COVID-19 Vaccines over Three Years after the Outbreak of the COVID-19 Epidemic.

The outbreak of COVID-19 started in December 2019 and spread rapidly all over the world. It became clear that the development of an effective vaccine was the only way to stop the pandemic. It was the first time in the history of infectious diseases that the process of the development of a new vaccine was conducted on such a large scale and accelerated so rapidly. At the end of 2020, the first COVID-19 vaccines were approved for marketing. At the end of March 2023, over three years after the outbreak of the COVID-19 pandemic, 199 vaccines were in pre-clinical development and 183 in clinical development. The candidate vaccines in the clinical phase are based on the following platforms: protein subunit, DNA, RNA, non-replication viral vector, replicating viral vector, inactivated virus, virus-like particles, live attenuated virus, replicating viral vector combined with an antigen-presenting cell, non-replication viral vector combined with an antigen-presenting cell, and bacterial antigen-spore expression vector. Some of the new vaccine platforms have been approved for the first time for human application. This review presents COVID-19 vaccines currently available in the world, procedures for assurance of the quality and safety of the vaccines, the vaccinated population, as well as future perspectives for the new vaccine platforms in drug and therapy development for infectious and non-infectious diseases.

Affective Polarization and Political Belief Systems: The Role of Political Identity and the Content and Structure of Political Beliefs.

We investigate the extent that political identity, political belief content (i.e., attitude stances), and political belief system structure (i.e., relations among attitudes) differences are associated with affective polarization (i.e., viewing ingroup partisans positively and outgroup partisans negatively) in two multinational, cross-sectional studies (Study 1 N = 4,152, Study 2 N = 29,994). First, we found a large, positive association between political identity and group liking-participants liked their ingroup substantially more than their outgroup. Second, political belief system content and structure had opposite associations with group liking: Sharing similar belief system content with an outgroup was associated with more outgroup liking, but similarity with the ingroup was associated with less ingroup liking. The opposite pattern was found for political belief system structure. Thus, affective polarization was greatest when belief system content similarity was low and structure similarity was high.

When the sun goes down: low political knowledge and high national narcissism predict climate change conspiracy beliefs.

The present research empirically examines the links between political knowledge, national narcissism, and climate change conspiracy beliefs. National narcissism (i.e., an unrealistic belief about in-group's greatness which is maladaptive both from the perspective of intra- and inter-group processes) was previously linked to conspiracy beliefs. In this research, we hypothesized that low theoretical political knowledge would boost national narcissism and further lead to adopting climate change conspiracy theories. METHODS: This hypothesis was tested in a two-wave study conducted among Polish participants (N = 558). RESULTS: We found negative effect of political knowledge on climate change conspiracy beliefs. Moreover, national narcissism mediated between theoretical political knowledge and conspiracy beliefs. CONCLUSION: People having low political knowledge are prone to believe in climate change conspiracy theories. Moreover, those less informed about the way political system works in their country are more narcissistically identified with their nation and, thus, deny the climate change.

A vicious circle? Longitudinal relationships between different modes of in-group identity and COVID-19 conspiracy thinking.

Since March 2020, when the World Health Organization declared the spread of COVID-19 a global pandemic, conspiracy theories have continued to rise. This research examines the role of different forms of in-group identity in predicting conspiracy thinking in the context of the coronavirus pandemic. We hypothesized that conspiracy thinking would be predicted positively by national narcissism (i.e., a belief in in-group's greatness which is contingent on its external validation and makes in-group members sensitive to psychological threats) but negatively by secure national identification (i.e., a confidently held ingroup evaluation, which serves as a buffer against psychological threats). In a three-wave longitudinal study conducted on a representative sample of adult Poles (N = 650), conspiracy thinking was positively predicted by national narcissism, but negatively by national identification. Further, we found evidence that conspiracy thinking strengthened national narcissism (but not national identification) over time. Implications for intra- and intergroup processes are discussed.

From Individual Anxiety to Collective Narcissism? Adult Attachment Styles and Different Types of National Commitment.

National narcissism and national identification, two distinct types of national commitment, differ in terms of their psychological concomitants. Therefore, in the current article, we hypothesized that they would also relate to different adult attachment styles. Namely, we proposed that national narcissism would be positively associated with higher attachment anxiety, while national identification would be associated with lower attachment anxiety and avoidance. These hypotheses were tested in three cross-sectional surveys (Study 1 N = 570; Study 3 N = 558; Study 4 N = 649) and one longitudinal survey (Study 2 N = 808). In all studies, we found a consistent positive relationship between attachment anxiety and national narcissism, and a negative relationship between attachment avoidance and national identification. Finally, we also demonstrated indirect effects of attachment anxiety (via national narcissism) on maladaptive group-related outcomes: conspiracy beliefs, non-normative collective action, and willingness to conspire.

Evaluation of precipitation time of the aluminum salts adsorbed potentially frozen vaccines used in the Polish National Immunization Schedule for their pre-qualification before the administration.

Purpose: Vaccines adsorbed on aluminum adjuvants irreversibly lose potency after freezing and their safety is affected. To prevent the administration of such vaccines, the World Health Organization developed the Shake Test designed to determine whether adsorbed vaccines have been frozen or not. However, the Shake Test is difficult and time-consuming when routinely conducted at the place of vaccination. In this study, a modified shake test for prequalification of potentially frozen vaccines was elaborated. Materials and Methods: Vaccines used in the Polish Immunization Schedule were investigated and the analysis includes an assessment of precipitation time and the influence of the container type, amount and type of aluminum compound, and a volume of vaccine dose on the precipitation time. Results: Significant differences between the precipitation time of frozen and non-frozen vaccines routinely used in the Polish Immunization Schedule were observed. The precipitation time of all non-frozen vaccines was above 30 minutes. The longest precipitation time of frozen vaccines was 10 minutes. Conclusion: The finding of the study can be used in practice by the personnel administering vaccines to patients. Step-by-step recommendations for the preparation of the test have been proposed in the article.

COVID-19: Why Do People Refuse Vaccination? The Role of Social Identities and Conspiracy Beliefs: Evidence from Nationwide Samples of Polish Adults.

In the present research, we focus on COVID-19 vaccine hesitancy, and empirically examine how different forms of social identity (defensive vs. secure national identity and identification with all humanity) and conspiracy beliefs are associated with COVID-19 vaccine hesitancy. In two cross-sectional nationwide surveys (Study 1, n = 432, and Study 2, n = 807), we found that willingness to vaccinate against COVID-19 was negatively linked to national narcissism, but positively related to a secure national identification, that is, national identification without the narcissistic component. In both studies, we also found that the relationship between narcissistic (vs. secure) national identity and unwillingness to vaccinate against COVID-19 was mediated by COVID-19 vaccine conspiracy beliefs. These effects were present even when we accounted for basic demographics (Studies 1 and 2) and identification with all humanity (Study 2), which had been found to be a significant predictor of health behaviors during COVID-19. In line with previous research, identification with all humanity was positively associated with the willingness to vaccinate against COVID-19. We discuss the implications for understanding the role of the way in which people identify with their national and supranational groups in antiscience attitudes and (mal)adaptive behaviors during COVID-19 pandemic.

Diphtheria-tetanus-pertussis vaccine: past, current & future.

The diphtheria-tetanus-pertussis (DTP) vaccine can prevent diphtheria, tetanus and pertussis. The component antigens of the DTP vaccine had long been monovalent vaccines. The pertussis vaccine was licensed in 1914. The same year, the mixtures of diphtheria toxin and antitoxin were put into use. In 1926, alum-precipitated diphtheria toxoid was registered, and in 1937 adsorbed tetanus toxoid was put on the market. The development of numerous effective DTP vaccines quickly stimulated efforts to combine DTP with other routine vaccines for infants. This overview covers the most important information regarding the invention of DTP vaccines, their modifications and the needs that should be focused on in the future.

Threatened Masculinity: Gender-Related Collective Narcissism Predicts Prejudice Toward Gay and Lesbian People among Heterosexual Men in Poland.

We examined the relationships between different types of in-group positivity and prejudice toward gay and lesbian people among heterosexual men. We assumed that prejudice toward gay and lesbian people among heterosexual men should be predicted by gender-related collective narcissism (i.e., an unrealistic belief about in-group's greatness which is contingent on external validation and extremely sensitive to any signs of threats) and not secure gender in-group identification (i.e., a confidently held in-group evaluation which is independent of the recognition of the group by others and serves as a buffer against threats). Across two studies (final Ns = 212 and 180) we found that gender-related collective narcissism (but not secure gender in-group identification or gender self-esteem) is positively related to prejudice toward gay and lesbian people among heterosexual men. The results of Study 2 demonstrated that this relationship was largely accounted for by the perceived out-group threat.

Changes in Life Situations during the SARS-CoV-2 Virus Pandemic and Their Impact on Eating Behaviors for Residents of Europe, Australia as Well as North and South America.

Many people's life situations are changing as a result of restrictions being imposed by national governments to limit the spread of the virus. These may be associated with additional factors (emotional or financial, for example) that influence eating behavior and physical activity levels. Therefore, the aim of this study was to show whether there is a relationship between a changing life situation during the pandemic and eating behavior as well as physical activity. An online survey was conducted between 28 April and 16 July 2020 with 921 participants from European countries and countries outside Europe (South and North America, Australia). An analysis of the obtained results showed an unfavorable relationship between a change in life situation during the pandemic and eating behavior as well as physical activity. This was observed mainly among students who returned to their family homes and respondents whose working hours increased. Students were more likely to snack between meals (51.13%, p < 0.001) and to consume more sweets (45.11%, p < 0.001) and savory snacks (30.83%, p < 0.001). Those whose working hours had increased, consumed morefast foods (13.57%, p < 0.05) during that time. On the other hand, the study results indicated that a change in life situation during the pandemic can also have a positive impact on eating behavior and physical activity. This was exhibited by individuals who transitioned to remote working. An improvement in the regularity of eating (38.86%, p < 0.001) was recorded for this group. The relationship between a change in life situation and eating behavior was further emphasized by the fact that people whose life situation had not changed were more likely to declare no change in the regularity of eating (62.86%, p < 0.001) and snacking (61.71%, p < 0.001). At the same time, they were less likely to exhibit a higher intake of sweets (22.29%, p < 0.01) and salty snacks (13.14%, p < 0.01). The study results indicated that a change in the nutritional situation during the pandemic may have had both negative and positive effects on eating behavior and physical activity. Finding these relationships may help identify groups that are particularly vulnerable to reduced diet quality and reduced levels of physical activity. Considering the immunomodulating effects of diets and the fact that physical activity is essential for maintaining good health, further research in this area is needed.

Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein.

Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides-besides transcription-an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP-together with the RBM4 splicing factor-in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model.

The aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST-multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.

Changes in Eating Behaviour during SARS-CoV-2 Pandemic among the Inhabitants of Five European Countries.

Psychological factors and restrictions imposed due to the pandemic may influence eating behaviours and physical activity. With the above thesis in mind, questionnaire-based surveys were conducted amongst residents of five European countries: Poland, Italy, Spain, Portugal and Great Britain (England and Scotland). A specially devised, structured questionnaire was used to conduct anonymous internet surveys between 28 April and 16 July 2020. It contained questions pertaining to sociodemographic data, eating behaviours, the impact of the pandemic on the diet and physical activity. The questionnaire was made available to internet users in Poland, Italy, Spain, Great Britain (England and Scotland), and Portugal. The questionnaire was translated by native speakers into five languages: Polish, English, Spanish, Italian and Portuguese. Survey results were then analysed using StatSoft's Statistica v. 13 software and Cytel's StatXact v. 9.0.0. Age was the parameter that impacted changing eating behaviours to the largest extent during the pandemic. It was also found that during the pandemic, regular consumption of meals was most dependent on various factors. The negative impact of the pandemic within this scope was most profound amongst women, city residents regardless of gender and people over 35 years of age. A change in the frequency of consumption of selected product groups during the pandemic was also observed. Reduced consumption of meat and fish was identified. Especially among people under 35 living in Portugal, almost half-45.5% (p = 0.0210) declared lower consumption of meat, and more than half-54.5% (p = 0.011) reported lower consumption of fish. An analysis of the obtained results also showed an increase in the consumption of products with lower nutritional values, particularly amongst people under 35 years of age and also amongst residents of Great Britain (regardless of age). Moreover, the results showed that the pandemic may have had an impact on the weight reduction diet. A negative impact was declared by 16.5% of people, compared to 9.7% who said that the pandemic facilitated the use of the weight reduction diet (p = 0.006). The results of our survey also showed a decrease in the level of physical activity among people over 35 living in Poland (69.6%, p = 0.0497) and people living in Portuguese cities (72.73%, p = 0.0245). Our survey results showed that the impact of the pandemic on eating behaviours was particularly profound when it came to meal consumption regularity. Changes to the consumption of products with lower nutritional values, which may decrease immunity, have also been found during the pandemic. Our results showed that the problem associated with consuming products with lower nutritional values was particularly evident amongst people under 35. Considering the global character of SARS-CoV-2 transmission, further research is necessary to determine its impact on the diet, nutritional status and physical activity.

Epstein-Barr virus inactivates the transcriptome and disrupts the chromatin architecture of its host cell in the first phase of lytic reactivation.

Epstein-Barr virus (EBV), a herpes virus also termed HHV 4 and the first identified human tumor virus, establishes a stable, long-term latent infection in human B cells, its preferred host. Upon induction of EBV's lytic phase, the latently infected cells turn into a virus factory, a process that is governed by EBV. In the lytic, productive phase, all herpes viruses ensure the efficient induction of all lytic viral genes to produce progeny, but certain of these genes also repress the ensuing antiviral responses of the virally infected host cells, regulate their apoptotic death or control the cellular transcriptome. We now find that EBV causes previously unknown massive and global alterations in the chromatin of its host cell upon induction of the viral lytic phase and prior to the onset of viral DNA replication. The viral initiator protein of the lytic cycle, BZLF1, binds to >105 binding sites with different sequence motifs in cellular chromatin in a concentration dependent manner implementing a binary molar switch probably to prevent noise-induced erroneous induction of EBV's lytic phase. Concomitant with DNA binding of BZLF1, silent chromatin opens locally as shown by ATAC-seq experiments, while previously wide-open cellular chromatin becomes inaccessible on a global scale within hours. While viral transcripts increase drastically, the induction of the lytic phase results in a massive reduction of cellular transcripts and a loss of chromatin-chromatin interactions of cellular promoters with their distal regulatory elements as shown in Capture-C experiments. Our data document that EBV's lytic cycle induces discrete early processes that disrupt the architecture of host cellular chromatin and repress the cellular epigenome and transcriptome likely supporting the efficient de novo synthesis of this herpes virus.

Adherence to safety and self-isolation guidelines, conspiracy and paranoia-like beliefs during COVID-19 pandemic in Poland - associations and moderators.

BACKGROUND: Due to coronavirus pandemic, governments have ordered a nationwide isolation. In this situation, we hypothesised that people holding conspiracy beliefs are less willing to adhere to medical guidelines. Furthermore, we explored what possible factors may modify relationships between conspiracy, paranoia-like beliefs, and adherence to epidemiological guidelines. Also, we examined the prevalence of different coronavirus conspiracy beliefs. METHODS: Two independent internet studies. Study 1 used a proportional quota sample that was representative of the population of Poles in terms of gender and settlement size (n=507). Study 2 employed a convenience sample (n=840). RESULTS: Coronavirus conspiracy beliefs are negatively related to safety guidelines. Mixed results suggest that paranoia-like beliefs are related negatively to safety guidelines. Prevalence of firmly held coronavirus conspiracy beliefs is rare. Nevertheless, certain percentage of participants agree with conspiracy beliefs at least partially. Coronavirus related anxiety, trust in media, and internal motivation to isolation moderate the relationship between conspiracy beliefs and adherence to safety guidelines. Paranoia-like beliefs partially mediate between boredom and conspiracy beliefs. CONCLUSIONS: Conspiracy beliefs concerning coronavirus are present in the population and are negatively related to adherence to safety guidelines. Conspiracy beliefs originate partially from boredom and paranoia proneness. Certain factors - trust in media and internal motivation to isolation - are potentially worthwhile to address to enhance adherence to safety guidelines. Non-probabilistic sampling suggests caution in interpretation of the present findings.

An Experiencer, An Animal or An Object? Erection Salience Decreases Men's Perceived Agency.

Three experiments investigated the influence of penile erection on ascriptions of mental capabilities to men. Drawing on sexual objectification literature and the distinction between agency and experience in mind perception, three competing predictions were formulated. The mind redistribution hypothesis assumed that penile erection would lower agency and heighten experience attributions, the animalistic dehumanization hypothesis predicted the decrease in agency, but not experience, and the literal objectification hypothesis implied the simultaneous decrease in both agency and experience. In Experiment 1 (N = 219; 128 females), erection salience lowered agency, but not experience capabilities ascribed to male targets. Experiment 2 (N = 201, 113 females) replicated the negative effect of erection salience on perceived agency (but not experience) and revealed that erection salience lowered intentions to hire a male target. This effect was explained with the loss of perceived agency. Experiment 3 (N = 203, 98 females) verified the causal relationship between penile erection, agency and hiring intentions. Taken together, these results supported the animalistic dehumanization hypothesis.

Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL.

BACKGROUND: Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data. METHODS: We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. RESULTS: With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. CONCLUSION: Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.

The Role of Family Time Together in Meeting the Recommendation for Physical Activity among Primary School Children.

Family time may have an influence on children's physical activity (PA) participation or may contribute to increased sedentary behaviour. The aim of this paper was to examine whether spending family time is associated with the PA of children aged 10-11. Cross-sectional data on 158 primary school children (80 girls and 78 boys) with a mean age of 10.6 ± 0.49 years were collected. Weight and height were used to calculate body mass index. The level of moderate-to-vigorous physical activity (MVPA) was determined with a physical activity screening measure. Participants wore a Vivofit® wrist band activity tracker to measure their daily number of steps. The Health Behaviour in School-Aged Children questionnaire was used to obtain information from children about the frequency of activities undertaken by the family. Analyses entailed descriptive statistics of the total sample and by gender, t-test, and the Mann-Whitney U-test to examine the gender differences and Spearman's correlation coefficients. It was found that 32.3% of the children did not accomplish at least 60 min per day on ≥5 of the seven days and more than 75.9% of them did not accumulate at least 12,000 or more steps daily. More boys than girls tended to be sufficiently active and met the guideline of at least 60 min per day on ≥5 of the seven days (70.5% and 65.0%, respectively) or 12,000 steps per day (25.8% and 10.0%, respectively). The number of steps during the weekday was significantly and inversely associated both in girls and in boys with active family time (r = -0.27 and r = -0.25, respectively), and with total family time (r = -0.28) and non-active family time (r = -0.25) only in boys. Average MVPA was also inversely correlated with active family time (r = -0.31), non-active family time (r = -0.24), and total family time (r = -0.29) in boys. The correlation effect size values ranged between small to medium significant differences for these measures. The findings underscore the need for community-based PA programmes designed for whole families to meet the recommended PA of children and also to develop and promote active leisure activities among families.

First Days in the Life of Naive Human B Lymphocytes Infected with Epstein-Barr Virus.

Epstein-Barr virus (EBV) infects and activates resting human B lymphocytes, reprograms them, induces their proliferation, and establishes a latent infection in them. In established EBV-infected cell lines, many viral latent genes are expressed. Their roles in supporting the continuous proliferation of EBV-infected B cells in vitro are known, but their functions in the early, prelatent phase of infection have not been investigated systematically. In studies during the first 8 days of infection using derivatives of EBV with mutations in single genes of EBVs, we found only Epstein-Barr nuclear antigen 2 (EBNA2) to be essential for activating naive human B lymphocytes, inducing their growth in cell volume, driving them into rapid cell divisions, and preventing cell death in a subset of infected cells. EBNA-LP, latent membrane protein 2A (LMP2A), and the viral microRNAs have supportive, auxiliary functions, but mutants of LMP1, EBNA3A, EBNA3C, and the noncoding Epstein-Barr virus with small RNA (EBERs) had no discernible phenotype compared with wild-type EBV. B cells infected with a double mutant of EBNA3A and 3C had an unexpected proliferative advantage and did not regulate the DNA damage response (DDR) of the infected host cell in the prelatent phase. Even EBNA1, which has very critical long-term functions in maintaining and replicating the viral genomic DNA in established cell lines, was dispensable for the early activation of infected cells. Our findings document that the virus dose is a decisive parameter and indicate that EBNA2 governs the infected cells initially and implements a strictly controlled temporal program independent of other viral latent genes. It thus appears that EBNA2 is sufficient to control all requirements for clonal cellular expansion and to reprogram human B lymphocytes from energetically quiescent to activated cells.IMPORTANCE The preferred target of Epstein-Barr virus (EBV) is human resting B lymphocytes. We found that their infection induces a well-coordinated, time-driven program that starts with a substantial increase in cell volume, followed by cellular DNA synthesis after 3 days and subsequent rapid rounds of cell divisions on the next day accompanied by some DNA replication stress (DRS). Two to 3 days later, the cells decelerate and turn into stably proliferating lymphoblast cell lines. With the aid of 16 different recombinant EBV strains, we investigated the individual contributions of EBV's multiple latent genes during early B-cell infection and found that many do not exert a detectable phenotype or contribute little to EBV's prelatent phase. The exception is EBNA2 that is essential in governing all aspects of B-cell reprogramming. EBV relies on EBNA2 to turn the infected B lymphocytes into proliferating lymphoblasts preparing the infected host cell for the ensuing stable, latent phase of viral infection. In the early steps of B-cell reprogramming, viral latent genes other than EBNA2 are dispensable, but some, EBNA-LP, for example, support the viral program and presumably stabilize the infected cells once viral latency is established.

Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection.

Epstein-Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV's oncogenic potential in vivo. How lymphoblastoid cell lines (LCLs) evolve from the infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B lymphocytes. EBV reprograms the cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 h and precede any metabolic and phenotypic changes. Within 72 h, the virus activates the cells, changes their phenotypes with respect to cell size, RNA, and protein content, and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day 3 postinfection. The transcriptional program that EBV initiates consists of 3 waves of clearly discernable clusters of cellular genes that peak on day 2, 3, or 4 and regulate RNA synthesis, metabolic pathways, and cell division, respectively. Upon onset of cell doublings on day 4, the cellular transcriptome appears to be completely reprogrammed to support the proliferating cells, but 3 additional clusters of EBV-regulated genes fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 11,000 genes are regulated upon EBV infection as naïve B cells exit quiescence to enter a germinal center-like differentiation program, which culminates in immortalized, proliferating cells that partially resemble plasmablasts and early plasma cells.