Race between virus and inflammasomes: inhibition or escape, intervention and therapy.

The inflammasome is a multiprotein complex that further regulates cell pyroptosis and inflammation by activating caspase-1. The assembly and activation of inflammasome are associated with a variety of diseases. Accumulative studies have shown that inflammasome is a key modulator of the host's defense response to viral infection. Indeed, it has been established that activation of inflammasome occurs during viral infection. At the same time, the host has evolved a variety of corresponding mechanisms to inhibit unnecessary inflammasome activation. Therefore, here, we review and summarize the latest research progress on the interaction between inflammosomes and viruses, highlight the assembly and activation of inflammosome in related cells after viral infection, as well as the corresponding molecular regulatory mechanisms, and elucidate the effects of this activation on virus immune escape and host innate and adaptive immune defenses. Finally, we also discuss the potential therapeutic strategies to prevent and/or ameliorate viral infection-related diseases via targeting inflammasomes and its products.

The role of HMGB1 in COVID-19-induced cytokine storm and its potential therapeutic targets: A review.

Hyperinflammation characterized by elevated proinflammatory cytokines known as 'cytokine storms' is the major cause of high severity and mortality seen in COVID-19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID-19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS-CoV-2 infection might release a large amount of HMGB1 and RNA of SARS-CoV-2 into extracellular space. HMGB1 is a well-known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS-CoV-2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1-SARS-CoV-2 RNA complexes mediate proinflammatory responses in COVID-19. The contribution of these pathways to impair host immune responses against SARS-CoV-2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1-SARS-CoV-2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1- SARS-CoV-2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID-19 therapy.

Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is characterized not only by severe immunodeficiency but also by persistent inflammation and immune activation. These characteristics persist in people living with HIV (PLHIV) receiving effective antiretroviral therapy (ART) and are associated with morbidity and mortality in nonacquired immunodeficiency syndrome (AIDS) events. ART can inhibit HIV replication and promote immune reconstitution, which is currently the most effective way to control AIDS. However, despite effective long-term ART and overall suppression of plasma HIV RNA level, PLHIV still shows chronic low-level inflammation. The exact mechanisms that trigger chronic inflammation are unknown. Activation of the inflammasome is essential for the host response to pathogens, and some recent studies have confirmed the role of the inflammasome in the pathogenesis of inflammatory diseases. The NLRP3 inflammasome has been widely studied, which is a pyrin domain-containing protein 3 belonging to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent studies suggest that inflammasome-mediated pyroptosis is associated with CD4+ T cell loss in the absence of persistent infectious HIV replication. This article reviews the mechanism of the NLRP3 inflammasome and its correlation with immune reconstitution in PLHIV treated with ART.

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses.

Host genetic and environmental factors including age, biological sex, diet, geographical location, microbiome composition and metabolites converge to influence innate and adaptive immune responses to vaccines. Failure to understand and account for these factors when investigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy may impair the development of the next generation of vaccines. Most studies aimed at identifying mechanisms of vaccine-mediated immune protection have focused on adaptive immune responses. It is well established, however, that mobilization of the innate immune response is essential to the development of effective cellular and humoral immunity. A comprehensive understanding of the innate immune response and environmental factors that contribute to the development of broad and durable cellular and humoral immune responses to SARS-CoV-2 and other vaccines requires a holistic and unbiased approach. Along with optimization of the immunogen and vectors, the development of adjuvants based on our evolving understanding of how the innate immune system shapes vaccine responses will be essential. Defining the innate immune mechanisms underlying the establishment of long-lived plasma cells and memory T cells could lead to a universal vaccine for coronaviruses, a key biomedical priority.

Reviewing the Etiologic Agents, Microbe-Host Relationship, Immune Response, Diagnosis, and Treatment in Chromoblastomycosis.

Chromoblastomycosis (CBM) is a neglected human disease, caused by different species of pigmented dematiaceous fungi that cause subcutaneous infections. This disease has been considered an occupational disease, occurring among people working in the field of agriculture, particularly in low-income countries. In 1914, the first case of CBM was described in Brazil, and although efforts have been made, few scientific and technological advances have been made in this area. In the field of fungi and host cell relationship, a very reduced number of antigens were characterized, but available data suggest that ectoantigens bind to the cell membrane of host cells and modulate the phagocytic, immunological, and microbicidal responses of immune cells. Furthermore, antigens cleave extracellular proteins in tissues, allowing fungi to spread. On the contrary, if phagocytic cells are able to present antigens in MHC molecules to T lymphocytes in the presence of costimulation and IL-12, a Th1 immune response will develop and a relative control of the disease will be observed. Despite knowledge of the resistance and susceptibility in CBM, up to now, no effective vaccines have been developed. In the field of chemotherapy, most patients are treated with conventional antifungal drugs, such as itraconazole and terbinafine, but these drugs exhibit limitations, considering that not all patients heal cutaneous lesions. Few advances in treatment have been made so far, but one of the most promising ones is based on the use of immunomodulators, such as imiquimod. Data about a standard treatment are missing in the medical literature; part of it is caused by the existence of a diversity of etiologic agents and clinical forms. The present review summarizes the advances made in the field of CBM related to the diversity of pathogenic species, fungi and host cell relationship, antigens, innate and acquired immunity, clinical forms of CBM, chemotherapy, and diagnosis.

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.

Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics.

The Human Immunodeficiency Virus type 1 (HIV-1) virion contains a conical shell, termed capsid, encasing the viral RNA genome. After cellular entry of the virion, the capsid is released and ensures the protection and delivery of the HIV-1 genome to the host nucleus for integration. The capsid relies on many virus-host factor interactions which are regulated spatiotemporally throughout the course of infection. In this paper, we will review the current understanding of the highly dynamic HIV-1 capsid-host interplay during the early stages of viral replication, namely intracellular capsid trafficking after viral fusion, nuclear import, uncoating, and integration of the viral genome into host chromatin. Conventional anti-retroviral therapies primarily target HIV-1 enzymes. Insights of capsid structure have resulted in a first-in-class, long-acting capsid-targeting inhibitor, GS-6207 (Lenacapavir). This inhibitor binds at the interface between capsid protein subunits, a site known to bind host factors, interferes with capsid nuclear import, HIV particle assembly, and ordered assembly. Our review will highlight capsid structure, the host factors that interact with capsid, and high-throughput screening techniques, specifically genomic and proteomic approaches, that have been and can be used to identify host factors that interact with capsid. Better structural and mechanistic insights into the capsid-host factor interactions will significantly inform the understanding of HIV-1 pathogenesis and the development of capsid-centric antiretroviral therapeutics.

Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer.

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.

Natural killer cells play an important role in virus infection control: Antiviral mechanism, subset expansion and clinical application.

With the global spread of coronavirus disease 2019 (COVID-19), the important role of natural killer (NK) cells in the control of various viral infections attracted more interest, via non-specific activation, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and activating receptors, as well as specific activation, such as memory-like NK generation. In response to different viral infections, NK cells fight viruses in different ways, and different NK subsets proliferate. For instance, cytomegalovirus (CMV) induces NKG2C + CD57 + KIR+ NK cells to expand 3-6 months after hematopoietic stem cell transplantation (HSCT), but human immunodeficiency virus (HIV) induces KIR3DS1+/KIR3DL1 NK cells to expand in the acute phase of infection. However, the similarities and differences among these processes and their molecular mechanisms have not been fully discussed. In this article, we provide a summary and comparison of antiviral mechanisms, unique subset expansion and time periods in peripheral blood and tissues under different conditions of CMV, HIV, Epstein-Barr virus (EBV), COVID-19 and hepatitis B virus (HBV) infections. Accordingly, we also discuss current clinical NK-associated antiviral applications, including cell therapy and NK-related biological agents, and we state the progress and future prospects of NK cell antiviral treatment.

Success of prophylactic antiviral therapy for SARS-CoV-2: Predicted critical efficacies and impact of different drug-specific mechanisms of action.

Repurposed drugs that are safe and immediately available constitute a first line of defense against new viral infections. Despite limited antiviral activity against SARS-CoV-2, several drugs are being tested as medication or as prophylaxis to prevent infection. Using a stochastic model of early phase infection, we evaluate the success of prophylactic treatment with different drug types to prevent viral infection. We find that there exists a critical efficacy that a treatment must reach in order to block viral establishment. Treatment by a combination of drugs reduces the critical efficacy, most effectively by the combination of a drug blocking viral entry into cells and a drug increasing viral clearance. Below the critical efficacy, the risk of infection can nonetheless be reduced. Drugs blocking viral entry into cells or enhancing viral clearance reduce the risk of infection more than drugs that reduce viral production in infected cells. The larger the initial inoculum of infectious virus, the less likely is prevention of an infection. In our model, we find that as long as the viral inoculum is smaller than 10 infectious virus particles, viral infection can be prevented almost certainly with drugs of 90% efficacy (or more). Even when a viral infection cannot be prevented, antivirals delay the time to detectable viral loads. The largest delay of viral infection is achieved by drugs reducing viral production in infected cells. A delay of virus infection flattens the within-host viral dynamic curve, possibly reducing transmission and symptom severity. Thus, antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk.

How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review.

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.

HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy.

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A.

Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients' outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

A Model for SARS-CoV-2 Infection with Treatment.

The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key interactions between SARS-CoV-2 spike protein and its host (epithelial cell) receptor, also known as angiotensin-converting enzyme 2 (ACE2). It controls both the cross-species and human-to-human transmissions of SARS-CoV-2. In view of this, we propose and analyze a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a postinfection immunostimulant drug (pidotimod) is administered at regular intervals. Dynamics of the system with and without impulses have been analyzed using the basic reproduction number. This study shows that the proper dosing interval and drug dose both are important to eradicate the viral infection.

Bifidobacterium animalis subsp lactis HN019 presents antimicrobial potential against periodontopathogens and modulates the immunological response of oral mucosa in periodontitis patients.

OBJECTIVE: To evaluate the effects of Bifidobacterium animalis subsp. lactis HN019 (HN019) on clinical periodontal parameters (plaque accumulation and gingival bleeding), on immunocompetence of gingival tissues [expression of beta-defensin (BD)-3, toll-like receptor 4 (TLR4), cluster of differentiation(CD)-57 and CD-4], and on immunological properties of saliva (IgA levels) in non-surgical periodontal therapy in generalized chronic periodontitis (GCP) patients. Adhesion to buccal epithelial cells (BEC) and the antimicrobial properties of HN019 were also investigated. MATERIALS AND METHODS: Thirty patients were recruited and monitored clinically at baseline (before scaling and root planing-SRP) and after 30 and 90 days. Patients were randomly assigned to Test (SRP+Probiotic, n = 15) or Control (SRP+Placebo, n = 15) group. Probiotic lozenges were used for 30 days. Gingival tissues and saliva were immunologically analyzed. The adhesion of HN019 with or without Porphyromonas gingivalis in BEC and its antimicrobial properties were investigated in in vitro assays. Data were statistically analyzed (p<0.05). RESULTS: Test group presented lower plaque index (30 days) and lower marginal gingival bleeding (90 days) when compared with Control group. Higher BD-3, TLR4 and CD-4 expressions were observed in gingival tissues in Test group than in Control group. HN019 reduced the adhesion of P. gingivalis to BEC and showed antimicrobial potential against periodontopathogens. CONCLUSION: Immunological and antimicrobial properties of B. lactis HN019 make it a potential probiotic to be used in non-surgical periodontal therapy of patients with GCP. CLINICAL RELEVANCE: B. lactis HN019 may be a potential probiotic to improve the effects of non-surgical periodontal therapy. Name of the registry and registration number (ClinicalTrials.gov): "Effects of probiotic therapy in the treatment of periodontitis"-NCT03408548.

New Agents in Development for Sepsis: Any Reason for Hope?

Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has  resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

Gene Therapy: Contest between Adeno-Associated Virus and Host Cells and the Impact of UFMylation.

Adeno-associated virus (AAV)-based gene therapy is currently limited by (1) decline in therapeutic gene expression over time, (2) immune cell activation and (3) neutralization by pre-existing antibodies. Hence, studying the interaction of AAV vectors with various cellular pathways during the production and transduction process is necessary to overcome such barriers. Post-translational modifications (PTM) of AAV vectors during the production and transduction process is known to limit its transduction efficiency and further evoke the immune response. Further, AAV vectors are known to trigger cellular stress, resulting in an upregulation of distinct arms of the unfolded protein response (UPR) pathway. Recognition of the AAV genome by Toll-like receptor-9 triggers the myeloid differentiation primary response signaling cascade for innate (IL-6, IFN-α, IFN-ß) and adaptive (CD8+ T-cell, B-cell) immune response against the viral capsid and the transgene product. Herein, we highlight a potential intersection of the UPR, PTMs, and intracellular trafficking pathways, which could be fine-tuned to augment the outcome of AAV-based gene delivery.

Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes.

Colorectal cancer (CRC) is a multifaceted disease influenced by both environmental and genetic factors. A large body of literature has demonstrated the role of gut microbes in promoting inflammatory responses, creating a suitable microenvironment for the development of skewed interactions between the host and the gut microbiota and cancer initiation. Even if surgery is the primary therapeutic strategy, patients with advanced disease or cancer recurrence after surgery remain difficult to cure. Therefore, the gut microbiota has been proposed as a novel therapeutic target in light of recent promising data in which it seems to modulate the response to cancer immunotherapy. The use of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics, and fecal microbiota transplantation, is therefore considered to support current therapies in CRC management. In this review, we will discuss the importance of host-microbe interactions in CRC and how promoting homeostatic immune responses through microbe-targeted therapies may be useful in preventing/treating CRC development.