Host Cell Immune Responses Research Articles

Toxoplasma gondii infection possibly reverses host immunosuppression to restrain tumor growth

Tumor cells can successfully escape the host immune attack by inducing the production of immunosuppressive cells and molecules, leading to an ineffective tumor treatment and poor prognosis. Although immunotherapies have improved the survival rate of cancer patients in recent years, more effective drugs and therapies still need to be developed. As an intracellular parasite, Toxoplasma gondii can trigger a strong Th1 immune response in host cells, including upregulating the expression of interleukin-12 (IL-12) and interferon-γ (IFN-γ). Non-replicating uracil auxotrophic strains of T. gondii were used to safely reverse the immunosuppression manipulated by the tumor microenvironment. In addition to the whole lysate antigens, T. gondii-secreted effectors, including Toxoplasma profilin, rhoptry proteins (ROPs), and dense granule antigens (GRAs), are involved in arousing the host’s antigen presentation system to suppress tumors. When T. gondii infection relieves immunosuppression, tumor-related myeloid cells, including macrophages and dendritic cells (DCs), are transformed into immunostimulatory phenotypes, showing a powerful Th1 immune response mediated by CD8+ T cells. Afterwards, they target and kill the tumor cells, and ultimately reduce the size and weight of tumor tissues. This article reviews the latest applications of T. gondii in tumor therapy, including the activation of cellular immunity and the related signal pathways, which will help us understand why T. gondii infection can restrain tumor growth.

Bacterial nucleoid-associated protein HU as an extracellular player in host-pathogen interaction.

HU protein is a member of nucleoid-associated proteins (NAPs) and is an important regulator of bacterial virulence, pathogenesis and survival. NAPs are mainly DNA structuring proteins that influence several molecular processes by binding the DNA. HU´s indispensable role in DNA-related processes in bacteria was described. HU protein is a necessary bacterial transcription factor and is considered to be a virulence determinant as well. Less is known about its direct role in host-pathogen interactions. The latest studies suggest that HU protein may be secreted outside bacteria and be a part of the extracellular matrix. Moreover, HU protein can be internalized in a host cell after bacterial infection. Its role in the host cell is not well described and further studies are extremely needed. Existing results suggest the involvement of HU protein in host cell immune response modulation in bacterial favor, which can help pathogens resist host defense mechanisms. A better understanding of the HU protein’s role in the host cell will help to effective treatment development.

Insight into Viral Hijacking of CRL4 Ubiquitin Ligase through Structural Analysis of the pUL145-DDB1 Complex.

Viruses evolve mechanisms to exploit cellular pathways that increase viral fitness, e.g., enhance viral replication or evade the host cell immune response. The ubiquitin-proteosome system, a fundamental pathway-regulating protein fate in eukaryotes, is hijacked by all seven classes of viruses. Members of the Cullin-RING family of ubiquitin (Ub) ligases are frequently co-opted by divergent viruses because they can target a broad array of substrates by forming multisubunit assemblies comprised of a variety of adapters and substrate receptors. For example, the linker subunit DDB1 in the cullin 4-RING (CRL4)-DDB1 Ub ligase (CRL4DDB1) interacts with an H-box motif found in several unrelated viral proteins, including the V protein of simian virus 5 (SV5-V), the HBx protein of hepatitis B virus (HBV), and the recently identified pUL145 protein of human cytomegalovirus (HCMV). In HCMV-infected cells, pUL145 repurposes CRL4DDB1 to target STAT2, a protein vital to the antiviral immune response. However, the details of how these divergent viral sequences hijack DDB1 is not well understood. Here, we use a combination of binding assays, X-ray crystallography, alanine scanning, cell-based assays, and computational analysis to reveal that viral H-box motifs appear to bind to DDB1 with a higher affinity than the H-box motifs from host proteins DCAF1 and DDB2. This analysis reveals that viruses maintain native hot-spot residues in the H-box motif of host DCAFs and also acquire favorable interactions at neighboring residues within the H-box. Overall, these studies reveal how viruses evolve strategies to produce high-affinity binding and quality interactions with DDB1 to repurpose its Ub ligase machinery. IMPORTANCE Many different viruses modulate the protein machinery required for ubiquitination to enhance viral fitness. Specifically, several viruses hijack the cullin-RING ligase CRL4DDB1 to degrade host resistance factors. Human cytomegalovirus (HCMV) encodes pUL145 that redirects CRL4DDB1 to evade the immune system through the targeted degradation of the antiviral immune response protein STAT2. However, it is unclear why several viruses bind specific surfaces on ubiquitin ligases to repurpose their activity. We demonstrate that viruses have optimized H-box motifs that bind DDB1 with higher affinity than the H-box of native binders. For viral H-boxes, native interactions are maintained, but additional interactions that are absent in host cell H-boxes are formed, indicating that rewiring CRL4DDB1 creates a selective advantage for the virus. The DDB1-pUL145 peptide structure reveals that water-mediated interactions are critical to the higher affinity. Together, our data present an interesting example of how viral evolution can exploit a weakness in the ubiquitination machinery.

Hepatitis B and circadian rhythm of the liver.

The circadian rhythm in humans is determined by the central clock located in the hypothalamus’s suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus’s life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.

Identification and integrated analysis of lncRNAs and miRNAs in IPEC-J2 cells provide novel insight into the regulation of the innate immune response by PDCoV infection

BackgroundNoncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are pivotal regulators involved in the pathogenic mechanism of multiple coronaviruses. Porcine deltacoronavirus (PDCoV) has evolved multiple strategies to escape the innate immune response of host cells, but whether ncRNAs are involved in this process during PDCoV infection is still unknown.ResultsIn this study, the expression profiles of miRNAs, lncRNAs and mRNAs in IPEC-J2 cells infected with PDCoV at 0, 12 and 24 hours postinfection (hpi) were identified through small RNA and RNA sequencing. The differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were screened from the comparison group of IPEC-J2 cells at 0 and 12 hpi as well as the comparison group of IPEC-J2 cells at 12 and 24 hpi. The target genes of these DEncRNAs were predicted. The bioinformatics analysis of the target genes revealed multiple significantly enriched functions and pathways. Among them, the genes that were associated with innate immunity were specifically screened. The expression of innate immunity-related ncRNAs and mRNAs was validated by RT–qPCR. Competing endogenous RNA (ceRNA) regulatory networks among innate immunity-related ncRNAs and their target mRNAs were established. Moreover, we found that the replication of PDCoV was significantly inhibited by two innate immunity-related miRNAs, ssc-miR-30c-3p and ssc-miR-374b-3p, in IPEC-J2 cells.ConclusionsThis study provides a data platform to conduct studies of the pathogenic mechanism of PDCoV from a new perspective and will be helpful for further elucidation of the functional role of ncRNAs involved in PDCoV escaping the innate immune response.

Hepatocellular carcinoma-associated antigen 59 and ADP-ribosylation factor 1 with poly (lactic-co-glycolic acid): A promising candidate as nanovaccine against haemonchosis

Haemonchus contortus (H. contortus) ADP-ribosylation factor 1 (Hc-ARF1) and Hepatocellular carcinoma-associated antigen 59 (Hc-HCA59) are recognized to largely regulate the immune responses of host cells. However, studies about the protective efficacy of the two molecules are poorly unknown. In this research, combinations of recombinant Hc-HCA59 (rHc-HCA59) and Hc-ARF1 (rHc-ARF1) proteins were amalgamated with poly (lactic-co-glycolic acid) (PLGA) nanoparticles adjuvant in order to investigate their protection potential against H. contortus in goats. The results demonstrated that the levels of IgG, IgA, IgE, and IL-4 were noticeably enhanced in the rHc-HCA59 and rHc-ARF1 (rHc-HCA59+rHc-ARF1) group before H. contortus third-stage larvae (L3) challenge. After the L3 challenge, the levels of IL-17, IL-9, and TGF-β were considerably upregulated in the rHc-HCA59+rHc-ARF1 group. In the meantime, the abomasal worm burdens and the fecal eggs were reduced by 63.2% and 69.4% respectively in the rHc-HCA59+rHc-ARF1 group. According to the studies, PLGA nanoparticles immobilized with rHc-HCA59 and rHc-ARF1 proteins conferred partial protection and were expected to be a potential candidate for developing nano vaccines to combat goat haemonchosis.

DDX5: an expectable treater for viral infection- a literature review.

Background and ObjectiveDEAD-box protein (DDX)5 plays important roles in multiple aspects of cellular processes that require modulating RNA structure. Alongside the canonical role of DDX5 in RNA metabolism, many reports have shown that DDX5 influences viral infection by directly interacting with viral proteins. However, the functional role of DDX5 in virus-associated cancers, as well as the identity of DDX5 in virus infection-associated signaling pathways, has remained largely unexplained. Here, we further explore the precise functions of DDX5 and its potential targets for antiviral treatment.MethodsWe searched the PubMed and PMC databases to identify studies on role of DDXs, especially DDX5, during various viral infection published up to May 2022.Key Content and FindingsDDX5 functions as both a viral infection helper and inhibitor, which depends on virus type. DDXs proteins have been identified to play roles on multiple aspects covering RNA metabolism and function.ConclusionsDDX5 influences viral pathogenesis by participating in viral replication and multiple viral infection-related signaling pathways, it also plays a double-edge sword role under different viral infection conditions. Deep investigation into the mechanism of DDX5 modulating immune response in host cells revealed that it holds highly potential usage for future antiviral therapy. We reviewed current studies to provide a comprehensive update of the role of DDX5 in viral infection.

Research Progress in Porcine Reproductive and Respiratory Syndrome Virus-Host Protein Interactions.

Simple SummaryPRRSV–host protein interactions are of great significance in finding new antiviral targets. We summarize the effects of all the PRRSV structural and nonstructural protein interactions with host proteins and on the protein interactions of the virus itself. These results provide a theoretical foundation for the therapeutic targeting of the intrinsic immune factors of the host protein and exploring viral replication mechanisms.Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), which has been regarded as a persistent challenge for the pig industry in many countries. PRRSV is internalized into host cells by the interaction between PRRSV proteins and cellular receptors. When the virus invades the cells, the host antiviral immune system is quickly activated to suppress the replication of the viruses. To retain fitness and host adaptation, various viruses have evolved multiple elegant strategies to manipulate the host machine and circumvent against the host antiviral responses. Therefore, identification of virus–host interactions is critical for understanding the host defense against viral infections and the pathogenesis of the viral infectious diseases. Most viruses, including PRRSV, interact with host proteins during infection. On the one hand, such interaction promotes the virus from escaping the host immune system to complete its replication. On the other hand, the interactions regulate the host cell immune response to inhibit viral infections. As common antiviral drugs become increasingly inefficient under the pressure of viral selectivity, therapeutic agents targeting the intrinsic immune factors of the host protein are more promising because the host protein has a lower probability of mutation under drug-mediated selective pressure. This review elaborates on the virus–host interactions during PRRSV infection to summarize the pathogenic mechanisms of PRRSV, and we hope this can provide insights for designing effective vaccines or drugs to prevent and control the spread of PRRS.

Advances in bacterial c-di-AMP-specific phosphodiesterase

<p indent="0mm">Cyclic dimeric adenosine 3′,5′-monophosphate (c-di-AMP) is an emerging second messenger with multiple functions in <italic>Archaea</italic>, Gram-positive bacteria, <italic>Mycoplasma</italic>, <italic>Chlamydia</italic>, <italic>Cyanobacteria</italic>, and some other Gram-negative bacteria. C-di-AMP-specific phosphodiesterase (PDE) maintains the balance of c-di-AMP metabolism in bacteria. PDEs in bacteria have a vibrant structure and can be classified into three categories based on their functional domains. The first characterized PDE includes GdpP and DhhP homologs. GdpP has two transmembrane helices, a PAS (Per-Arnt-Sim) domain, a degenerate GGDEF domain, and the catalytic domains DHH and DHHA1. DhhP is a stand-alone DHH-DHHA1 domain protein compared with GdpP. Both DhhP and GdpP homologs degrade c-di-AMP via DHH/DHHA1 (Asp-His-His) domain. The second involves PgpH homologs, HD (Asp-His) is the main functional domain of hydrolyzing c-di-AMP. The HD domain structure remains conserved, although the amino acid sequence identity is low in certain bacteria. The newly discovered bacterial extracellular nucleosidases contain CdnP and AtaC and are sensitive to pH and metal ions. However, their catalytic domain for enzymatic activity and specific hydrolysis mechanism needs improvement. C-di-AMP-specific PDE could degrade c-di-AMP to one pApA molecule or two AMP molecules. Some PDEs hydrolyze in two steps, while others only hydrolyze in one, which could be due to conserved metal ion centers and unique substrate binding sites found in different PDEs. However, some c-di-AMP-specific PDEs, such as DhhP, can hydrolyze not only c-di-AMP and pApA but also c-di-GMP and pGpG. Most c-di-AMP-containing bacteria encode two or more PDEs simultaneously, which sense different signals or display distinct substrate preferences to perform diverse cellular functions individually or cooperatively. PDEs are important for maintaining the physiological function of bacteria and eliciting the immune response of host cells by regulating the bacterial c-di-AMP level. Recent studies suggest that PDE deletion or mutation affects multiple physiological functions including bacterial growth, virulence, and sensitivity to the external environment. GdpP leads to a dramatic increase of c-di-AMP in <italic>Staphylococcus aureus</italic>, thus reducing bacterial metabolic activity and growth. PDE absence in <italic>Lactococcus lactis </italic>improves bacterial heat tolerance and increases susceptibility to osmotic stress. PDE deletion could inhibit the overall virulence of particle pathogenic bacteria such as <italic>Streptococcus</italic>. Thus, PDE can be concluded as a potential virulence factor of pathogenic bacteria. Meanwhile, PDE also mediates bacterial biofilm formation via modulating c-di-AMP, which may be a key element in microbial drug resistance. Furthermore, c-di-AMP can effectively activate key molecules of the host cell immune response during pathogen infection; however, its levels are strictly regulated by PDE. This indicates the PDE’s importance in bacterial physiological function and host immune response. Therefore, c-di-AMP-specific PDEs have great significance in the field of antibacterial drugs as a target for preventing and treating pathogenic infections. This paper reviews the types, structures, and biological functions of PDE, aiming to provide references for related research.

Profiling and functional analysis of differentially expressed\xa0circular\xa0RNAs identified in foot-and-mouth disease virus infected PK-15 cells

Circular RNAs (circRNAs) are a new type of endogenous noncoding RNA that exhibit a variety of biological functions. However, it is not clear whether they are involved in foot-and-mouth disease virus (FMDV) infection and host response. In this study, we established circRNA expression profiles in FMDV-infected PK-15 cells using RNA-seq (RNA-sequencing) technology analysis. The biological function of the differentially expressed circRNAs was determined by protein interaction network, Gene Ontology (GO), and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment. We found 1100 differentially expressed circRNAs (675 downregulated and 425 upregulated) which were involved in various biological processes such as protein ubiquitination modification, cell cycle regulation, RNA transport, and autophagy. We also found that circRNAs identified after FMDV infection may be involved in the host cell immune response. RNA-Seq results were validated by circRNAs qRT-PCR. In this study, we analyzed for the first time circRNAs expression profile and the biological function of these genes after FMDV infection of host cells. The results provide new insights into the interactions between FMDV and host cells.

Wolbachia Impacts Anaplasma Infection in Ixodes scapularis Tick Cells.

The specific interactions of members of tick bacterial microbiota and their effects on pathogen transmission remains relatively unexplored. Here, we introduced a novel Wolbachia infection type into Ixodes scapularis tick cells and examined the antipathogenic effects on the intracellular pathogen Anaplasma phagocytophilum. An increase in A. phagocytophilum replication was observed in Wolbachia-infected tick cells. However, Wolbachia infection densities decreased when cells were serially passaged and ultimately the infection was lost. Host-cell immune response was also examined as an additional factor that could have affected A. phagocytophilum replication in Wolbachia-infected cells. In early passages post-Wolbachia infection, a decreased immune response was observed, but in later passages of cells with low Wolbachia densities, there was no change in the immune response. The results are discussed in relation to the importance of studying the interactions of the tick microbiota, the host cell, and the pathogen and the development of novel tick and tick-borne disease-control approaches.

Major Surface Antigens in Zoonotic Babesia.

Human babesiosis results from a combination of tick tropism for humans, susceptibility of a host to sustain Babesia development, and contact with infected ticks. Climate modifications and increasing diagnostics have led to an expanded number of Babesia species responsible for human babesiosis, although, to date, most cases have been attributed to B. microti and B. divergens. These two species have been extensively studied, and in this review, we mostly focus on the antigens involved in host–parasite interactions. We present features of the major antigens, so-called Bd37 in B. divergens and BmSA1/GPI12 in B. microti, and highlight the roles of these antigens in both host cell invasion and immune response. A comparison of these antigens with the major antigens found in some other Apicomplexa species emphasizes the importance of glycosylphosphatidylinositol-anchored proteins in host–parasite relationships. GPI-anchor cleavage, which is a property of such antigens, leads to soluble and membrane-bound forms of these proteins, with potentially differential recognition by the host immune system. This mechanism is discussed as the structural basis for the protein-embedded immune escape mechanism. In conclusion, the potential consequences of such a mechanism on the management of both human and animal babesiosis is examined.

Mesenchymal Stromal/Stem Cells-Derived Exosomes as an Antimicrobial Weapon for Orodental Infections.

The oral cavity as the second most various microbial community in the body contains a broad spectrum of microorganisms which are known as the oral microbiome. The oral microbiome includes different types of microbes such as bacteria, fungi, viruses, and protozoa. Numerous factors can affect the equilibrium of the oral microbiome community which can eventually lead to orodental infectious diseases. Periodontitis, dental caries, oral leukoplakia, oral squamous cell carcinoma are some multifactorial infectious diseases in the oral cavity. In defending against infection, the immune system has an essential role. Depending on the speed and specificity of the reaction, immunity is divided into two different types which are named the innate and the adaptive responses but also there is much interaction between them. In these responses, different types of immune cells are present and recent evidence demonstrates that these cell types both within the innate and adaptive immune systems are capable of secreting some extracellular vesicles named exosomes which are involved in the response to infection. Exosomes are 30–150 nm lipid bilayer vesicles that consist of variant molecules, including proteins, lipids, and genetic materials and they have been associated with cell-to-cell communications. However, some kinds of exosomes can be effective on the pathogenicity of various microorganisms and promoting infections, and some other ones have antimicrobial and anti-infective functions in microbial diseases. These discrepancies in performance are due to the origin of the exosome. Exosomes can modulate the innate and specific immune responses of host cells by participating in antigen presentation for activation of immune cells and stimulating the release of inflammatory factors and the expression of immune molecules. Also, mesenchymal stromal/stem cells (MSCs)-derived exosomes participate in immunomodulation by different mechanisms. Ease of expansion and immunotherapeutic capabilities of MSCs, develop their applications in hundreds of clinical trials. Recently, it has been shown that cell-free therapies, like exosome therapies, by having more advantages than previous treatment methods are emerging as a promising strategy for the treatment of several diseases, in particular inflammatory conditions. In orodental infectious disease, exosomes can also play an important role by modulating immunoinflammatory responses. Therefore, MSCs-derived exosomes may have potential therapeutic effects to be a choice for controlling and treatment of orodental infectious diseases.

Memory-phenotype CD4+ T Lymphocytes: A Novel Therapeutic Target in Infectious or Autoimmune Diseases?

Infectious diseases are posing threats to the world. Although several types of antibiotics and antivirals have been created to treat the diseases, emerging/re-emerging infectious diseases, as well as those caused by pathogens with multidrug resistance, remain to be significant challenges. As a new therapeutic approach, “host-directed therapy” that enhances immune responses of host cells has been proposed. Nevertheless, the agents used in this strategy often lead to a side effect of hyperinflammation, posing a challenge in developing safe and effective drugs. In this review, I suggest boosting a novel CD4+ T lymphocyte population called “memory-phenotype (MP) cells” as a target of the host-directed therapy. MP cells are homeostatically generated from peripheral naïve precursors via recognition of self rather than foreign antigens and are maintained via rapid proliferation in steady state. Surprisingly, MP cells possess innate immune function; they can respond to an inflammatory cytokine IL-12 in the absence of antigen recognition to produce IFN-γ, thereby contributing to host defense against Toxoplasma and Mycobacterium. In this article, I summarize our current understanding of the mechanisms of generation, maintenance, differentiation, and innate effector function of MP CD4+ T lymphocytes and further discuss how we can target these cells as a new therapeutic strategy to infectious and autoimmune/inflammatory diseases.

Regulation of Tripartite Motif-Containing Proteins on Immune Response and Viral Evasion.

Tripartite motif-containing proteins (TRIMs), exhibiting ubiquitin E3 ligase activity, are involved in regulation of not only autophagy and apoptosis but also pyrotosis and antiviral immune responses of host cells. TRIMs play important roles in modulating signaling pathways of antiviral immune responses via type I interferon, NF-κB, Janus kinase/signal transducer and activator of transcription (JAK/STAT), and Nrf2. However, viruses are able to antagonize TRIM activity or evenly utilize TRIMs for viral replication. This communication presents the current understanding of TRIMs exploited by viruses to evade host immune response.

Capsule-dependent impact of MAPK signalling on host cell invasion and immune response during infection of the choroid plexus epithelium by Neisseria meningitidis

BackgroundThe Gram-negative bacterium Neisseria meningitidis (Nm) can cause meningitis in humans, but the host signalling pathways manipulated by Nm during central nervous system (CNS) entry are not completely understood.MethodsWe investigate the role of the mitogen-activated protein kinases (MAPK) Erk1/2 and p38 in an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with Nm serogroup B (NmB) and serogroup C (NmC) strains. A transcriptome analysis of HIBCPP cells following infection with Nm by massive analysis of cDNA ends (MACE) was done to further characterize the cellular response to infection of the barrier.ResultsInterestingly, whereas NmB and NmC wild type strains required active Erk1/2 and p38 pathways for infection, invasion by capsule-deficient mutants was independent of Erk1/2 and, in case of the NmB strain, of p38 activity. The transcriptome analysis of HIBCPP cells following infection with Nm demonstrated specific regulation of genes involved in the immune response dependent on Erk1/2 signalling. Gene ontology (GO) analysis confirmed loss of MAPK signalling after Erk1/2 inhibition and revealed an additional reduction of cellular responses including NFκB and JAK-STAT signalling. Interestingly, GO terms related to TNF signalling and production of IL6 were lost specifically following Erk1/2 inhibition during infection with wild type Nm, which correlated with the reduced infection rates by the wild type in absence of Erk1/2 signalling.ConclusionOur data point towards a role of MAPK signalling during infection of the CP epithelium by Nm, which is strongly influenced by capsule expression, and affects infection rates as well as the host cell response.

Comparative proteomics reveals Cryptosporidium parvum manipulation of the host cell molecular expression and immune response.

Cryptosporidium is a life-threating protozoan parasite belonging to the phylum Apicomplexa, which mainly causes gastroenteritis in a variety of vertebrate hosts. Currently, there is a re-emergence of Cryptosporidium infection; however, no fully effective drug or vaccine is available to treat Cryptosporidiosis. In the present study, to better understand the detailed interaction between the host and Cryptosporidium parvum, a large-scale label-free proteomics study was conducted to characterize the changes to the proteome induced by C. parvum infection. Among 4406 proteins identified, 121 proteins were identified as differentially abundant (> 1.5-fold cutoff, P < 0.05) in C. parvum infected HCT-8 cells compared with uninfected cells. Among them, 67 proteins were upregulated, and 54 proteins were downregulated at 36 h post infection. Analysis of the differentially abundant proteins revealed an interferon-centered immune response of the host cells against C. parvum infection and extensive inhibition of metabolism-related enzymes in the host cells caused by infection. Several proteins were further verified using quantitative real-time reverse transcription polymerase chain reaction and western blotting. This systematic analysis of the proteomics of C. parvum-infected HCT-8 cells identified a wide range of functional proteins that participate in host anti-parasite immunity or act as potential targets during infection, providing new insights into the molecular mechanism of C. parvum infection.

DHAV-1 Blocks the Signaling Pathway Upstream of Type I Interferon by Inhibiting the Interferon Regulatory Factor 7 Protein.

Duck hepatitis A virus (DHAV), which mainly infects 1- to 4-week-old ducklings, has a fatality rate of 95% and poses a huge economic threat to the duck industry. However, the mechanism by which DHAV-1 regulates the immune response of host cells is rarely reported. This study examined whether DHAV-1 contains a viral protein that can regulate the innate immunity of host cells and its specific regulatory mechanism, further exploring the mechanism by which DHAV-1 resists the host immune response. In the study, the dual-luciferase reporter gene system was used to screen the viral protein that regulates the host innate immunity and the target of this viral protein. The results indicate that the DHAV-1 3C protein inhibits the pathway upstream of interferon (IFN)-β by targeting the interferon regulatory factor 7 (IRF7) protein. In addition, we found that the 3C protein inhibits the nuclear translocation of the IRF7 protein. Further experiments showed that the 3C protein interacts with the IRF7 protein through its N-terminus and that the 3C protein degrades the IRF7 protein in a caspase 3-dependent manner, thereby inhibiting the IFN-β-mediated antiviral response to promote the replication of DHAV-1. The results of this study are expected to serve as a reference for elucidating the mechanisms of DHAV-1 infection and pathogenicity.

Structure of African Swine Fever Virus and Associated Molecular Mechanisms Underlying Infection and Immunosuppression: A Review.

African swine fever (ASF) is an acute, highly contagious, and deadly infectious disease. The mortality rate of the most acute and acute ASF infection is almost 100%. The World Organization for Animal Health [Office International des épizooties (OIE)] lists it as a legally reported animal disease and China lists it as class I animal epidemic. Since the first diagnosed ASF case in China on August 3, 2018, it has caused huge economic losses to animal husbandry. ASF is caused by the African swine fever virus (ASFV), which is the only member of Asfarviridae family. ASFV is and the only insect-borne DNA virus belonging to the Nucleocytoplasmic Large DNA Viruses (NCLDV) family with an icosahedral structure and an envelope. Till date, there are still no effective vaccines or antiviral drugs for the prevention or treatment of ASF. The complex viral genome and its sophisticated ability to regulate the host immune response may be the reason for the difficulty in developing an effective vaccine. This review summarizes the recent findings on ASFV structure, the molecular mechanism of ASFV infection and immunosuppression, and ASFV-encoded proteins to provide comprehensive proteomic information for basic research on ASFV. In addition, it also analyzes the results of previous studies and speculations on the molecular mechanism of ASFV infection, which aids the study of the mechanism of clinical pathological phenomena, and provides a possible direction for an intensive study of ASFV infection mechanism. By summarizing the findings on molecular mechanism of ASFV- regulated host cell immune response, this review provides orientations and ideas for fundamental research on ASFV and provides a theoretical basis for the development of protective vaccines against ASFV.

Unique Tropism and Entry Mechanism of Mumps Virus.

Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its entry, interaction with host factors, and host-cell immune responses. Although the underlying mechanisms of MuV tropism remain to be fully understood, recent studies on virus–host interactions have provided insights into viral pathogenesis. This review was aimed at summarizing the entry process of MuV by focusing on the glycan receptors, particularly the recently identified receptors with a trisaccharide core motif, and their interactions with the viral attachment proteins. Here, we describe the receptor structures, their distribution in the human body, and the recently identified host factors for MuV and analyze their relationship with MuV tropism.