A cross-sectional study of COVID-19 outbreak in Indian population.

Background: Presently India is the second most populous country in the world with an estimated population of 1.4 billion people and has recently been affected by COVID-19 pandemic and subsequent mutant viral outbreak. To date, India has administered its population with over 1.30 billion cumulative doses of COVID-19 vaccine. The consequences of COVID-19 vaccination on the outbreak in India has not been reported until now. Therefore, we probed to assess the impact of COVID-19 outbreak in India from December 2019 to December 2021. Methods: Indian COVID-19 related data were extracted from "ourworldindata.org" and "cowin.gov.in" databases. The incidence rate of COVID-19 per million people was calculated and other parameters such as new cases, positive rate, reproduction rate, new death and stringency index values were extracted from the database for statistical analysis. Results: Data indicate that the COVID-19 positive rate declined as the number of vaccinations rose over time. The Pearson correlation values between new cases and the cumulative percentage of vaccination or the percentage of fully vaccinated population showed no correlation (P < 0.01). COVID-19 vaccination has significantly decreased the R-value and positive rate of SARS-CoV-2 in India (P < 0.01). Furthermore, containment measures showed no correlation with the incidence rate of SARS-CoV-2 in India which may be in contradictory to the global trends. Conclusion: Vaccination against COVID-19 was efficacious in the control of the SARS-CoV-2 outbreak and the decrease in the positive rate. Further, the containment measures had no effect on the spread of COVID-19 infection in India, thus far.

Coactivation of Toll-like receptor-3 and -7 in immune complex glomerulonephritis.

The molecular mechanisms of viral infection-induced glomerulonephritis are poorly understood. Toll-like receptor (TLR)-3 and TLR7 recognize viral RNA and their exposure to TLR3 or TLR7 can trigger the exacerbation of established immune complex disease in MRLlpr mice. Because coactivation of TLR3 and TLR7 was shown to synergistically activate dendritic cells in vitro, we hypothesized that simultaneous ligation of TLR3 and TLR7 would elicit additive effects on the exacerbation of glomerulonephritis in MRLlpr mice. Saline, 50 microg pI:C RNA, 25 microg of the TLR7 agonist imiquimod, or a combination of both were injected every other day to MRLlpr mice from week 16-18 of age. Coinjection of pI:C RNA and imiquimod had no synergistic effect on serum levels of IL-6 and IL12p70, dsDNA autoantibody levels, and glomerulonephritis. This was consistent with a lack of synergistic effects on cytokine release of TNF- and IFNgamma-prestimulated monocytes in vitro. Furthermore, in glomerular mesangial cells a synergistic effect of pI:C RNA and imiquimod was generally absent due to the lack of TLR7 expression. We conclude that a number of mechanisms protect the host from additive effects of TLR3-TLR7 coactivation on renal pathology in vivo.

Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis.

Lupus nephritis develops from a combination of genetic and environmental factors such as microbial infection. A role for microbial nucleic acids (e.g., via nucleic acid-specific Toll-like receptors [TLR]) was hypothesized, in this context, because microbial nucleic acids can trigger multiple aspects of autoimmunity in vitro and in vivo. Eight-week-old MRL(lpr/lpr) and MRL wild-type mice received an injection of pI:C RNA (ligand to TLR-3), imiquimod (ligand to TLR-7), or CpG-DNA (ligand to TLR-9) on alternate days for 2 wk. Only CpG-DNA triggered the onset of lupus nephritis in MRL(lpr/lpr) mice, as defined by diffuse proliferative glomerulonephritis associated with glomerular IgG and complement C3 deposition, proteinuria, and glomerular macrophage infiltrates. None of the compounds caused DNA autoantibody production or glomerulonephritis in MRL wild-type mice. The role of CpG-DNA to trigger lupus nephritis in MRL(lpr/lpr) mice was found to relate to its potent immunostimulatory effects at multiple levels: B cell IL12p40 production, B cell proliferation, double-stranded DNA autoantibody secretion, and dendritic cell IFN-alpha production. The induction of lupus nephritis by CpG-DNA is motif specific and could be prevented by co-injection of inhibitory DNA. In summary, among the ligands tested, CpG-DNA triggers lupus nephritis in genetically predisposed hosts. These data support the concept that systemic lupus erythematosus is triggered by pathogens that release CG-rich DNA.

Toll-like receptor-7 modulates immune complex glomerulonephritis.

Viral infections may trigger immune complex glomerulonephritis via Toll-like receptors (TLR), as certain TLR trigger immunity upon recognition of viral nucleic acids. On the basis of previous findings regarding viral double-stranded RNA and TLR3 in experimental lupus erythematosus, a similar role for TLR7 that recognizes viral single-stranded RNA was hypothesized. Immunostaining of kidney sections of nephritic MRLlpr/lpr mice revealed TLR7 expression in infiltrating ER-HR3-positive macrophages and few CD11c-positive dendritic cells but not in glomerular mesangial cells as observed for TLR3. This finding was consistent with the distribution pattern of intravenously injected single-stranded RNA in nephritic MRLlpr/lpr mice. TLR7 ligation activated monocytes and dendritic cells, both isolated from MRLlpr/lpr mice, to secrete IFN-alpha, IL-12p70, IL-6, and CCL2. In vivo, a single injection of the TLR7 ligand imiquimod increased serum levels of IL-12p70, IFN-alpha, and IL-6. A course of 25 microg of imiquimod given every other day from week 16 to 18 of age aggravated lupus nephritis in MRLlpr/lpr mice. This was associated with increased glomerular immune complex deposits as well as interstitial expression of CCL2 in imiquimod-treated MRLlpr/lpr mice. Different types of viral nucleic acids seem to modulate systemic autoimmunity through specific interactions with their respective TLR. Different TLR expression profiles on immune cell subsets and nonimmune parenchymal cell types determine the molecular mechanisms involved in viral infection-associated exacerbation of lupus nephritis and possibly other types of immune complex glomerulonephritis.

Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis.

BACKGROUND: The molecular mechanisms of pathogen recognition that initiate infective pyelonephritis are poorly understood. Toll-like receptor-4 (TLR4) mutant mice infected with uropathogenic Escherichia coli lack renal CXCL2 mRNA expression, subsequent neutrophil recruitment, and renal abscess formation. METHODS: We used a bone marrow transplant approach in order to investigate the contribution of TLR4 in intrinsic renal cells or bone-marrow-derived immune cells to neutrophil recruitment during infective pyelonephritis. RESULTS: Both chimera either expressing mutant tlr4 in intrinsic renal cells and wild-type tlr4 in bone marrow-derived cells or vice versa showed an impaired response to uropathogenic E. coli infection in terms of leukocyturia and renal abscess formation when compared to tlr4 wild-type mice with congenic bone marrow transplants. CONCLUSION: These data suggest that TLR4 is required on both intrinsic renal cells (e.g., tubular epithelial cells) and bone marrow-derived immune cells for the control of ascending uropathogenic E. coli infection by initiating chemokine-driven renal neutrophil recruitment.

G-rich DNA suppresses systemic lupus.

Whereas the role of immune complexes in mediating renal cell and immune cell activation is well established, the contribution of sequence-specific immunomodulatory actions of the chromatin part remains unclear. Toll-like receptor-9 (TLR-9) mediates immunostimulatory effects of unmethylated microbial CpG-DNA. It was hypothesized that hypomethylated CpG-DNA in vertebrates may have similar effects and may contribute to disease progression in lupus nephritis. A synthetic G-rich DNA, known to block CpG-DNA effects, was used in this study. In macrophages, G-rich DNA suppressed CpG-DNA-but not LPS-induced production of CCL5 in a dose-dependent manner. Injections of G-rich DNA suppressed lymphoproliferation induced by CpG-DNA injections in mice. In MRL(lpr/lpr) mice with lupus nephritis, labeled G-rich DNA co-localized to glomerular immune complexes and was taken up into endosomes of TLR-9-positive infiltrating macrophages. Eleven-week-old MRL(lpr/lpr) mice that received injections of either saline or G-rich DNA for 13 wk revealed decreased lymphoproliferation and less autoimmune tissue injury in lungs and kidneys as compared with saline-treated controls. G-rich DNA reduced the levels of serum dsDNA-specific IgG2a as well as the renal immune complex deposits. This was consistent with the blocking effect of G-rich DNA on CpG-DNA-induced proliferation of B cells that were isolated from MRL(lpr/lpr) mice. As oligodeoxyribonucleotide 2114-treated MRL(lpr/lpr) mice were not exposed to exogenous CpG-DNA, these effects should relate to a blockade of CpG motifs in endogenous DNA. It is concluded that adjuvant activity of self-DNA contributes to the pathogenesis of lupus nephritis. Modulating the CpG-DNA-TLR-9 pathway may offer new opportunities for the understanding and treatment of lupus.

Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells.

How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL(lpr/lpr) mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL(lpr/lpr) mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN-alpha levels. A course of 50 microg of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL(lpr/lpr) mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL(lpr/lpr) mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis.