Initiation Of Innate Responses Research Articles

Current Understanding of the Innate Control of Toll-like Receptors in Response to SARS-CoV-2 Infection.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19.

Innate antiviral responses are induced by TLR3 and TLR4 ligands in chicken tracheal epithelial cells: Communication between epithelial cells and macrophages

The chicken upper respiratory tract is the portal of entry for respiratory pathogens including avian influenza virus (AIV). There is a paucity of information about the role of airway epithelial cells in the induction of antiviral responses in the chicken trachea. A better understanding of the role of these cells in the initiation of innate responses may improve prophylactic or therapeutic strategies for control of viral infections. The present study aimed to characterize antiviral innate responses in chicken tracheal epithelial cells (cTECs) induced by TLR ligands. The results demonstrated that stimulation of cTECs with TLR ligands induced antiviral responses, and subsequently reduced the replication of AIV in cTECs. Additionally, stimulated cTECs were able to influence the function of other cells such as macrophages. Overall, these results provided evidence that cTECs mount antiviral responses after stimulation with TLR ligands through IRF7 and NF-κB signaling pathways, leading to activation of other cells, such as macrophages.

Gut microbiota modulates type I interferon and antibody-mediated immune responses in chickens infected with influenza virus subtype H9N2.

Commensal gut microbes play a critical role in shaping host defences against pathogens, including influenza viruses. The current study was conducted to assess the role and mechanisms of action of commensal gut microbiota on the innate and antibody-mediated responses of layer chickens against influenza virus subtype H9N2. A total of 104 one-day-old specific pathogen free chickens were assigned to either of the four treatments, which included two levels of antibiotics treatment (ABX- and ABX+) and two levels of H9N2 virus infection (H9N2- and H9N2+). At day 17 of age, chickens in the H9N2+ group were infected via the oral-nasal route with 400 μl of 107 TCID50/ml (200 μl/each route). Oropharyngeal and cloacal swabs at days 1, 3, 5, 7 and 9 post-infection (p.i.) for virus shedding, tissue samples at 12 h, 24 h and 36 h p.i. for mRNA measurement, and serum samples at days 7 and 14 p.i. for hemagglutination inhibition (HI) assay and IgG antibodies were collected. Virus shedding analysis showed that antibiotic treated (depleted)-H9N2 virus infected chickens showed a significantly higher oropharyngeal virus shedding at all time points, and cloacal shedding at days 3 and 5 p.i. compared to control treated (undepleted)-H9N2 infected chickens. Analysis of mRNA expression showed that infection of depleted chickens with H9N2 virus resulted in significantly down-regulated type I interferon responses both in the respiratory and gastrointestinal tracts compared to undepleted-H9N2 infected chickens. However, antibody-mediated immune response analysis showed a significantly higher HI antibody titre and IgG levels in the serum of chickens depleted with antibiotics and infected with H9N2 virus compared to undepleted-H9N2 infected chickens. In conclusion, findings from the current study suggest that the gut microbiota of chickens plays an important role in the initiation of innate responses against influenza virus infection, while the antibody-mediated immune response remains unaffected.

Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity.

Apoptotic cells drive innate regulatory responses that result in tolerogenic immunity. This is a critical aspect of cell physiology as apoptotic cells expose potentially dangerous nuclear antigens on the surface in apoptotic blebs, and failure in their recognition, phagocytosis, or destruction can cause dramatic autoimmunity in experimental models and is linked to development and progression of systemic pathology in human. The marginal zone is a specialized splenic environment that serves as a transitional site from circulation to peripheral lymphoid structures. The marginal zone serves a key role in trapping of particulates and initiation of innate responses against systemic microbial pathogens. However in recent years, it has become clear the marginal zone is also important for initiation of immune tolerance to apoptotic cells, driving a coordinated response involving multiple phagocyte and lymphocyte subsets. Recent reports linking defects in splenic macrophage function to systemic lupus erythematosus in a manner analogous to marginal zone macrophages in lupus-prone mice provide an impetus to better understand the mechanistic basis of the apoptotic cell response in the marginal zone and its general applicability to apoptotic cell-driven tolerance at other tissue sites. In this review, we discuss immune responses to apoptotic cells in the spleen in general and the marginal zone in particular, the relationship of these responses to autoimmune disease, and comparisons to apoptotic cell immunity in humans.

TLR9 ligand enhances proliferation of rat CD4+ T cell and modulates suppressive activity mediated by CD4+ CD25+ T cell

Toll-like receptors (TLRs) play a crucial role in the initiation of innate responses following microbial infection and also in adaptive immune responses by orchestrating the activation of different cell populations. TLRs are expressed at high levels in antigen-presenting cells and recent studies have demonstrated the expression and biological role of TLRs in mouse and human CD4(+) T cells. In this study, we analyzed TLR mRNA expression in rat CD4(+) T cells using stringent quantitative reverse transcription-PCR conditions enabling a direct comparison of the levels of each TLR. We show that TLR3, 5, 6 and 9 mRNAs are the highest TLRs expressed in rat CD4(+) T cells and that TLR5 mRNA is highly expressed in regulatory CD4(+) CD25(+) T cells. In addition, we show that the TLR9 ligand (TLR9L), CpG oligodeoxynucleotide, synergizes with anti-CD3 to induce proliferation of both CD4(+) CD25(-) and regulatory CD4(+) CD25(+) T cells and that TLR9L partially abrogates the suppressive activity mediated by regulatory CD4(+) CD25(+) T cells. This loss of suppression is in part due to the direct effect of TLR9L on effector T cells that are rendered more resistant to the regulation exerted by regulatory T cells. To our knowledge, this is the first study describing the expression of TLR mRNA in rat CD4(+) T cells and the capacity of TLR9L to directly regulate rat T cell responses. Thus, TLR9L may rapidly increase the host's adaptive immunity by expanding effector cells and also by attenuating the suppressive activity mediated by regulatory T cells.