Immunological Observations Research Articles

When to vaccinate for seasonal influenza? Check the peak forecast.

Seasonal influenza infects 5-20% of people every year in the United States, resulting in hospitalizations, deaths, and adverse economic impacts. To mitigate these impacts, influenza vaccines are developed and distributed annually; however, growing evidence suggests that vaccine effectiveness (VE) wanes over the course of a flu season. Delaying influenza vaccination for older adults has attracted attention as a potential public health strategy. However, given the uncertainties in seasonal peak, vaccine effectiveness, and waning rates, postponing vaccination could also lead to increased morbidity, motivating an evaluation of a range of potential scenarios. We systematically investigated a broad range of vaccination start times for five age groups under six combinations of initial effectiveness and waning rates, based on influenza cases and vaccine uptake data from 10 influenza seasons. We defined the most favorable vaccination schedule as the one that resulted in the greatest reduction in disease burden. In scenarios with fast waning, all age groups benefit from delaying vaccination regardless of initial VE and peak timing. In scenarios with slower waning, results are mixed. For the ≥65 group, high initial VE and slow waning suggests that in early-peaking seasons, early vaccination most effectively reduces disease burden, while in late-peaking seasons delaying vaccination is most effective. For the ≥65 group in medium and low initial VE, and slow waning scenarios, delaying vaccination appears to prevent the greatest number of cases, regardless of whether the season peaks early or late. The most favorable vaccination schedule is sensitive to changes in initial VE, waning rate, and peak timing. Given estimates of these quantities from statistical and immunological models and observations, our methods can inform vaccination recommendations in order to most effectively reduce the annual disease burden caused by seasonal influenza. Specifically, accurate peak timing forecasts for the upcoming season have the potential to guide decisions on when to vaccinate.

Influence of extracellular ATP on mammalian sperm physiology.

In addition to its central role in cellular metabolism, adenosine 5'-triphosphate (ATP) is an important extracellular signalling molecule involved in various physiological processes. In reproduction, extracellular ATP participates in both autocrine and paracrine paths regulating gametogenesis, gamete maturation and fertilisation. This review focusses on how extracellular ATP modulates sperm physiology with emphasis on the mammalian acrosome reaction. The presence of extracellular ATP in the reproductive tract is primarily determined by the ion channels and transporters that influence its movement within the cells comprising the tract. The main targets of extracellular ATP in spermatozoa are its own transporters, particularly species-specific sperm purinergic receptors. We also discuss notable phenotypes from knock-out mouse models and human Mendelian inheritance related to ATP release mechanisms, along with immunological, proteomic, and functional observations regarding sperm purinergic receptors and their involvement in sperm signalling.

Comparative evaluation of two different xenogenic acellular matrices on full-thickness skin wound healing.

The purpose of the study was to compare the healing potential of bubaline small intestinal matrix (bSIM) and fish swim bladder matrix (FSBM) on full-thickness skin wounds in rabbits. Four full-thickness skin wounds (each 20×20mm) were created on the dorsum of 18 rabbits that were divided into three groups based on treatment: untreated sham control (I), implanted with double layers of bSIM (II) and implanted with double layers of FSBM (III). Macroscopic, immunologic and histologic observations were made to evaluate wound healing. Gross healing progression in the bSIM and FSBM groups showed significantly (p<0.05) less wound contraction compared with the sham group. The IgG concentration in rabbit sera was significantly (p<0.05) lower in the FSBM group compared with the bSIM group by enzyme-linked immunosorbent assay. The stimulation index of peripheral blood lymphocytes was significantly (p<0.05) lower in the FSBM group compared with the bSIM group by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Implantation of FSBM resulted in improved re-epithelialisation, neovascularisation and fibroplasia. The FSBM is a more effective dermal substitute when compared with the bSIM for full-thickness skin wound repair in rabbit.

Application of a Novel Proteomic Microarray Reveals High Exposure to Diarrhoeagenic Escherichia coli among Children in Zambia Participating in a Phase I Clinical Trial.

Diarrhoeagenic E. coli (DEC) significantly contributes to the burden of diarrhoea among children. Currently, there is no approved vaccine against DEC, but several vaccines against the enterotoxigenic E. coli (ETEC) pathotype are in advanced clinical trial stages, including the ETVAX® vaccine, undergoing evaluation in Zambia. This study reports on the reactivity of antibodies from ETVAX® vaccine and placebo recipients in a phase I clinical trial to proteins derived from (DEC) other than ETEC. Plasma samples collected at two time points (prior to any vaccination and post-third dose vaccination) from 16 vaccinated and 4 placebo participants in a phase 1 clinical trial examining the safety, tolerability, and immunogenicity of ETVAX® with dmLT adjuvant were evaluated for IgG response to E. coli antigens other than ETEC using the Pan-DEC protein microarray. This was the first field application of the novel pan-DEC array as a new tool in assessing the antigenic breadth of antibody responses induced by the ETVAX vaccine, as well as to assess early life exposure to DEC pathotypes and other bacterial enteric pathogens. We observed that plasma obtained from ETVAX® and placebo recipients had high antibody reactivity to Ipa, SseC and EspB proteins. These findings suggest that there is high exposure early in life to DEC pathogens, like EPEC, EHEC, EAEC and EIEC in addition to ETEC, in the Zambian population. These immunological observations are consistent with the results of recent epidemiological studies assessing the etiology of diarrheal disease among infants and young children in Zambia.

Progressive memory loss in previously COVID-19-infected patients: Genetic and immunological observations

Progressive memory loss in previously COVID-19-infected patients: Genetic and immunological observations

Cross protection to SARS-CoV-2 variants in hamsters with naturally-acquired immunity

Since SARS-CoV-2 was first reported in late 2019, multiple variations of the original virus have emerged. Each variant harbors accumulations of mutations, particularly within the spike glycoprotein, that are associated with increased viral transmissibility and escape immunity. The different mutations in the spike protein of different variants shape the subsequent antibody and T cell responses, such that exposure to different spike proteins can result in reduced or enhanced responses to heterologous variants further down the line. Globally, people have been exposed and re-exposed to multiple variations of the Ancestral strain, including the five variants of concerns. Studies have shown that the protective immune response of an individual is influenced by which strain or combination of strains they are exposed to. The initial exposure to a specific strain may also shape their subsequent immune patterns and response to later infections with a heterologous virus. Most immunological observations were carried out early during the pandemic when the Ancestral strain was circulating. However, SARS-CoV-2 variants exhibit varying patterns of disease severity, waning immunity, immune evasion and sensitivity to therapeutics. Here we investigated the cross-protection in hamsters previously infected with a variant of concern (VOC) and subsequently re-infected with a heterologous variant. We also determined if cross-protection and immunity were dependent on the specific virus to which the hamster was first exposed. We further profiled the host cytokine response induced by each SARS-CoV-2 variants as well as subsequent to re-infection. A comparative analysis of the three VOCs revealed that Alpha variant was the most pathogenic VOC to emerge. We showed that naturally acquired immunity protected hamsters from subsequent re-infection with heterologous SARS-CoV-2 variant, regardless which variant the animal was first exposed to. Our study supports observations that heterologous infection of different SARS-CoV-2 variants do not exacerbate disease in subsequent re-infections. The continual emergence of new SARS-CoV-2 variants mandates a better understanding of cross-protection and immune imprinting in infected individuals. Such information is essential to guide vaccine strategy and public policy to emerging SARS-CoV-2 VOCs and future novel pandemic coronaviruses.

From second thoughts on the germ theory to a full-blown host theory

In 1955, René Dubos famously expressed his “second thoughts on the germ theory”, attributing infectious diseases to various “changing circumstances” that weaken the host by unknown mechanisms. He rightly stressed that only a small minority of individuals infected by almost any microbe develop clinical disease. Intriguingly, though, he did not mention the abundant and elegant findings reported from 1905 onward that unambiguously pointed to host genetic determinants of infection outcome in plants and animals, including human inborn errors of immunity. Diverse findings over the next 50 y corroborated and extended these earlier genetic and immunological observations that René Dubos had neglected. Meanwhile, the sequential advent of immunosuppression- and HIV–driven immunodeficiencies unexpectedly provided a mechanistic basis for his own views. Collectively, these two lines of evidence support a host theory of infectious diseases, with inherited and acquired immunodeficiencies as the key determinants of severe infection outcome, relegating the germ to an environmental trigger that reveals an underlying and preexisting cause of disease and death.

Sarcoidosis and autoimmunity: In the depth of a complex relationship.

Sarcoidosis is a chronic granulomatous disease that can virtually affect any organ. Its etiology is unknown, although it has been proposed that environmental or biological agents can act as triggers, ultimately leading to chronic inflammation in genetically predisposed individuals. The main component of sarcoid inflammation is represented by an exaggerated T- lymphocytic cellular response to a putative antigen that could not be efficiently cleared in the patient. However, several clinical and immunological observations, such as the association of sarcoidosis to autoimmune diseases or the presence of autoantibodies in the serum of patients with sarcoidosis, suggest that humoral-mediated immune response might also play a role in the pathogenesis of sarcoidosis. The aim of this review is to deepen the relationship between sarcoidosis and autoimmunity, by analyzing the most recent advances and proposing new fields of research.

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications.

Myelodysplastic syndromes (MDS) constitute a very heterogeneous group of diseases with a high prevalence in elderly patients and a propensity for progression to acute myeloid leukemia. The complexity of these hematopoietic malignancies is revealed by the multiple recurrent somatic mutations involved in MDS pathogenesis and the paradoxical common phenotype observed in these patients characterized by ineffective hematopoiesis and cytopenia. In the context of population aging, the incidence of MDS will strongly increase in the future. Thus, precise diagnosis and evaluation of the progression risk of these diseases are imperative to adapt the treatment. Dysregulations of both innate and adaptive immune systems are frequently detected in MDS patients, and their critical role in MDS pathogenesis is now commonly accepted. However, different immune dysregulations and/or dysfunctions can be dynamically observed during the course of the disease. Monitoring the immune system therefore represents a new attractive tool for a more precise characterization of MDS at diagnosis and for identifying patients who may benefit from immunotherapy. We review here the current knowledge of the critical role of immune dysfunctions in both MDS and MDS precursor conditions and discuss the opportunities offered by the detection of these dysregulations for patient stratification.

Shiitake Mantar Ekstraktı İlaveli Yemlerin Gökkuşağı Alabalığında (Oncorhynchus mykiss) Büyüme, Non-Spesifik İmmun Parametreler ve in-vitro Aeromonas hyrophila Enfeksiyonuna Karşı Direnç Üzerine Etkileri

The activity of Lentinula edodes (shiitake) medicinal mushroom extract were examined on the non-specific immune response and biometrical performance of rainbow trout (Oncorhynchus mykiss). Fish (20 g initial weight) were divided into 3 treatment groups (60 fish/group) and duplicated groups for 6 weeks having two experimental diets supplemented with 1-2% shiitake extract and a control diet. During the feeding process, immunological, biochemical, and biometrical observations were determined using the fish and blood samples taken at weeks 1, 2, 3, 4, 5, and 6, respectively. The results of immunological, biochemical, and biometrical parameters evaluation determined that the maximum influence occurs in rainbow trout fed with 2% shiitake extract. The amount of respiratory burst activity in the blood of fish in the trial groups significantly increased in each diet on the 2nd and 6th weeks compared to controls. The amount of total protein, bactericidal activity were significantly increased in fish being fed a mushroom supplemented diet. Cholesterol level decreased in fish blood, which fed with 2% shiitake extract supplemented diet at 3rd and 6th weeks. These results support the findings that the non-specific immune responses of rainbow trout was stimulated in fish by feeding shiitake medicinal mushroom extract yielding positive results in measured parameters compared to the control group also enhancing the overall growth performance of rainbow trout.

DMD – ANIMAL MODELS: EP.96 Micro-dystrophin gene therapy delivery and therapeutic plasma exchange in nonhuman primates

Gene transfer therapy using systemic adeno-associated virus (AAV) delivery is being studied extensively for the treatment of monogenic diseases, such as Duchenne muscular dystrophy. Gene therapies are advancing rapidly, and it is crucial to optimize safety and efficacy as well as dosing of individuals with pre-existing antibodies against the vectors used for delivery. This nonhuman primate (NHP) study investigated the impact of various immunosuppression strategies on the safety and efficacy of gene transfer therapy and analyzed the safety and efficacy of therapeutic plasma exchange (TPE) as a potential pretreatment for individuals with pre-existing immunity. In part 1 of the study, we intravenously dosed 5 treatment-naive NHP cohorts (n=3 each) with rAAVrh74.MHCK7.micro-dystrophin (SRP-9001). We trialed different immunosuppression regimens pre- and post-vector administration in each cohort. Cohort 1 (control) had no immunosuppression treatment. We treated cohorts 2-4 with prednisone at different time points and cohort 5 with rituximab, sirolimus, and prednisone. We analyzed transduction and micro-dystrophin expression in muscle pre- and post-vector administration. To assess safety and immune response, we monitored serum chemistries and immunology. In part 2, we treated NHPs that were dosed in part 1 and were positive for AAVrh74 antibodies (cohorts 2-4) with TPE prior to a second SRP-9001 dose and assessed safety and efficacy. After 2-3 consecutive rounds of TPE, circulating antibodies toward AAVrh74 were reduced and the NHPs were successfully redosed. The procedure was well tolerated, with no abnormal clinical or immunological observations. Cohort 5 NHPs were redosed at very high levels of circulating antibodies and had hypersensitivity reactions, which were controlled. These findings suggest that TPE in conjunction with AAVrh74 vector delivery is safe and efficacious in NHPs. The results may inform human studies involving redosing or pre-existing immunity.

Dupilumab: An Opportunity to Unravel In Vivo Actions of IL-4 and IL-13 in Humans

The application of biologics in clinical practice allows immunological observations under real-life conditions. In a new article in the Journal of Investigative Dermatology, Bakker etal. (2021) use deep immune cell phenotyping to demonstrate how dupilumab acts in a targeted fashion on skin-homing T cells, the driver cells of atopic dermatitis.

RESULTS OF MONITORING FOR TOXOCAROSIS IN THE SOUTH OF RUSSIA

Toxocariasis is a widespread socially significant zoonotic helminthiasis. Infestation with human toxocariasis occurs through the ingestion of infected Toxocara eggs, which mainly accumulate in the soil. The aim of our study was long-term sanitaryparasitological and immunological observations of toxocariasis in a number of territories in southern Russia. For sanitary and parasitological analysis of soil from 2002 to 2019 in the territory of the Rostov region and the Republic of Adygea, 1664 samples were taken and examined. Determination of indicators of contamination of soil samples with eggs of helminths and invasiveness of Toxocara spp. carried out using the methods outlined in 4.2.2661-10 "Methods of sanitary and parasitological research". During the same period of time, an enzyme-linked immunosorbent assay (ELISA) of 6831 blood serum of a conventionally healthy population of the Rostov region and the Republic of Adygea was carried out using the diagnostic test systems "Toksokara-IgG-IFA-BEST". According to the results of ELISA, high seroprevalence values were obtained, indicating the frequency of contact of the population with the causative agent of toxocariasis and indicating a possibly higher incidence rate than the officially registered one. The results of the conducted sanitary and parasitological studies, which showed a consistently high degree of contamination of the soils of the studied territories of southern Russia, indicate the continuing risk of infection of the population and animals with toxocariasis.

The Coronavirus Network Explorer: mining a large-scale knowledge graph for effects of SARS-CoV-2 on host cell function

BackgroundLeveraging previously identified viral interactions with human host proteins, we apply a machine learning-based approach to connect SARS-CoV-2 viral proteins to relevant host biological functions, diseases, and pathways in a large-scale knowledge graph derived from the biomedical literature. Our goal is to explore how SARS-CoV-2 could interfere with various host cell functions, and to identify drug targets amongst the host genes that could potentially be modulated against COVID-19 by repurposing existing drugs. The machine learning model employed here involves gene embeddings that leverage causal gene expression signatures curated from literature. In contrast to other network-based approaches for drug repurposing, our approach explicitly takes the direction of effects into account, distinguishing between activation and inhibition.ResultsWe have constructed 70 networks connecting SARS-CoV-2 viral proteins to various biological functions, diseases, and pathways reflecting viral biology, clinical observations, and co-morbidities in the context of COVID-19. Results are presented in the form of interactive network visualizations through a web interface, the Coronavirus Network Explorer (CNE), that allows exploration of underlying experimental evidence. We find that existing drugs targeting genes in those networks are strongly enriched in the set of drugs that are already in clinical trials against COVID-19.ConclusionsThe approach presented here can identify biologically plausible hypotheses for COVID-19 pathogenesis, explicitly connected to the immunological, virological and pathological observations seen in SARS-CoV-2 infected patients. The discovery of repurposable drugs is driven by prior knowledge of relevant functional endpoints that reflect known viral biology or clinical observations, therefore suggesting potential mechanisms of action. We believe that the CNE offers relevant insights that go beyond more conventional network approaches, and can be a valuable tool for drug repurposing. The CNE is available at https://digitalinsights.qiagen.com/coronavirus-network-explorer.

Modulation of microRNome by Human Cytomegalovirus and Human Herpesvirus 6 Infection in Human Dermal Fibroblasts: Possible Significance in the Induction of Fibrosis in Systemic Sclerosis.

Human cytomegalovirus (HCMV) and Human herpesvirus 6 (HHV-6) have been reportedly suggested as triggers of the onset and/or progression of systemic sclerosis (SSc), a severe autoimmune disorder characterized by multi-organ fibrosis. The etiology and pathogenesis of SSc are still largely unknown but virological and immunological observations support a role for these beta-herpesviruses, and we recently observed a direct impact of HCMV and HHV-6 infection on the expression of cell factors associated with fibrosis at the cell level. Since miRNA expression has been found profoundly deregulated at the tissue level, here we aimed to investigate the impact on cell microRNome (miRNome) of HCMV and HHV-6 infection in in vitro infected primary human dermal fibroblasts, which represent one of the main SSc target cells. The analysis, performed by Taqman arrays detecting and quantifying 754 microRNAs (miRNAs), showed that both herpesviruses significantly modulated miRNA expression in infected cells, with evident early and late effects and deep modulation (>10 fold) of >40 miRNAs at each time post infection, including those previously recognized for their key function in fibrosis. The correlation between these in vitro results with in vivo observations is strongly suggestive of a role of HCMV and/or HHV-6 in the multistep pathogenesis of fibrosis in SSc and in the induction of fibrosis-signaling pathways finally leading to tissue fibrosis. The identification of specific miRNAs may open the way to their use as biomarkers for SSc diagnosis, assessment of disease progression and possible antifibrotic therapies.

Efficacy of Miltefosine and Artemether on Infected Biomphalaria Alexandrina Snails with Schistosoma Mansoni: Immunological and Histological Studies.

SummaryBiomphalaria alexandrina snails have received much attention due to their great medical importance as vectors for transmitting Schistosoma mansoni infection to humans. The main objective of the present work was to assess the efficacy of miltefosin a synthetic molluscicidal drug and artemether a natural molluscicidal drug. The correlation between immunological and histological observations from light and electron microscopy of the hemocytes of B. alexandrina post treatment with both drugs was also evaluated. LC50 and LC90 values were represented by 13.80 ppm and 24.40 ppm for miltefosine and 16.88 ppm and 27.97 ppm for artemether, respectively. The results showed that the treatment of S. mansoni-infected snails and normal snails with sublethal dose of miltefosine (LC25=8.20 ppm) and artemether (LC25=11.04 ppm) induced morphological abnormalities and a significant reduction in hemocytes count.

Infant Acute Myeloid Leukemia with t(X;6)(p11;q23)/MYB-GATA1- a First Female Case in the Entity

Introduction T(X;6)(p11;q23) is a rear but recurrent chromosomal translocation in infant acute myeloid leukemia (AML). It leads to the formation ofMYB-GATA1fusion gene that interferes with granulocyte lineage commitment thus causing AML preliminary with basophilic phenotype. Only males were seen previously in this entity [Dastugue et al. 1997, Belloni et al. 2011, Quelen et al. 2011]. Here we report extensive molecular characterization of 2 infant AML cases with t(X;6)(p11;q23)/MYB-GATA1enrolled in the Russian AML registration study with one of them being a girl. Case reports A boy aged 5,5 mo. with WBC 27,7*109/L and 45% blasts in bone marrow was diagnosed AML, M5a by morphological, cytochemical and immunological observations. He was treated according to AML-BFM-2004 protocol and received allogenic HSCT from matched unrelated donor in the first remission. Patient stays in complete remission for 4 years now. A girl aged 8 mo. was headed to a hospital with febrile fever and petechiae. She had initial WBC 33,8*109/L and 35% bone marrow blasts of basophilic phenotype. Spinal tap confirmed CNS involvement (cytosis 2,6/mm3, 3% blasts). Patient received induction therapy (cytarabine, etoposide, daunorubicin) and achieved a complete remission. However, she developed severe myelodepression and died of infection 3 mo. after the diagnosis. Results MYB-GATA1.GTG-banded karyotyping showed a rearrangement between chromosomes 6 and X as a sole abnormality in both patients - insertion of chromosome 6 material into Xp11 band in a boy and reciprocal translocation t(X;6)(p11;q23) in a girl. FISH for relevant age-specific translocations, includingKMT2Arearrangements and t(7;12)(q36;p12)/ETV6-HLXB, was negative. RNA-seq (TruSeqRNA, Illumina, San-Diego, CA, USA) revealedMYB-GATA1fusion expression with exon 8 - exon 5 junction identical in both patients which was validated by RT-PCR and Sanger sequencing. Direct genomic PCR confirmed breakpoints withinMYBintron 8 andGATA1intron 4 and uncovered patient-specific junctions (see Figure). Reciprocal fusions.The formation of reciprocal fusions was also shown in two studied patients. A boy demonstratedGATA1-TUBE(6q21) intron 4 - intron 7 junction. It is non-functional due to tail-to-tail transcriptional orientation. Such structures are likely to form sinceMYBandGATA1are located in an opposite genomic orientation, so our finding goes in line with previous unsuccessful attempts to look for reciprocalGATA1fusion transcripts expression [Quelen et al. 2011]. However, a girl patient had reciprocalGATA1-CD164fusion (exon 4 - exon 6) actively transcribed together with third fusionMYB-CD164. On the one hand, this confirms that additional event such as inversion of either chromosomal fragment is required for t(X;6)(p11;q23) to manifest. On the other hand, this is, to our knowledge, the first demonstration of reciprocalGATA1fusion transcript expression inMYB-GATA1-associated AML. Wild-type MYB and GATA1 expression.AlongsideMYB-GATA1expression both patients demonstrated the overexpression of wild-typeMYBby qPCR. This is in agreement with MYB overexpression being a feature of undifferentiated cells and diminishing during differentiation [Bartunek et al. 2003]. Wild-typeGATA1expression (its lossper se) is of key importance inMYB-GATA1-associated AL. It was previously proposed that the loss of wild-typeGATA1is essential for leukemogenesis in male patients as the only copy of this gene is disturbed by chromosomal translocation [Quelen et al. 2011]. We observed no wild-typeGATA1expression in our male patient. However, in the female patient wild-type GATA1 expression was present. Additional events.The samples were also screened for additional genetic events associated with myeloid neoplasia by targeted DNA NGS (QIAact Myeloid DNA UMI Panel, Qiagen, Hilden, Germany), fragment analysis (NPM1,FLT3-ITD) and Sanger sequencing (cKIT,FLT3-TKD). NoFLT3,NPM1and cKIT pathogenic variants were found. NoGATA1truncating mutations were found. Deleterious variants were found inNRASgene (p.G12C in a boy, p.G13D in a girl). Female patient also demonstrated pathogenic variants inKRAS(p.A59E) andJAK2(p.N683G). Conclusions Thus, here we report a first case of female patient with t(X;6)(p11;q23)/MYB-GATA1. This raises a question whetherGATA1insufficiency is the primary mechanisms of leukemogenesis in this genetic subgroup. Figure Disclosures No relevant conflicts of interest to declare.

Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and "New Old Friends".

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial “new old friends” such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called “trained immunity.” Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other “new old friends.”

Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development.

Systemic sclerosis (SSc) is a severe autoimmune disorder characterized by vasculopathy and multi-organ fibrosis; its etiology and pathogenesis are still largely unknown. Herpesvirus infections, particularly by human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), have been suggested among triggers of the disease based on virological and immunological observations. However, the direct impact of HCMV and/or HHV-6 infection on cell fibrosis and apoptosis at the cell microenvironment level has not yet been clarified. Thus, this study aimed to investigate the effects of HCMV and HHV-6 infection on the induction of pro-fibrosis or pro-apoptosis conditions in primary human dermal fibroblasts, one of the relevant SSc target cells. The analysis, performed by microarray in in vitro HCMV- or HHV-6-infected vs. uninfected cells, using specific panels for the detection of the main cellular factors associated with fibrosis or apoptosis, showed that both viruses significantly modified the expression of at least 30 pro-fibrotic and 20 pro-apoptotic factors. Notably, several recognized pro-fibrotic factors were highly induced, and most of them were reported to be involved in vivo in the multifactorial and multistep pathogenic process of SSc, thus suggesting a potential role of both HCMV and HHV-6.

Healing potential of chitosan and decellularized intestinal matrix with mesenchymal stem cells and growth factor in burn wound in rat

Abstract Background Burns are one of the most common and devastating forms of trauma. Patients with serious thermal injury require immediate specialized care in order to minimize morbidity and mortality. The objective of this study was to evaluate the healing potential of porcine decellularized small intestinal submucosa (SIS) matrix and chitosan with mesenchymal stem cells (rMSC) and epidermal growth factor (mEGF) on the healing of full thickness burn wound in rat model. Methods One 2 × 2 cm2 size full thickness burn wound was created on the dorsum of each animal under general anaesthesia. Burn wounds were treated with silver sulfadiazine; medical grade chitosan; chitosan with rMSC; chitosan with rMSC and mEGF; decellularized porcine SIS; rMSC seeded with SIS; rMSC seeded with SIS and mEGF in groups A, B, C, D, E, F and G, respectively. Healing was evaluated on the basis of percentage of wound contraction, colour digital imaging, immunological, histopathological, immunohistochemistry and gelatin zymography observations. Results A decrease in wound area was noticed in stem cell and m-EGF treated groups. Early angiogenesis and epithelialisation was observed in groups, where decellularized SIS matrix was combined with r-MSC and m-EGF. Type III collagen was found more in control group by immunohistochemistry which indicated abnormal collagen deposition. Gelatin zymography revealed expression of MMPs in the control group suggesting a chronic nature of wound. Chitosan in combination of rMSC and mEGF proved to be efficient for full-thickness burn wound healing. Conclusion Decellularized SIS matrix when combined with r-MSC and m-EGF has healing potential and showed best healing response than conventional treatment for the reconstruction of full-thickness skin burn wounds in rats.