is still unclear. Here, purified recombinant TSST-1 (rTSST-1) was prepared and used to stimulate mouse peritoneal macrophages. The results showed that under the action of adenosine-triphosphate (ATP), rTSST-1 significantly induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) production in mouse macrophages and the production was dose-dependent. In addition, rTSST-1+ATP-stimulated cytokine production in macrophage depends on the activation of toll like receptor 4 (TLR4), but not TLR2 on the cells. Furthermore, the macrophages of NLRP3^−/− mice stimulated with rTSST-1+ATP showed significantly low levels of IL-1β production compared to that of wild-type mice. These results demonstrated that TSST-1 can induce the expression of inflammatory cytokines in macrophages via the activation of the TLR4 and NLRP3 signaling pathways. Our study provides new information about the mechanism of the TSST-1-inducing host’s innate immune responses.

Streptococcus pneumoniae (S. pneumoniae) causes severe pulmonary diseases, leading to high morbidity and mortality. It has been reported that inflammasomes such as NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) play an important role in the host defense against S. pneumoniae infection. However, the role of NLRP6 in vivo and in vitro against S. pneumoniae remains unclear. Therefore, we investigated the role of NLRP6 in regulating the S. pneumoniae-induced inflammatory signaling pathway in vitro and the role of NLRP6 in the host defense against S. pneumoniae in vivo by using NLRP6^−/− mice. The results showed that the NLRP6 inflammasome regulated the maturation and secretion of IL-1β, but it did not affect the induction of IL-1β transcription in S. pneumoniae-infected macrophages. Furthermore, the activation of caspase-1, caspase-11, and gasdermin D (GSDMD) as well as the oligomerization of apoptosis-associated speck-like protein (ASC) were also mediated by NLRP6 in S. pneumoniae-infected macrophages. However, the activation of NLRP6 reduced the expression of NF-κB and ERK signaling pathways in S. pneumoniae-infected macrophages. In vivo study showed that NLRP6^−/− mice had a higher survival rate, lower number of bacteria, and milder inflammatory response in the lung compared with wild-type (WT) mice during S. pneumoniae infection, indicating that NLRP6 plays a negative role in the host defense against S. pneumoniae. Furthermore, increased bacterial clearance in NLRP6 deficient mice was modulated by the recruitment of macrophages and neutrophils. Our study provides a new insight on S. pneumoniae-induced activation of NLRP6 and suggests that blocking NLRP6 could be considered as a potential therapeutic strategy to treat S. pneumoniae infection.

Pseudorabies virus (PRV), the causative agent of Aujeszky’s disease, is one of the most important infectious pathogens threatening the global pig industry. Like other members of alphaherpesviruses, PRV establishes a lifelong latent infection and occasionally reactivates from latency after stress stimulus in infected pigs. Latent infected pigs can then serve as the source of recurrent infection, which is one of the difficulties for PRV eradication. Virus latency refers to the retention of viral complete genomes without production of infectious progeny virus; however, following stress stimulus, the virus can be reactivated into lytic infection, which is known as the latency-reactivation cycle. Recently, several research have indicated that alphaherpesvirus latency and reactivation is regulated by a complex interplay between virus, neurons, and the immune system. However, with those limited reports, the relevant advances in PRV latency are lagging behind. Therefore, in this review we focus on the regulatory mechanisms in PRV latency via summarizing the progress of PRV itself and that of other alphaherpesviruses, which will improve our understanding in the underlying mechanism of PRV latency and help design novel therapeutic strategies to control PRV latency.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen with the characteristics of high mortality and morbidity, which brings great challenges to prevent and control epidemic disease in the swine industry. Cathelicidins (CATH) are antimicrobial peptides with antimicrobial and immunomodulatory activities. In this study, bactericidal and anti-inflammatory effects of chicken cathelicidin-1 (CATH-1) were investigated in vitro and in vivo against SS2 infection. The results show that CATH-1 exhibited a better bactericidal effect compared to other species’ cathelicidins including chickens (CATH-2, -3, and -B1), mice (CRAMP) and pigs (PMAP-36 and PR-39), which rapidly killed bacteria in 20 min by a time-killing curve assay. Furthermore, CATH-1 destroyed the bacterial morphology and affected bacterial ultrastructure as observed under electron microscopy. Moreover, CATH-1 antibacterial activity in vivo shows that CATH-1 increased survival rate of SS2-infected mice by 60% and significantly reduced the bacterial load in the lungs, liver, spleen, blood, and peritoneal lavage as well as the release of SS2-induced inflammatory cytokines including IL-1α, IL-1β, IL-12, and IL-18. Importantly, CATH-1 did not show severe histopathological changes in mice. Further studies on the mechanism of anti-inflammatory activity show that CATH-1 not only reduced the inflammatory response through direct neutralization, but also by regulating the TLR2/4/NF-κB/ERK pathway. This study provides a scientific basis for the research and development of antimicrobial peptides as new antimicrobial agents.