Host Innate Immune System Research Articles

Thapsigargin: An Unlikely Drug in the Battle Against Viral Pandemics

Antiviral resistance is an increasingly categorized phenomenon, and with the high pandemic potential of emergent pathogens such as coronaviruses, the need for novel therapeutic agents is dire. Thapsigargin, a potent endoplasmic reticulum stress inducer found in the Mediterranean region, has shown significant promise in combatting replication of several viruses including coronaviruses by harnessing the host's innate immune system, even being more efficacious than some antivirals currently used. There is a major gap in knowledge regarding the exact mechanism of action that permits Thapsigargin to be an incredible endoplasmic reticulum stress inducer and an potent antiviral. We hypothesize that interferon 1 production and SERCA-inhibition caused by thapsigargin mediates the antiviral effects observed. This review outlines what is currently known about this novel compound, the gap in research, and details methodologies including gene expression analyses, protein quantification, and mammalian cell culturing, to address the gap and answer the hypothesis.

DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA-hepatic proteins interaction profiling, DNA sensor ATP-binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA-binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase-separated condensates by the poly-glutamine (PolyQ) region of the N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx-mediated ubiquitination and degradation of SRY-box transcription factor 4（SOX4）, leading to defects in SOX4-mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.

Toxoplasma gondii ROP5 Enhances Type I IFN Responses by Promoting Ubiquitination of STING.

Toxoplasma gondii is a widely spread opportunistic pathogen that can infect nearly all warm-blooded vertebrates and cause serious toxoplasmosis in immunosuppressed animals and patients. However, the relationship between the host's innate immune system and effector proteins is poorly understood, particularly with regard to how effectors antagonize cGAS-STING signaling during T. gondii infection. In this study, the ROP5 from the PRU strain of T. gondii was found to promote cGAS-STING-mediated immune responses. Mechanistically, ROP5 interacted with STING through predicted domain 2 and modulated cGAS-STING signaling in a predicted domain 3-dependent manner. Additionally, ROP5 strengthened cGAS-STING signaling by enhancing the K63-linked ubiquitination of STING. Consistently, ROP5 deficient PRU (PRUΔROP5) induced fewer type I IFN-related immune responses and replicated faster than the parental strain in RAW264.7 cells. Taken together, this study provides new insights into the mechanism by which ROP5 regulates T. gondii infection and provides new clues for strategies to prevent and control toxoplasmosis.

Current progress on trained immunity-based vaccines

Trained immunity-based vaccines (TIbV) is an emerging vaccine strategy in the field of vaccine research, referring to vaccines designed based on the principles of trained immunity (TI). TI involves the enhanced immune response of innate immune cells upon re-stimulation after being trained. TIbV, built on the concept of TI, aims to enhance resistance to various infectious pathogens by training the host's innate immune system to acquire natural immune memory. This approach is designed to bolster immunity against a wide range of infectious agents, including those not covered by conventional vaccines. This article reviews the concepts, mechanisms, application areas, and future prospects of TIbV, intending to offer a new perspective for vaccine development and design.

In Vitro Analysis of Tandem Peptides from Human CD5 and CD6 Scavenger Receptors as Potential Anti-Cryptococcal Agents.

Cryptococcus neoformans is included in the World Health Organization fungal priority pathogen list, complied to expedite improved research and public-health interventions. The limited number of available antifungal drugs, their associated toxicity, and the emergence of drug-resistant strains make the development of new therapeutic strategies mandatory. Pattern-recognition receptors (PRRs) from the host's innate immune system constitute a potential source of new antimicrobial agents. CD5 and CD6 are lymphoid members of the ancient scavenger receptor cysteine-rich superfamily (SRCR-SF) which bind pathogen-associated molecular patterns (PAMPs) of fungal and bacterial origin. Evidence supports the concept that such binding maps to 11-mer sequences present in each of their three SRCR extracellular domains. Herein, we have designed synthetic peptides containing tandems of such 11-mer sequences (namely CD5-T and CD6-T) and analyzed their C. neoformans-binding properties in vitro. Our results show both inhibitory effects on fungal growth and an ability to impact capsule formation and titanization, two critical virulence factors of C. neoformans involved in immune evasion. These effects hold promise for CD5-T and CD6-T peptides as single or adjuvant therapeutic agents against cryptococcosis.

Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.

Protective immune response against Rhodococcus equi: An innate immunity-focused review.

Rhodococcus equi causes pyogranulomatous pneumonia in foals and immunocompromised people. Despite decades of research efforts, no vaccine is available against this common cause of disease and death in foals. The purpose of this narrative review is to summarise the current understanding of interactions between R. equi and the host innate immune system, to describe features of the immune response that are associated with resistance or susceptibility to R. equi infection, and help guide strategies for developing novel approaches for preventing R. equi infections. Virulence of R. equi in foals has been attributed to the virulence associated protein A which allows intracellular survival in macrophages by preventing acidification of R. equi-containing vacuole. Additionally, foal susceptibility to R. equi infection is associated with immaturity and naivety of innate and adaptive immune systems, while adult horses with fully functional immune system are resistant to pneumonia. Specific interaction between R. equi and innate immune cells can result in bacterial survival or death; learning how to manipulate these responses to control infection is critical to prevent pneumonia in foals. Administration of live vaccines and stimulation of innate immune responses appears to improve foals' immune response and has the potential to overcome the challenges of foal active vaccination and elicit protection against pneumonia.

The Application of Organoids in the Study of Antiviral Innate Immunity.

Antiviral innate immunity plays a critical role in the defense against viral infections, yet its complex interactions with viruses have been challenging to study using traditional models. Organoids, three-dimensional (3D) tissue-like structures derived from stem cells, have emerged as powerful tools for modeling human tissues and studying the complex interactions between viruses and the host innate immune system. This chapter summarizes relevant applications of organoids in antiviral innate immunity studies and provides detailed information and experimental procedures for using organoids to study antiviral innate immunity.

Infection characteristics among Serratia marcescens capsule lineages.

Serratia marcescens is a healthcare-associated pathogen that causes bloodstream infections, pneumonia, and urinary tract infections. The capsule polysaccharide of S. marcescens is a critical fitness determinant during infection and recent work established the relationship between capsule locus (KL) genetic sequences within the species. Strains belonging to KL1 and KL2 capsule clades produce sialylated polysaccharides and represent the largest subpopulation of isolates from clinical origin while the S. marcescens type strain and other environmental isolates were classified as KL5. In this work, the contribution of these and other capsules to pathogenesis in multiple infection models was determined. Using a murine tail vein injection model of bacteremia, clinical strains demonstrated capsule-dependent colonization of spleen, liver, and kidney following inoculation. The KL5 strain, in contrast, exhibited no loss of survival in this model when capsule genes were deleted. Furthermore, the wild-type KL5 strain was cleared more rapidly from both the spleen and liver compared to a KL1 strain. Similar results were observed in a bacteremic pneumonia model in that all tested strains of clinical origin demonstrated a requirement for capsule in both the primary lung infection site and for bloodstream dissemination to other organs. Finally, strains from each KL clade were tested for the role of capsule in internalization by bone marrow-derived macrophages. Only the sialylated KL1 and KL2 clade strains, representing the majority of clinical isolates, exhibited capsule-dependent inhibition of internalization, suggesting that capsule-mediated resistance to macrophage phagocytosis may enhance survival and antibacterial defenses during infection.

Immune checkpoint-regulatable hydrogel-immobilized nanotherapeutics for post-surgical treatment of osteosarcoma

Osteosarcoma recurrence following surgical resection is notoriously prevalent and resistant to chemotherapy (i.e., doxorubicin, DOX) due to its intricate immunosuppressive tumor microenvironment, which remains one of the most life-threatening tumors. In this study, we report the fabrication of an in-situ injectable hydrogel-immobilized nanotherapeutics, tailored to stimulate tumoricidal immunity, thus mitigate both localized osteosarcoma recurrence and the propagation of metastatic tumors subsequent to surgical intervention. Zeolitic imidazolate framework-8 nanoparticles (ZIF NPs), encapsulating a chemotherapeutic agent (i.e., DOX) and immunotherapeutic agents (i.e., αPDL1 and αCD47), are loaded in fibrin hydrogels. These bioengineered constructs are judiciously deployed at surgical sites to orchestrate chemo-immunotherapeutic interventions, effectuated through the controlled release of doxorubicin and the initiation of T cell-mediated immune responses. DOX has the capability to eradicate tumor cells and initiate immunogenic cell death. Notably, αPDL1 engenders the circumvention of PDL1-mediated resistance and dominates metastatic tumor expansion, thereby exerting a pivotal role in the context of systemic immunosuppression. αCD47 blocks the ‘don’t eat me’ signaling axis intrinsic to cancer cells, thereby potentiating their phagocytosis by macrophages. This orchestrated blockade synergistically activates the host immune milieu, thereby repressing tumor recurrence and curtailing the growth of metastatic lesions post-surgical resection in the subcutaneous tumor model (lateral and bilateral) and tibial tumor model (orthotopic and metastatic), respectively. Additionally, zinc ions from the degradation of ZIF NPs acts as the stimulator of interferon genes (STING) agonists to enhance the immunotherapeutic activity against distal and metastatic tumors. The reported immune checkpoint-regulatable cancer immunotherapy activates the host innate and adaptive immune systems, which shows promising for the treatment of osteosarcoma patients.

Siglec7 functions as an inhibitory receptor of non-specific cytotoxic cells and can regulate the innate immune responses in a primitive vertebrate (Oreochromis niloticus)

In mammals, siglec7, an integral component of the siglecs, is principally found on the surface of natural killer (NK) cells, macrophages, and monocytes, where it interacts with various pathogens to perform immunological regulatory activities. Nonetheless, the immune defense and mechanism of siglec7 in early vertebrates remain unknown. In this study, we identified siglec7 from Oreochromis niloticus (OnSiglec7) and revealed its immune functions. Specifically, OnSiglec7 was abundantly expressed in immune-related tissues of healthy tilapia and its transcription level was strongly activated after being challenged with A. hydrophila, S. agalactiae, and Poly: IC. Meanwhile, OnSiglec7 protein was purified and analyzed, which could recognize multiple pathogens through binding and agglutinating activity. Moreover, OnSiglec7-positive cells were mainly distributed in non-specific cytotoxic cells (NCC) of tilapia HKLs and showed cell membrane localization. Furthermore, OnSiglec7 blockage affected multiple innate immune responses (inflammation, apoptosis, and pyroptosis process) by regulating the activation of MAPK, NF-κB, TLR, and JAK-STAT pathways. Finally, OnSiglec7 blockage also greatly enhanced the cytotoxic effect of tilapia NCC. Summarily, this study uncovers immune functions and mechanisms of siglec7 in primitive vertebrates, thereby enhancing our understanding of the systemic evolution and ancient functions of other siglecs within the host's innate immune system (to our knowledge).

Human cytomegalovirus microRNAs: strategies for immune evasion and viral latency.

Viruses use various strategies and mechanisms to deal with cells and proteins of the immune system that form a barrier against infection. One of these mechanisms is the encoding and production of viral microRNAs (miRNAs), whose function is to regulate the gene expression of the host cell and the virus, thus creating a suitable environment for survival and spreading viral infection. miRNAs are short, single-stranded, non-coding RNA molecules that can regulate the expression of host and viral proteins, and due to their non-immunogenic nature, they are not eliminated by the cells of the immune system. More than half of the viral miRNAs are encoded and produced by Orthoherpesviridae family members. Human cytomegalovirus (HCMV) produces miRNAs that mediate various processes in infected cells to contribute to HCMV pathogenicity, including immune escape, viral latency, and cell apoptosis. Here, we discuss which cellular and viral proteins or cellular pathways and processes these mysterious molecules target to evade immunity and support viral latency in infected cells. We also discuss current evidence that their function of bypassing the host's innate and adaptive immune system is essential for the survival and multiplication of the virus and the spread of HCMV infection.

Mycobacterium tuberculosis-Human Immunodeficiency Virus Infection and the Role of T Cells in Protection.

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (M. tb), remains a widespread fatal health issue that becomes significantly detrimental when coupled with HIV. This study explores the host's innate and adaptive immune system response to TB in HIV immunocompromised patients, highlighting the significant role of CD8+ T cells. While the crucial role of macrophages and cytokines, like TNF-α and IFN-γ, in managing the host's immune response to M. tb is examined, the emphasis is on the changes that occur as a result of HIV coinfection. With the progression of HIV infection, the primary source of IFN-γ changes from CD4+ to CD8+ T cells, especially when latent TB advances to an active state. This study sheds light on the necessity of developing new preventative measures such as vaccines and new treatment approaches to TB, especially for immunocompromised patients, who are at a higher risk of life-threatening complications due to TB-HIV coinfection.

Unravelling the interaction between Influenza virus and the nuclear pore complex: insights into viral replication and host immune response.

Influenza viruses are known to cause severe respiratory infections in humans, often associated with significant morbidity and mortality rates. Virus replication relies on various host factors and pathways, which also determine the virus's infectious potential. Nonetheless, achieving a comprehensive understanding of how the virus interacts with host cellular components is essential for developing effective therapeutic strategies. One of the key components among host factors, the nuclear pore complex (NPC), profoundly affects both the Influenza virus life cycle and the host's antiviral defenses. Serving as the sole gateway connecting the cytoplasm and nucleoplasm, the NPC plays a vital role as a mediator in nucleocytoplasmic trafficking. Upon infection, the virus hijacks and alters the nuclear pore complex and the nuclear receptors. This enables the virus to infiltrate the nucleus and promotes the movement of viral components between the nucleus and cytoplasm. While the nucleus and cytoplasm play pivotal roles in cellular functions, the nuclear pore complex serves as a crucial component in the host's innate immune system, acting as a defense mechanism against virus infection. This review provides a comprehensive overview of the intricate relationship between the Influenza virus and the nuclear pore complex. Furthermore, we emphasize their mutual influence on viral replication and the host's immune responses.

Immunotherapy in the context of sepsis-induced immunological dysregulation.

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.

Targeting gut microbiota for immunotherapy of diseases.

With advances in next-generation sequencing technology, there is growing evidence that the gut microbiome plays a key role in the host's innate and adaptive immune system. Gut microbes and their metabolites directly or indirectly regulate host immune cells. Crucially, dysregulation of the gut microbiota is often associated with many immune system diseases. In turn, microbes modulate disease immunotherapy. Data from preclinical to clinical studies suggest that the gut microbiota may influence the effectiveness of tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs). In addition, the most critical issue now is a COVID-19 vaccine that generates strong and durable immunity. A growing number of clinical studies confirm the potential of gut microbes to enhance the efficacy of COVID-19 vaccines. However, it is still unclear how gut bacteria interact with immune cells and what treatments are based on gut microbes. Here, we outline recent advances in the effects and mechanisms of the gut microbiota and its metabolites (tryptophan metabolites, bile acids, short-chain fatty acids, and inosine) on different immune cells (dendritic cells, CD4+T cells, and macrophages). It also highlights innovative intervention strategies and clinical trials of microbiota-based checkpoint blocking therapies for tumor immunity, and ongoing efforts to maintain the long-term immunogenicity of COVID-19 vaccines. Finally, the challenges to be overcome in this area are discussed. These provide an important basis for further research and clinical translation of gut microbiota.

The Role of Macrophage Death in Periodontitis: A Review.

Periodontitis, an infectious inflammatory disease influenced by various factors, disrupts the delicate balance between the host microbiota and immunity. The resulting excessive immune response exacerbates the progressive destruction of the supporting periodontal tissue. Macrophages are essential elements of the host innate immune system. They are pivotal components in the periodontal immune microenvironment and actively participate in both physiological and pathological processes of periodontal tissue. When confronted with periodontitis-related irritant factors, macrophages may differentiate to pro- or anti-inflammatory subtypes that affect tissue homeostasis. Additionally, macrophages may die in response to bacterial infections, potentially affecting the severity of periodontitis. This article reviews the typical mechanisms underlying macrophage death and its effects on periodontitis. We describe five forms of macrophage death in periodontitis: apoptosis, pyroptosis, necroptosis, ferroptosis, and ETosis. Our review of macrophage death in the pathophysiology of periodontitis enhances comprehension of the pathogenesis of periodontitis that will be useful for clinical practice. Although our review elucidates the complex mechanisms by which macrophage death and inflammatory pathways perpetuate periodontitis, unresolved issues remain, necessitating further research.

Innate immune response against vector-borne bunyavirus infection and viral countermeasures.

Bunyaviruses are a large group of important viral pathogens that cause significant diseases in humans and animals worldwide. Bunyaviruses are enveloped, single-stranded, negative-sense RNA viruses that infect a wide range of hosts. Upon entry into host cells, the components of viruses are recognized by host innate immune system, leading to the activation of downstream signaling cascades to induce interferons (IFNs) and other proinflammatory cytokines. IFNs bind to their receptors and upregulate the expression of hundreds of interferon-stimulated genes (ISGs). Many ISGs have antiviral activities and confer an antiviral state to host cells. For efficient replication and spread, viruses have evolved different strategies to antagonize IFN-mediated restriction. Here, we discuss recent advances in our understanding of the interactions between bunyaviruses and host innate immune response.

Abstract NG04: Targeting DHX9 to trigger viral mimicry and immunotherapy responsiveness in small cell lung cancer

Abstract NG04: Targeting DHX9 to trigger viral mimicry and immunotherapy responsiveness in small cell lung cancer

Nor climate nor human impact factors: Chytrid infection shapes the skin bacterial communities of an endemic amphibian in a biodiversity hotspot.

The bacterial communities of the amphibian skin (i.e., the bacteriome) are critical to the host's innate immune system. However, it is unclear how different drivers can alter this function by modulating the bacteriome's structure. Our aim was to assess the extent to which different host attributes and extrinsic factors influence the structure of the bacterial communities of the skin. Skin bacterial diversity was examined in 148 individuals of the four-eyed frog (Pleurodema thaul) from 16 localities spanning almost 1800 km in latitude. The richness and beta diversity of bacterial families and the richness and abundance of Bd-inhibitory bacterial genera were used to describe their structure. Predictors associated with the host (developmental stage, genetic lineage, individual Batrachochytrium dendrobatidis [Bd] infection status) and the landscape (current climate, degree of anthropogenic disturbance) were used in the statistical modeling in an information theoretical approach. Bd infection and host developmental stage were the only predictors affecting bacteriome richness, with Bd+ individuals and postmetamorphic stages (adults and juveniles) having higher richness than Bd- ones and tadpoles. High diversity in Bd+ individuals is not driven by bacterial genera with known anti-Bd properties. Beta diversity was not affected by Bd infection and was mainly a consequence of bacterial family turnover rather than nestedness. Finally, for those bacterial genera known to have inhibitory effects on chytrid, Bd+ individuals had a slightly higher diversity than Bd- ones. Our study confirms an association between Bd infection and the host developmental stage with the bacterial communities of the skin of P. thaul. Unexpectedly, macroclimate and human impact factors do not seem to play a role in shaping the amphibian skin microbiome. Our study exemplifies that focusing on a single host-parasite system over a large geographic scale can provide essential insights into the factors driving host-parasite-bacteriome interactions.