Resilient T cell responses to B.1.1.529 (Omicron) SARS-CoV-2 variant

Emergence of the SARS-CoV-2 variant-of-concern (VOC) B.1.1.529 (Omicron) in late 2021 has raised alarm among scientific and health care communities due to a surprisingly large number of mutations in its spike protein. Public health surveillance indicates that the Omicron variant is significantly more contagious than the previously dominant VOC, B.1.617.2 (Delta). Several early reports demonstrated that Omicron exhibits a higher degree (~10-30-fold) of escape from antibody neutralization compared to earlier lineage variants. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron in people following COVID-19 infection and/or vaccination. To that purpose, we analyzed a cohort (n=345 subjects) of two- or three- dose messenger RNA (mRNA) vaccine recipients and COVID-19 post infection subjects (including those receiving 2 doses of mRNA vaccine after infection), recruited to the CDC-sponsored AZ HEROES research study, alongside 32 pre-pandemic control samples. We report that T cell responses against Omicron spike peptides were largely preserved in all cohorts with established immune memory. IFN-gamma producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (<20%) loss in IL-2 single- or IL-2+IFN-gamma+ poly-functional responses. Three-dose vaccinated participants had similar responses to Omicron relative to convalescent or convalescent plus two-dose vaccinated groups and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.

Inflammatory laboratory findings associated with severe illness among hospitalized individuals with COVID-19 in Medan, Indonesia: a cross-sectional study

Background: Coronavirus disease (COVID-19) remains a global health problem. COVID-19 patients with severe pneumonia have a higher risk for critical illness, mostly complicated by acute respiratory distress syndrome. The inflammatory response is critical, and the cytokine storm increases the severity of COVID-19. Many factors could be associated with a cytokine storm but they are incompletely understood. This study presents characteristics of COVID-19 patients and explore the clinical and inflammatory parameters of severe and critically ill COVID-19 patients in the intensive care unit (ICU). Method: This cross-sectional study was conducted in all severe COVID-19 patients admitted to the ICU. Peripheral blood was taken for laboratory examination within 24 hours of admission. Haematologic parameters, serum electrolyte, renal function, liver function, pancreas enzyme, D-dimer, inflammatory cytokines interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (CRP) were assessed in this study. Comparative analyses were done between sex, existing comorbidities, body mass index (BMI), and COVID-19 vaccination status. Results: A total of 80 subjects were included in the study. The most frequent comorbidities found among the subjects were obesity (36.35%) and diabetes (22.5%). Only 13.75% of subjects were vaccinated. Laboratory results indicated leucocytosis and neutrophilia, with a neutrophil-lymphocyte-ratio (NLR) of 7. The mean inflammatory findings (IL-6, IL-10, TNF-alpha, IFN-gamma, MCP-1), D-dimer, CRP, and lipase increased. Lipase levels were higher in men (p = 0.003) and in comorbidity groups. No significant differences were found among different BMI groups. Lipase, IL-6, and MCP-1 levels were significantly higher (p=0.019, <0.0001, and 0.03, respectively) in the non-vaccinated group. Conclusions: Most patients with severe COVID-19 have comorbidities and increased inflammatory markers.

Differential Virus-Specific IFN-Gamma Producing T Cell Responses to Marek’s Disease Virus in Chickens With B19 and B21 MHC Haplotypes

Marek’s disease virus (MDV), the etiologic agent for Marek’s disease (MD), causes a deadly lymphoproliferative disease in chickens. Causes of the well-documented association between genetically defined lines of chicken and resistance to MD remain unknown. Here, the frequencies of IFN-gamma producing pp38 and MEQ-specific T cell responses were determined in line N (B21 haplotype; MD-resistant) and line P2a (B19 haplotype, MD-susceptible) chickens after infection with vaccine and/or virulent (RB1B) strains of MDV using both standard ex vivo and cultured chIFN-gamma ELISPOT assays. Notably, MDV infection of naïve and vaccinated MD-resistant chickens induced higher frequencies of IFN-gamma producing MDV-specific T cell responses using the cultured and ex vivo ELISPOT assay, respectively. Remarkably, vaccination did not induce or boost MEQ-specific effector T cells in the susceptible chickens, while it boosted both pp38-and MEQ-specific response in resistant line. Taken together, our results revealed that there is a direct association between the magnitude of T cell responses to pp38 and MEQ of MDV antigens and resistance to the disease.

UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells

Background Mesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen presenting cells in response to interferon (IFN)-gamma treatment under a specific treatment regimen. This suggests that the immune function of MSCs can be pharmacologically modulated. Given the capacity of the agonist pyrimido-indole derivative UM171a to trigger the expression of various antigen presentation-related genes in human hematopoietic progenitor cells, we explored the potential use of UM171a as a means to pharmacologically instill and/or promote antigen presentation by MSCs. Methods Besides completing a series of flow-cytometry-based phenotypic analyses, several functional antigen presentation assays were conducted using the SIINFEKL-specific T-cell clone B3Z. Anti-oxidants and electron transport chain inhibitors were also used to decipher UM171a’s mode of action in MSCs. Finally, the potency of UM171a-treated MSCs was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with pre-established syngeneic EG.7T-cell lymphoma. Results Treatment of MSCs with UM171a triggered potent increase in H2-Kb cell surface levels along with the acquisition of antigen cross-presentation abilities. Mechanistically, such effects occurred in response to UM171a-mediated production of mitochondrial-derived reactive oxygen species as their neutralization using anti-oxidants or Antimycin-A mitigated MSCs’ ability to cross-present antigens. Processing and presentation of the immunogenic ovalbumin-derived SIINFEKL peptide was caused by de novo expression of the Psmb8 gene in response to UM171a-triggered oxidative stress. When evaluated for their anti-tumoral properties in the context of therapeutic vaccination, UM171a-treated MSC administration to immunocompetent mice with pre-established T-cell lymphoma controlled tumor growth resulting in 40% survival without the need of additional supportive therapy and/or standard-of-care. Conclusions Altogether, our findings reveal a new immune-related function for UM171a and clearly allude to a direct link between UM171a-mediated ROS induction and antigen cross-presentation by MSCs. The fact that UM171a treatment modulates MSCs to become antigen-presenting cells without the use of IFN-gamma opens-up a new line of investigation to search for additional agents capable of converting immune-suppressive MSCs to a cellular tool easily adaptable to vaccination. Graphical abstract

PD-1 /PD-L1 Adoptive Checkpoint Biosynthesis Separately Are Regulated By Gamma Common Which Regulate PD-1, Globin, and IFN-Gamma

PD-1 /PD-L1 is adoptive checkpoint mechanism, where PD-1 is an adopting its PD-L1 ligand activities by presence of specific helical kinase proteins in its compositions: _gamma common chains,_LNK” lymphocyte adaptor protein, _or SH2B adaptor _protein “tyrosine kinases, and _”SOCS” suppressor of cytokine signaling, that specified for controlling PD-1 and PD-L1 bindings activity through temporary resting the PD-L1 and consequently T-cells activities then transform incoming signals to exogenous processes in favor the of proper immune functions, But the permanent inhibition of PD-1 /PD-L1 binding is due to breaking down or inhibition in one or more of the adaptors helical proteins (lymphocyte adaptor protein, or SH2B) with the presence of SOCS” suppressor of cytokine signaling that will increase stability of binding without adopting and without activities, but cells survival can still exist through presence of tyrosine kinases , interferon stimulate kinases ,and gamma common.

Immune-Proteome Profiling in Classical Hodgkin Lymphoma Tumor Diagnostic Tissue

In classical Hodgkin Lymphoma (cHL), immunoediting via protein signaling is key to evading tumor surveillance. We aimed to identify immune-related proteins that distinguish diagnostic cHL tissues (=diagnostic tumor lysates, n = 27) from control tissues (reactive lymph node lysates, n = 30). Further, we correlated our findings with the proteome plasma profile between cHL patients (n = 26) and healthy controls (n = 27). We used the proximity extension assay (PEA) with the OlinkTM multiplex Immuno-Oncology panel, consisting of 92 proteins. Univariate, multivariate-adjusted analysis and Benjamini–Hochberg’s false discovery testing (=Padj) were performed to detect significant discrepancies. Proteins distinguishing cHL cases from controls were more numerous in plasma (30 proteins) than tissue (17 proteins), all Padj < 0.05. Eight of the identified proteins in cHL tissue (PD-L1, IL-6, CCL17, CCL3, IL-13, MMP12, TNFRS4, and LAG3) were elevated in both cHL tissues and cHL plasma compared with control samples. Six proteins distinguishing cHL tissues from controls tissues were significantly correlated to PD-L1 expression in cHL tissue (IL-6, MCP-2, CCL3, CCL4, GZMB, and IFN-gamma, all p ≤0.05). In conclusion, this study introduces a distinguishing proteomic profile in cHL tissue and potential immune-related markers of pathophysiological relevance.

Skin resident memory cells generated by the L. major centrin gene deleted parasites mediate protective immune response analogous to leishmanization

Leishmaniasis is a vector-borne parasitic disease transmitted through the bite of a sand fly with no available vaccine for humans. Recently, we have developed a live attenuated Leishmania major centrin gene deleted parasite strain (LmCen-/-) that induced protection against a homologous and heterologous challenges. The protection is mediated by IFN-gamma; secreting CD4+ T effector cells and multifunctional T cells, which is analogous to leishmanization. Previously, skin tissue resident memory T cells (TRM cells) were shown to be crucial for host protection in a leishmanization model. In this study, we evaluated generation and function of skin TRM cells following immunization with LmCen-/- parasites and compared those with leishmanization. In the absence of recoverable LmCen-/- parasites, the skin of immunized mice showed functional TRM cells comparable to leishmanized mice. The generation of the skin TRM cells was supported by the induction of cytokines and chemokines essential for their production and survival. Following challenge infection with wild type L. major, TRM cells specific to L. major were rapidly recruited and proliferated at the site of infection in the immunized mice which was similar to leishmanization. Further, upon challenge, CD4+ TRM cells induced higher levels of IFN-gamma; and Granzyme B in the immunized and leishmanized mice than non-immunized mice. Taken together, our studies demonstrate that a genetically modified live attenuated Leishmania vaccine generates functional CD4+ TRM cells that mediate protection and can be a safer alternative to leishmanization.

HIV-1 co-infection increases relapse rate and shortens survival in patients with visceral leishmaniasis

Patients co-infected with visceral leishmaniasis (VL) and HIV-1 (VL/HIV patients) suffer from recurrent VL relapses and increased mortality. The aim of our study was to test the hypothesis that HIV patients who present with their first episode of VL (primary VL/HIV patients) experience less relapses and lower mortality as compared to VL/HIV patients who have a previous history of VL relapses (recurrent VL/HIV patients). Our results show that primary VL/HIV patients have a lower parasite load and that their relapse-free survival is significantly longer. Relapses in both groups of patients occur independently of HIV viral load. Our clinical and immunological analyses of these patients at the time of diagnosis and during follow-up show that the poorer prognosis of recurrent VL/HIV patients is accompanied by lower weight gain and lower recovery of all blood cell lineages, as well as lower production of antigen-specific IFN-gamma, lower CD4+ T cell counts and higher expression levels of the inhibitory receptor PD1 on CD4+ and CD8+ T cells. We propose that in addition to the current treatments, novel interventions should be considered at the time of VL diagnosis in VL/HIV patients and suggest that improved anti-leishmanial and antiretroviral treatments, as well as immune therapy, through PD1/PDL-1 blockade and/or through IFN-gamma administration, could result in more efficient parasite killing and thereby reduce the relapse rate and improve survival.

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.