Introduction Tuberculosis (TB) infections and latent Mycobacterium tuberculosis (MTB) infection (LTBi) remain prevalent globally. Type 2 diabetes mellitus (DM) worsens TB outcomes but the immune mechanisms that cause this are not yet clear. We investigated a role of suppressor of cytokine signaling molecules (SOCS1 and SOC3) in regulating host cytokine responses in the diabetic host infected with MTB. Materials and Methods We studied peripheral blood cells from health endemic controls (EC), LTBi cases, diabetics with and without LTBi and TB patients. Mycobacterial antigen-stimulated cytokine secretion was determined using the Th1/Th2 11 plex cytokine assay. Antigen-induced gene expression of IFNγ, TNFα, IL6 and SOCS3 was determined by reverse-transcription PCR. Results Purified protein derivative (PPD) antigen stimulation induced higher levels of, IL-6, IL-2, TNFα and GM-CSF levels in DM-LTB as compared with EC and LTB cases. IL-13 levels were raised in DM-LTB cases as compared with DM cases. PPD-induced IFNγ and IL-6 transcripts were raised in DM-LTBi as compared with EC. TNFα mRNA levels were raised in DM-LTBi as compared with LTBi. SOCS3 mRNA levels were reduced in DM-LTBi as compared with LTBi. SOCS3 transcripts were higher in LTBi as compared with EC and TB groups. Discussion We found co-occurrence of LTBi with DM to be associated with an increased release of proinflammatory IL-6, IL-2 and TNF-α but reduced SOCS3 mRNA levels. SOCS3 protects against MTB infection therefore, reduced levels in DM-LTB may be contribute to progression from LTBi to active TB in individuals infected with MTB.
SARS-CoV-2 variants of concern (VOC) have been associated with increased viral transmission and disease severity. We investigated the mechanisms of pathogenesis caused by variants using a host blood transcriptome profiling approach. We analysed transcriptional signatures of COVID-19 patients comparing those infected with wildtype (wt), alpha, delta or omicron strains seeking insights into infection in Asymptomatic cases. Comparison of transcriptional profiles of Symptomatic and Asymptomatic COVID-19 cases showed increased differentially regulated gene (DEGs) of inflammatory, apoptosis and blood coagulation pathways, with decreased T cell and Interferon stimulated genes (ISG) activation. Between SARS-CoV-2 strains, an increasing number of DEGs occurred in comparisons between wt and alpha (196), delta (1425) or, omicron (2313) infections. COVID-19 cases with alpha or, delta variants demonstrated suppression transcripts of innate immune pathways. EGR1 and CXCL8 were highly upregulated in those infected with VOC; heme biosynthetic pathway genes (ALAS2, HBB, HBG1, HBD9) and ISGs were downregulated. Delta and omicron infections upregulated ribosomal pathways, reflecting increased viral RNA translation. Asymptomatic COVID-19 cases infected with delta infections showed increased cytokines and ISGs expression. Overall, increased inflammation, with reduced host heme synthesis was associated with infections caused by VOC infections, with raised type I interferon in cases with less severe disease.
Abstract Understanding key host protective mechanisms against SARS-CoV-2 infection can help improve treatment modalities for COVID-19. We used a blood transcriptome approach to study biomarkers associated with differing severity of COVID-19, comparing severe and mild Symptomatic disease with Asymptomatic COVID-19 and uninfected Controls. There was suppression of antigen presentation but upregulation of inflammatory and viral mRNA translation associated pathways in Symptomatic as compared with Asymptomatic cases. In severe COVID-19, CD177 a neutrophil marker, was upregulated while interferon stimulated genes (ISGs) were downregulated. Asymptomatic COVID-19 cases displayed upregulation of ISGs and humoral response genes with downregulation of ICAM3 and TLR8. Compared across the COVID-19 disease spectrum, we found type I interferon (IFN) responses to be significantly upregulated (IFNAR2, IRF2BP1, IRF4, MAVS, SAMHD1, TRIM1), or downregulated (SOCS3, IRF2BP2, IRF2BPL) in Asymptomatic as compared with mild and severe COVID-19, with the dysregulation of an increasing number of ISGs associated with progressive disease. These data suggest that initial early responses against SARS-CoV-2 may be effectively controlled by ISGs. Therefore, we hypothesize that treatment with type I interferons in the early stage of COVID-19 may limit disease progression by limiting SARS-CoV-2 in the host.
Background: COVID-19 related disease morbidity and mortality has varied worldwide. We investigated antibody and T cell responses to SARS-CoV-2 in COVID-19 cases and exposed but healthy individuals further compared with pre-pandemic controls in a high infectious disease burden setting. Methods: IgG antibodies against Spike and Spike Receptor Binding Domain (RBD) were determined by ELISA in a Health Care cohort (HC; n=304), COVID-19 cases (n=163) and Pre-Pandemic Controls (PPC; n=114). Neutralizing antibody assays and T cell ELISpot assays were also conducted. Findings: IgG anti Spike proteins and RBD were present in all three groups albeit at varying levels. The highest rate of positivity was observed in COVID-19 cases (87.7% to Spike; 53.9% to RBD); followed by HC (35% to Spike; 21.3% to RBD) and PPC (12.2% to Spike; 10.50% to RBD). Antibody positivity in HC rose from 4.5% in October 2020 to 61% in January 2021. Levels of IgG antibodies to Spike and RBD strongly correlated in COVID-19 and HC but not in PPC. IgG to RBD was associated with neutralizing activity against SARS-CoV-2. Spike reactive T cells were identified in COVID-19 patients (6/18), HC (2/7) and but only one PPC (1/6). Interpretation: IgG to Spike and RBD in pre-pandemic sera is likely associated with cross-protection induced by other pathogens. The increasing percentage of IgG antibody positivity in HCC over the pandemic period may be due to expansion of cross-reactive B cells as observed in PPC, due either to exposure or asymptomatic subclinical infection with SARS-CoV-2. Neutralizing activity of RBD IgG antibodies and reactive T cells to Spike in PPC suggests the presence of memory B and T cells to cross-reactive epitopes that can expand quickly, jumpstarting protection against SARS-CoV-2.Funding Information: This work was supported by the Provost’s Academic Priorities Fund, Aga Khan University. Funding support was also received through Swedish Research Council project SRL 4-182/2019. We acknowledge the support for recombinant protein provided by IBET, NOVA University, Portugal. MV was supported by the European Union H2020 ERA project (No 667824 – EXCELLtoINNOV).Conflict of Interests: The authors have no competing interests to declare.Ethical Approval: This study was approved by the Ethical Review Committee of The Aga Khan University (projects #2020-5152-11688 and 2020-3687-10181).
COVID-19 vaccinations have reduced morbidity and mortality from the disease. Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) have been associated with immune protection. Seroprevalence studies revealed high immunoglobulin G (IgG) antibody levels to SARS-CoV-2 in the Pakistani population before vaccinations. We investigated the effect of BBIBP-CorV vaccination on circulating IgG antibodies and interferon (IFN)-γ from T cells measured in a cohort of healthy individuals, with respect to age, gender, and history of COVID-19.
Background: COVID-19 related disease morbidity and mortality has varied worldwide. We investigated antibody and T cell responses to SARS-CoV-2 in COVID-19 cases and exposed but healthy individuals further compared with pre-pandemic controls in a high infectious disease burden setting.Methods: IgG antibodies against Spike and Spike Receptor Binding Domain (RBD) were determined by ELISA in a Health Care cohort (HC; n=304), COVID-19 cases (n=163) and Pre-Pandemic Controls (PPC; n=114). Neutralizing antibody assays and T cell ELISpot assays were also conducted.Findings: IgG anti Spike proteins and RBD were present in all three groups albeit at varying levels. The highest rate of positivity was observed in COVID-19 cases (87.7% to Spike; 53.9% to RBD); followed by HC (35% to Spike; 21.3% to RBD) and PPC (12.2% to Spike; 10.50% to RBD). Antibody positivity in HC rose from 4.5% in October 2020 to 61% in January 2021. Levels of IgG antibodies to Spike and RBD strongly correlated in COVID-19 and HC but not in PPC. IgG to RBD was associated with neutralizing activity against SARS-CoV-2. Spike reactive T cells were identified in COVID-19 patients (6/18), HC (2/7) and but only one PPC (1/6).Interpretation: IgG to Spike and RBD in pre-pandemic sera is likely associated with cross-protection induced by other pathogens. The increasing percentage of IgG antibody positivity in HCC over the pandemic period may be due to expansion of cross-reactive B cells as observed in PPC, due either to exposure or asymptomatic subclinical infection with SARS-CoV-2. Neutralizing activity of RBD IgG antibodies and reactive T cells to Spike in PPC suggests the presence of memory B and T cells to cross-reactive epitopes that can expand quickly, jumpstarting protection against SARS-CoV-2.Funding Information: This work was supported by the Provost’s Academic Priorities Fund, Aga Khan University. Funding support was also received through Swedish Research Council project SRL 4-182/2019. We acknowledge the support for recombinant protein provided by IBET, NOVA University, Portugal. MV was supported by the European Union H2020 ERA project (No 667824 – EXCELLtoINNOV).Declaration of Interests: The authors have no competing interests to declare.Ethics Approval Statement: This study was approved by the Ethical Review Committee of The Aga Khan University (projects #2020-5152-11688 and 2020-3687-10181).
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Abstract Long-term solutions against SARS-CoV-2 infections require understanding of immune protection induced by different vaccine COVID-19 formulations. We investigated humoral and cellular immunity induced by Sinopharm (BBIBP-CorV) in a region of high SARS-CoV-2 seroprevalence. Levels of IgG antibodies to SARS-CoV-2 spike protein and its receptor-binding domain (RBD) were determined 24-weeks. Cellular immunity was investigated using a commercially available IFN-γ release assay to SARS-CoV-2 spike (Ag1 and 2) and extended genome antigens (Ag3). Increasing IgG seropositivity to Spike protein and RBD was observed post-vaccination. Seropositivity was reduced in those over 50 years and raised in females and those with prior COVID-19. After 20 weeks post-vaccination, only one third of participants had positive T cell responses to SARS-CoV-2 antigens. Prior COVID-19 impacted IFNγ responses, with reactivity enhanced in those infected earlier. The frequency of IFNγ responses was highest to extended genome antigen set. Overall, BBIBP-CorV- induced antibody responses were impacted by age, gender and prior COVID-19. Cellular immunity was present in a limited number of individuals after 20 weeks but was enhanced by prior infection. This suggests the need for booster vaccinations in older individuals. BBIBP-CorV-induced cellular activation is broader than to spike, requiring further study to understand how to monitor vaccine effectiveness.
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