Infection and immunity: 'There Are Things Out There You (Don't) Need To Know About'.

This Special Issue of The FEBS Journal consists of 20 reviews covering various aspects and new developments in 'Infection and Immunity'. The issue includes expert views on the role of different immune cell populations, on the regulation of innate and adaptive immune responses, and novel concepts in host defence and inflammatory signalling. Many reviews in this issue also highlight potential targets for future therapeutic interventions that aim to tackle inflammatory and immune responses in health and disease.

IoT for Fight Against COVID-19

An emerging technology Internet of things is the backbone for better solution in medical science research, COVID infected sampling analysis, and device integration process. 2020 may be a year of healing not only for our mother earth, but for mankind too. It is a year of change and practice to develop ourselves against adversities. Due to the recent pandemic caused by COVID-19, many lives were affected. COVID-19 has created an adverse effect on the economy, education, mental health, and physical health of humans. It has been witnessed that despite lockdown, the death rate has increased. From several statistics, it can be observed that populations with less immunity have a higher mortality rate. This study has been performed to make a checkpoint on the factors which may be responsible for determining immunity level and based on that a prediction model may be prepared using a machine learning algorithm. This proposed work employs an IoT application to collect real-time symptom data from users to identify suspected coronavirus symptoms. IoT's sensor-based mechanism adopts for enhance capability of risk minimization specially in surgery cases compilation for COVID-19 type pandemic. © 2023, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

Can BCG Vaccine Be a Potential Tool for COVID-19?

SARS-CoV-2 has affected essentially all countries worldwide and caused millions of people to become infected and die. Therefore, it is extremely valuable to investigate new approaches to stop the most scarring ongoing pandemic. BCG vaccine has been proposed that it could reduce the rate of new COVID cases and limit the severity of infection since TB and COVID-19 have similar dominant effects, such as cytokine storm and improper immune response. This review aimed to focus on the latest literature data on trained immunity as well as the possible cross protection effect of BCG vaccine against COVID-19. The first immune response to BCG vaccines has started with the stimulation of adaptive immune response and establishment of the immunological memory of antigen-specific T and B cells to target infectious agents. In the past years, innate immune response was thought to be not having the talent to adapt and "learn” from previous exposure to a pathogen. Trained immunity is conceivable as 'de facto' innate immune system memory. Some researches argue that there is a strong relationship between BCG immunization and COVID-19 although some are against this argument. Based on the data obtained from different research studies and ongoing clinical trials, there is still no evidence that BCG vaccine is effective against COVID-19. Besides assumptions, knowns and unknowns, the clinical efficiency of BCG vaccine against SARS-CoV-2 should be validated by accurate scientific clinical reports in different age groups to understand the potential benefits of BCG vaccine to limit COVID-19 incidence and mortality.

Defending against SARS-CoV-2: The T cell perspective.

SARS-CoV-2-specific T cell response has been proven essential for viral clearance, COVID-19 outcome and long-term memory. Impaired early T cell-driven immunity leads to a severe form of the disease associated with lymphopenia, hyperinflammation and imbalanced humoral response. Analyses of acute SARS-CoV-2 infection have revealed that mild COVID-19 course is characterized by an early induction of specific T cells within the first 7 days of symptoms, coordinately followed by antibody production for an effective control of viral infection. In contrast, patients who do not develop an early specific cellular response and initiate a humoral immune response with subsequent production of high levels of antibodies, develop severe symptoms. Yet, delayed and persistent bystander CD8+ T cell activation has been also reported in hospitalized patients and could be a driver of lung pathology. Literature supports that long-term maintenance of T cell response appears more stable than antibody titters. Up to date, virus-specific T cell memory has been detected 22 months post-symptom onset, with a predominant IL-2 memory response compared to IFN-γ. Furthermore, T cell responses are conserved against the emerging variants of concern (VoCs) while these variants are mostly able to evade humoral responses. This could be partly explained by the high HLA polymorphism whereby the viral epitope repertoire recognized could differ among individuals, greatly decreasing the likelihood of immune escape. Current COVID-19-vaccination has been shown to elicit Th1-driven spike-specific T cell response, as does natural infection, which provides substantial protection against severe COVID-19 and death. In addition, mucosal vaccination has been reported to induce strong adaptive responses both locally and systemically and to protect against VoCs in animal models. The optimization of vaccine formulations by including a variety of viral regions, innovative adjuvants or diverse administration routes could result in a desirable enhanced cellular response and memory, and help to prevent breakthrough infections. In summary, the increasing evidence highlights the relevance of monitoring SARS-CoV-2-specific cellular immune response, and not only antibody levels, as a correlate for protection after infection and/or vaccination. Moreover, it may help to better identify target populations that could benefit most from booster doses and to personalize vaccination strategies.

T cell immunity ameliorates COVID-19 disease severity and provides post-exposure prophylaxis after peptide-vaccination, in Syrian hamsters.

Background: The emergence of novel SARS-CoV-2 variants that resist neutralizing antibodies drew the attention to cellular immunity and calls for the development of alternative vaccination strategies to combat the pandemic. Here, we have assessed the kinetics of T cell responses and protective efficacy against severe COVID-19 in pre- and post-exposure settings, elicited by PolyPEPI-SCoV-2, a peptide based T cell vaccine. Methods: 75 Syrian hamsters were immunized subcutaneously with PolyPEPI-SCoV-2 on D0 and D14. On D42, hamsters were intranasally challenged with 102 TCID50 of the virus. To analyze immunogenicity by IFN-γ ELISPOT and antibody secretion, lymphoid tissues were collected both before (D0, D14, D28, D42) and after challenge (D44, D46, D49). To measure vaccine efficacy, lung tissue, throat swabs and nasal turbinate samples were assessed for viral load and histopathological changes. Further, body weight was monitored on D0, D28, D42 and every day after challenge. Results: The vaccine induced robust activation of T cells against all SARS-CoV-2 structural proteins that were rapidly boosted after virus challenge compared to control animals (~4-fold, p<0.05). A single dose of PolyPEPI-SCoV-2 administered one day after challenge also resulted in elevated T cell response (p<0.01). The vaccination did not induce virus-specific antibodies and viral load reduction. Still, peptide vaccination significantly reduced body weight loss (p<0.001), relative lung weight (p<0.05) and lung lesions (p<0.05), in both settings. Conclusion: Our study provides first proof of concept data on the contribution of T cell immunity on disease course and provide rationale for the use of T cell-based peptide vaccines against both novel SARS-CoV-2 variants and supports post-exposure prophylaxis as alternative vaccination strategy against COVID-19.

Recombinant vesicular stomatitis virus-vectored vaccine induces long lasting immunity against Nipah virus disease.

The emergence of the novel henipavirus, Langya virus, received global attention earlier this month after the virus sickened over three dozen people in China. There is heightened concern henipaviruses as respiratory pathogens could spark another pandemic, most notably the deadly Nipah virus (NiV). NiV causes near annual outbreaks in Bangladesh and India and induces a highly fatal respiratory disease and encephalitis in humans. No licensed countermeasures against this pathogen exist. An ideal NiV vaccine would confer both fast-acting and long-lived protection. Recently, we reported the generation of a recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing the NiV glycoprotein (rVSV-ΔG-NiVBG) that protected 100% of nonhuman primates from NiV-associated lethality within a week. Here, to evaluate the durability of rVSV-ΔG-NiVBG, we vaccinated African green monkeys (AGMs) one year prior to challenge with a uniformly lethal dose of NiV. The rVSV-ΔG-NiVBG vaccine induced stable and robust humoral responses, whereas cellular responses were modest. All immunized AGMs (whether receiving a single dose or prime-boosted) survived with no detectable clinical signs or NiV replication. Transcriptomic analyses indicated adaptive immune signatures correlated with vaccine-mediated protection. While vaccines for certain respiratory infections (e.g., COVID-19) have yet to provide durable protection, our results suggest rVSV-ΔG-NiVBG elicits long-lasting immunity.

RNA INTERFERENCE IS THE BASIS OF HUMAN ANTIVIRAL DEFENSE.

Comparative analysis of antiviral protective mechanisms in protozoa and RNA interference of multicellular organisms has revealed their similarity, also providing a clue to understanding the adaptive immunity. In this article, we present the latest evidence on the importance of RNA-guided gene regulation in human antiviral defense. The role of neutralizing antibodies and interferon system in viral invasion is considered. The new concept has been introduced, i.e., antiviral protection of any living organism is based on the intracellular RNA-guided mechanisms. Simple and effective defense against viruses is that spacer segment of the viral DNA is inserted into the cellular chromosomes. Upon re-infection, the RNA transcript of the spacer directs nuclease enzymes against the foreign genome. This is a really adaptive immune defense that any cell potentially possesses. In humans, the interferon system provides an additional tool for early suppression of viral infections which shifts the cells to the alert regimen, thus preventing further spread of infection. The main task of the human central immune system is to maintain integrity and combat foreign organisms. Accordingly, a suitable index of acquired antiviral immunity should be a presence of specific spacer markers in DNA samples from reconvalescent persons, rather than detection of neutralizing antibodies, B and T memory cells. This article is addressed primarily to general medical community, and its practical conclusions are as follows: 1. Presence or absence of specific antibodies to SARS-CoV-2 is not a prognostic sign of the disease. Detection of specific antibodies in blood simply reflects the fact that the person has contacted with the viral agent. Absence of antibodies does not mean a lack of such contact, and the persons with high titers of specific antibodies are not protected from re-infection with SARS-CoV-2. 2. PCR testing: The PCR results may remain "false positive" in those subjects who have had COVID-19, if the genetic material is taken from the site of initial virus contraction (mainly, nasopharynx). In our opinion, negative PCR tests for COVID-19 in blood plasma and urine will be a more correct index for the absence of the disease, even with positive PCR tests from the nasopharyngeal samples. 3. It is necessary to draw attention of general practitioners to potential usage of retinol in prevention and treatment of COVID-19, given the importance of RLR receptors in recognition of viral RNAs and positive experience of vitamin A administration in measles, another dangerous viral disease. Copyright © 2022, SPb RAACI.

Age-related changes in the immune system and the consequences of immunosenescence

The cellular and molecular hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, changes in intracellular signaling, cellular senescence, and mitochondrial dysfunction. These lead to complex remodeling and changes involving both the innate and adaptive immune systems. Besides age related changes in immune cells, the microenvironment in the lymphoid and non-lymphoid organs, as well as circulating factors interacting with the immune system also contribute to immunosenescence. Overall, immunosenescence is characterized by reduction of immune response, an increase in inflammatory and oxidation background (inflamm-aging), and production of autoantibodies. One of the most prominent age-related changes in the adaptive immune system is the decline in regenerative thymic capacity. Similar aging related defects have also been observed in stroma of the bone marrow. While lymphocytes in infants show a naive phenotype, memory phenotype predominates after midlife. Though immune responses against recall antigens may still be conserved, the ability to mount primary response against novel antigens declines with age. As a result, increased susceptibility to infections, and suboptimal vaccine response is observed in the elderly. Apart from functional alternation in immune cells, there is a low-grade persistent elevation in inflammatory molecules. Inflamm-aging may result from the accumulation of misfold proteins, compromised gut barrier function, chronic infection, obesity, etc. Furthermore, aging is associated with immune dysregulation, with defective resolution of immune response after activation, and impaired clearance of dead cells with sustained inflammation. Excessive inflammation not only impairs antigen specific immunity, but also leads to tissue damage. In fact, this may partly account for the increased mortality of COVID infection in the elderly. Apart from vulnerability to infection and weakened vaccine response, immunosenescence also plays an important role in cancer and autoimmunity in the elderly. Because of increased tissue damage and apoptosis, coupled with inflamm-aging, increased autoantibodies production is observed in the elderly. Nevertheless, there is an age-related increase in peripheral regulatory T cells. While there is an increase in autoimmunity with aging, this does not always translate into an increase in autoimmune disease. On the other hand, the increase in regulatory T cells, along with other immunosuppressive cells and the senescence associated proinflammatory environment, promotes tumor development and progression in the elderly. As immunosenescence has a significant impact on health and disease, better understanding on this process is crucial for research and development in the future geriatric health care.

ROLE OF IFNgamma IN PATHOGENESIS OF SARS-CoV-2 INFECTION.

To date, there is no consensus explaining the relationship between varying concentrations of IFNgamma and the severity of infection caused by SARS-CoV-2. The aim of this article was to analyze and formulate conclusions from the selected studies and publications, which, in sum, provide a potentially reasonable view on the role of IFNgamma in COVID-19 pathogenesis. This article highlights current data on the immunological role of IFNgamma which affects differentiation of naive T helper cells, acting as a polarizing factor. It activates the major histocompatibility complex (MHC) class I and II, by increasing the expression of MHC I/II subunits, inhibiting replication of the viral particles by initiating activation of interferon-stimulated genes followed by subsequent synthesis of antiviral proteins. Moreover, IFNgamma activates the production of cytokines by T cells, enhancing cytotoxic activity of the T killers. IFNgamma exerts immunostimulatory and immunomodulatory effects via STAT1, SOCS1 and PIAS genes, thus regulating activation of the JAK-STAT signaling pathway. A number of studies were considered where the patterns of changes in serum IFNgamma concentration were examined in viral infections and SARS-CoV-2. We performed a systemic analysis of the results of studies that showed a relationship between high concentrations of IFNgamma and COVID-19 severity. In a number of studies, the significantly high levels of IFNgamma in COVID-19 patients were often associated with a poor outcome of the disease. The median values of the IFNgamma concentration in severe COVID-19 were found to be significantly higher compared to the results obtained in the cases of moderate severity. It shows an increase, in parallel with viral load in the nasopharyngeal samples upon worsening of the clinical condition. Based on the data on the decreased IFNgamma concentrations in convalescent patients, the mechanism of antagonism between IFNgamma and IL-4 is considered, where the decreases serum concentrations of IFNgamma along with increasing level of IL-4 may be an indirect proof of normal adaptive immune response with subsequent development of antibodies to SARS-CoV-2 and gradual elimination of the virus from the body. Moreover, the evidence is discussed that the patients harboring some parasitic infections (Toxoplasma gondii, Cryptosporidium, Blastocystis hominis, Giardia duodenalis, Entamoeba histolytica) with persistently elevated level of IFNgamma are at reduced risk for severe course of COVID-19. Copyright © 2022, SPb RAACI.

Impact Of Plant Based Vaccines On Covid-19

Human life has always been under a constant threat to emerging deadly viruses, Covid-19 is the newest. This deadliest virus become pandemic within a short span of time and brought great amount of concern to fight against it and overcome dynamic challenges. It demands the speedy manufacture of vaccines and drugs at the industrial level. A conventional vaccine is effective but has risk of being infected with foreign agents;to overcome this problem plant based vaccine is superior alternative. The VLPs are generated by recombinant technology and consumed orally and functionally plant cell distributes the antigen. The process consumes time, cost effective, easily conveyed and mucosal immunity induction. Benefit of plant counteract, they are free from any corruption and has minute risk of anomalous responses. VLPs are more stable than conventional vaccines and have immense potential to treat diseases. It contains few bioethical issues, such as transferring of allergens to humans. It requires the safe sites and skilled staff for the smooth administration of operations. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

DNA Oligonucleotides as Antivirals and Vaccine Constituents against SARS Coronaviruses: A Prospective Tool for Immune System Tuning.

The SARS-CoV-2 pandemic has demonstrated the need to create highly effective antivirals and vaccines against various RNA viruses, including SARS coronaviruses. This paper provides a short review of innovative strategies in the development of antivirals and vaccines against SARS coronaviruses, with a focus on antisense antivirals, oligonucleotide adjuvants in vaccines, and oligonucleotide vaccines. Well-developed viral genomic databases create new opportunities for the development of innovative vaccines and antivirals using a post-genomic platform. The most effective vaccines against SARS coronaviruses are those able to form highly effective memory cells for both humoral and cellular immunity. The most effective antivirals need to efficiently stop viral replication without side effects. Oligonucleotide antivirals and vaccines can resist the rapidly changing genomic sequences of SARS coronaviruses using conserved regions of their genomes to generate a long-term immune response. Oligonucleotides have been used as excellent adjuvants for decades, and increasing data show that oligonucleotides could serve as antisense antivirals and antigens in vaccine formulations, becoming a prospective tool for immune system tuning.

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Respiratory viruses: New frontiers-a Keystone Symposia report.

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Longitudinal single-cell analysis of SARS-CoV-2-reactive B cells uncovers persistence of early-formed, antigen specific clones.

Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from severe COVID-19 patients every third to seventh day during hospitalization and every third month after recovery. We profiled the antigen-specific immune cell dynamics by combining single cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-Seq, B cell receptor (BCR)-Seq with oligo-tagged antigen baits. While the proportion of Spike Receptor Binding Domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen specific cells, which was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to one year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen specific B cell responses in longitudinally sampled COVID-19 infected patients.

Impact of pre-existing chronic viral infection and reactivation on the development of long COVID.

BACKGROUND: The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS: In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS: We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52). CONCLUSION: Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. TRIAL REGISTRATION: Long-term Impact of Infection with Novel Coronavirus (LIINC); NCT04362150FUNDING. This work was supported by the National Institute of Allergy and Infectious Diseases NIH/NIAID 3R01AI141003-03S1 to TJ Henrich, R01AI158013 to M Gandhi and M Spinelli, K24AI145806 to P Hunt, and by the Zuckerberg San Francisco Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine. MJP is supported on K23 A137522 and received support from the UCSFBay Area Center for AIDS Research (P30-AI027763).