Infrared Spectroscopy for Rapid Triage of Cancer Using Blood Derivatives: A Reality Check.

Infrared (IR) spectroscopy of serum/plasma represents an alluring molecular diagnostic tool, especially for cancer, as it can provide a molecular fingerprint of clinical samples based on vibrational modes of chemical bonds. However, despite the superior performance, the routine adoption of this technique for clinical settings has remained elusive. This is due to the potential confounding factors that are often overlooked and pose a significant barrier to clinical translation. In this Perspective, we summarize the concerns associated with various confounding factors, such as fluid sampling, optical effects, hemolysis, abnormal cardiovascular and/or hepatic functions, infections, alcoholism, diet style, age, and gender of a patient or normal control cohort, and improper selection of numerical methods that ultimately would lead to improper spectral diagnosis. We also propose some precautionary measures to overcome the challenges associated with these confounding factors.

Corrigendum: IL-3 produced by T cells is crucial for basophil extravasation in hapten- induced allergic contact dermatitis.

[This corrects the article DOI: 10.3389/fimmu.2023.1151468.].

Obesity negatively impacts maintenance of antibody response to COVID-19 vaccines.

Severe obesity accelerates the decline of neutralizing antibodies to COVID-19 vaccines contributing to increased risk of hospitalization from breakthrough SARS-CoV-2 infections.1 These findings have repercussion on the vaccination policy for SARS-CoV-2 variants and other infectious diseases like influenza in obese population.

IL-3 produced by T cells is crucial for basophil extravasation in hapten-induced allergic contact dermatitis.

Basophils have been recognized as a characterized cellular player for Th2 immune responses implicated in allergic diseases, but the mechanisms responsible for basophil recruitment to allergic skin remain not well understood. Using a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) mouse model, we show that basophils in FITC-treated IL-3-knockout mice are defective in crossing the vascular endothelium to enter the inflamed skin. By generating mice in which IL-3 is selectively ablated in T cells, we further demonstrate that IL-3 produced by T cells mediates basophil extravasation. Moreover, basophils sorted from FITC-treated IL-3-knockout mice exhibit a decreased expression of integrins Itgam, Itgb2, Itga2b and Itgb7, which are potentially implicated in extravasation process. Interestingly, we observed that these basophils had a reduced expression of retinaldehyde dehydrogenase 1 family member A2 (Aldh1a2), an enzyme responsible for the production of retinoic acid (RA), and administration of all-trans RA restored partially the extravasation of basophils in IL-3-knockout mice. Finally, we validate that IL-3 induces the expression of ALDH1A2 in primary human basophils, and provide further evidence that IL-3 stimulation induces the expression of integrins particularly ITGB7 in an RA-dependent manner. Together, our data propose a model that IL-3 produced by T cells activates ALDH1A2 expression by basophils, leading to the production of RA, which subsequently induces the expression of integrins crucially implicated in basophil extravasation to inflamed ACD skin.

Immunoinformatics Approaches in Designing Vaccines Against COVID-19.

Since the onset of the COVID-19 pandemic, a number of approaches have been adopted by the scientific communities for developing efficient vaccine candidate against SARS-CoV-2. Conventional approaches of developing a vaccine require a long time and a series of trials and errors which indeed limit the feasibility of such approaches for developing a dependable vaccine in an emergency situation like the COVID-19 pandemic. Hitherto, most of the available vaccines have been developed against a particular antigen of SARS-CoV, spike protein in most of the cases, and intriguingly, these vaccines are not effective against all the pathogenic coronaviruses. In this context, immunoinformatics-based reverse vaccinology approaches enable a robust design of efficacious peptide-based vaccines against all the infectious strains of coronaviruses within a short frame of time. In this chapter, we enumerate the methodological trajectory of developing a universal anti-SARS-CoV-2 vaccine, namely, "AbhiSCoVac," through advanced computational biology-based immunoinformatics approach and its in-silico validation using molecular dynamics simulations.

Intravenous Immunoglobulin: Mechanism of Action in Autoimmune and Inflammatory Conditions.

Intravenous immunoglobulin (IVIG) is the mainstay of therapy for humoral immune deficiencies and numerous inflammatory disorders. Although the use of IVIG may be supplanted by several targeted therapies to cytokines, the ability of polyclonal normal IgG to act as an effector molecule as well as a regulatory molecule is a clear example of the polyfunctionality of IVIG. This article will address the mechanism of action of IVIG in a number of important conditions that are otherwise resistant to treatment. In this commentary, we will highlight mechanistic studies that shed light on the action of IVIG. This will be approached by identifying effects that are both common and disease-specific, targeting actions that have been demonstrated on cells and processes that represent both innate and adaptive immune responses.

The implication of anti-PD-1 therapy in cancer patients for the vaccination against viral and other infectious diseases.

The phenomenon of 'T cell exhaustion', a state of T cell dysfunction observed during chronic infections and cancers, has been a major obstacle in mounting appropriate immune responses against infectious agents or tumor antigens. The exhausted T cells are characterized by poor effector functions mainly due to the overexpression of inhibitory receptors such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing 3 (TIM3), lymphocyte activation gene 3 (LAG3), and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), commonly referred to as immune checkpoint (ICP) molecules. ICP blockade, especially of PD-1 that can potentially reverse T cell exhaustion and thereby re-stimulate the impaired immune system, is widely used in clinics as a promising therapeutic strategy for various cancers and is more recently being investigated in infectious diseases as well. In fact, cancer patients represent a population of immunocompromised individuals who are more susceptible to infections and associated complications, and thus the need for protective vaccinations against these diseases is of prime importance in this category. When it comes to vaccinating anti-PD-1-treated cancer patients against infectious diseases including COVID-19 and influenza, a special focus should be brought on the revived immune cells, which could be dynamically affected by the antigenic stimulation. However, since cancer patients are not generally included in clinical trials for designing vaccines against infectious diseases, the possible interaction between vaccine immune responses and ICP therapy is largely unexplored. Mechanistically, the reversal of T cell exhaustion by ICP in an otherwise immunocompromised population could be beneficial for the vaccine's efficacy, helping the immune system to mount a robust immune response. Nevertheless, patients with cancer undergoing anti-PD-1 blockade are known to experience immune-related adverse effects (irAEs). The risk of increasing the irAEs due to the overstimulation of the immune system during vaccination is a major concern. Therefore, while routine vaccination is indispensable for the protection of cancer patients, the impact of PD-1 blockade on vaccine responses against infectious agents requires careful consideration to avoid undesirable adverse effects that could impair the efficacy of anti-cancer treatment.

Comparative Binding Ability of Human Monoclonal Antibodies against Omicron Variants of SARS-CoV-2: An In Silico Investigation.

Mutation(s) in the spike protein is the major characteristic trait of newly emerged SARS-CoV-2 variants such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Delta-plus. Omicron (B.1.1.529) is the latest addition and it has been characterized by high transmissibility and the ability to escape host immunity. Recently developed vaccines and repurposed drugs exert limited action on Omicron strains and hence new therapeutics are immediately needed. Herein, we have explored the efficiency of twelve therapeutic monoclonal antibodies (mAbs) targeting the RBD region of the spike glycoprotein against all the Omicron variants bearing a mutation in spike protein through molecular docking and molecular dynamics simulation. Our in silico evidence reveals that adintivimab, beludivimab, and regadanivimab are the most potent mAbs to form strong biophysical interactions and neutralize most of the Omicron variants. Considering the efficacy of mAbs, we incorporated CDRH3 of beludavimab within the framework of adintrevimab, which displayed a more intense binding affinity towards all of the Omicron variants viz. BA.1, BA.2, BA.2.12.1, BA.4, and BA.5. Furthermore, the cDNA of chimeric mAb was cloned in silico within pET30ax for recombinant production. In conclusion, the present study represents the candidature of human mAbs (beludavimab and adintrevimab) and the therapeutic potential of designed chimeric mAb for treating Omicron-infected patients.

Tocilizumab-treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants.

Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.

THEME: "Vaccines and Vaccine Adjuvants/Immunomodulators for Infectious Diseases".

The discovery of vaccines has enabled the successful prevention of many deadly infectious diseases, decreased the overall mortality rate, and improved life expectancy worldwide [...].

Respiratory Tract Infections in Diabetes - Lessons From Tuberculosis and Influenza to Guide Understanding of COVID-19 Severity.

Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups. Several mechanisms have been proposed for this increased susceptibility, including pre-existing immune dysfunction, a lack of metabolic flexibility due to insulin resistance, inadequate dietary quality or adverse interactions with antidiabetic treatments or common comorbidities. Some mechanisms that predispose patients with T2D to severe COVID-19 may indeed be shared with other previously characterized respiratory tract infections. Accordingly, in this review, we give an overview of response to Influenza A virus and to Mycobacterium tuberculosis (Mtb) infections. Similar risk factors and mechanisms are discussed between the two conditions and in the case of COVID-19. Lastly, we address emerging approaches to address research needs in infection and metabolic disease, and perspectives with regards to deployment or repositioning of metabolically active therapeutics.

COVID-19: A Veterinary and One Health Perspective.

Interface with animals has been responsible for the occurrence of a major proportion of human diseases for the past several decades. Recent outbreaks of respiratory, haemorrhagic, encephalitic, arthropod-borne and other viral diseases have underlined the role of animals in the transmission of pathogens to humans. The on-going coronavirus disease-2019 (COVID-19) pandemic is one among them and is thought to have originated from bats and jumped to humans through an intermediate animal host. Indeed, the aetiology, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect and cause disease in cats, ferrets and minks, as well as be transmitted from one animal to another. The seriousness of the pandemic along with the zoonotic origin of the virus has been a red alert on the critical need for collaboration and cooperation among human and animal health professionals, as well as stakeholders from various other disciplines that study planetary health parameters and the well-being of the biosphere. It is therefore imminent that One Health principles are applied across the board for human infectious diseases so that we can be better prepared for future zoonotic disease outbreaks and pandemics.

Role of the PD-1 and PD-L1 axis in COVID-19.

Tweetable abstract Severe COVID-19 patients display dysregulated expression of checkpoint molecules PD-1 and its ligand PD-L1, suggesting that these checkpoint molecules could be considered as prognostic markers and therapeutic targets in severe cases of COVID-19.

IFN-γ Induces PD-L1 Expression in Primed Human Basophils.

Programmed death-ligand 1 (PD-L1) plays a key role in maintaining immune tolerance and also in immune evasion of cancers and pathogens. Though the identity of stimuli that induce PD-L1 in various human innate cells and their function are relatively well studied, data on the basophils remain scarce. In this study, we have identified one of the factors, such as IFN-γ, that induces PD-L1 expression in human basophils. Interestingly, we found that basophil priming by IL-3 is indispensable for IFN-γ-induced PD-L1 expression in human basophils. However, priming by other cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF) and thymic stromal lymphopoietin (TSLP) was dispensable. Analyses of a published microarray data set on IL-3-treated basophils indicated that IL-3 enhances IFNGR2, one of the chains of the IFNGR heterodimer complex, and CD274, thus providing a mechanistic insight into the role of IL-3 priming in IFN-γ-induced PD-L1 expression in human basophils.

SARS-CoV-2 Induces Cytokine Responses in Human Basophils.

Basophils play a key role in the orientation of immune responses. Though the interaction of SARS-CoV-2 with various immune cells has been relatively well studied, the response of basophils to this pandemic virus is not characterized yet. In this study, we report that SARS-CoV-2 induces cytokine responses and in particular IL-13, in both resting and IL-3 primed basophils. The response was prominent under IL-3 primed condition. However, either SARS-CoV-2 or SARS-CoV-2-infected epithelial cells did not alter the expression of surface markers associated with the activation of basophils, such as CD69, CD13 and/or degranulation marker CD107a. We also validate that human basophils are not permissive to SARS-CoV-2 replication. Though increased expression of immune checkpoint molecule PD-L1 has been reported on the basophils from COVID-19 patients, we observed that SARS-CoV-2 does not induce PD-L1 on the basophils. Our data suggest that basophil cytokine responses to SARS-CoV-2 might help in reducing the inflammation and also to promote antibody responses to the virus.

Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition.

BACKGROUND: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. METHODS: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. RESULTS: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. CONCLUSIONS: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.