scholarly journals CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Lei Zhang ◽  
Hongyong Li ◽  
Yan Hai ◽  
Wei Yin ◽  
Wenjian Li ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Notch Signaling ◽  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Adaptive Immune Responses ◽  
Tlr Signaling ◽  
Adaptive Immune ◽  
Syncytial Virus ◽  
The Impact

ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8+ lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs. IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and effective killed RSV vaccine. Using adjuvants to regulate innate and adaptive immune responses could be an effective method to prevent ERD. We evaluated the impact of TLR and Notch signaling on ERD by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling, during FI-RSV immunization. The data showed that treatment of TLR or Notch signaling alone did not suppress FI-RSV-enhanced airway inflammation, while CpG plus L685,458 markedly inhibited ERD. The mechanism appears to involve suppressing Th17 memory responses and promoting tissue-resident memory cells. Moreover, these results suggest that regulation of lung immune memory with adjuvant compounds containing more than one immune-stimulatory molecule may be a good strategy to prevent FI-RSV ERD.

scholarly journals Adaptive Immune Responses of Patients with Asthma to the Attachment (G) Glycoprotein of Respiratory Syncytial Virus

2001 ◽  
Vol 184 (12) ◽  
pp. 1589-1593 ◽  
Author(s):  
Gerald E. Hancock ◽  
Catherine A. Scheuer ◽  
Renata Sierzega ◽  
Karin S. Pryharski ◽  
John T. McBride ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Syncytial Virus

scholarly journals Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus

2021 ◽  
Vol 17 (12) ◽  
pp. e1010142
Author(s):  
Miaoge Xue ◽  
Yuexiu Zhang ◽  
Haitao Wang ◽  
Elizabeth L. Kairis ◽  
Mijia Lu ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Adaptive Immunity ◽  
Human Respiratory Syncytial Virus ◽  
Viral Rna ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Syncytial Virus ◽  
Tract Infections

Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in humans. A well-known challenge in the development of a live attenuated RSV vaccine is that interferon (IFN)-mediated antiviral responses are strongly suppressed by RSV nonstructural proteins which, in turn, dampens the subsequent adaptive immune responses. Here, we discovered a novel strategy to enhance innate and adaptive immunity to RSV infection. Specifically, we found that recombinant RSVs deficient in viral RNA N6-methyladenosine (m6A) and RSV grown in m6A methyltransferase (METTL3)-knockdown cells induce higher expression of RIG-I, bind more efficiently to RIG-I, and enhance RIG-I ubiquitination and IRF3 phosphorylation compared to wild-type virion RNA, leading to enhanced type I IFN production. Importantly, these m6A-deficient RSV mutants also induce a stronger IFN response in vivo, are significantly attenuated, induce higher neutralizing antibody and T cell immune responses in mice and provide complete protection against RSV challenge in cotton rats. Collectively, our results demonstrate that inhibition of RSV RNA m6A methylation enhances innate immune responses which in turn promote adaptive immunity.

scholarly journals Construction and characterization of recombinant vaccinia viruses co-expressing a respiratory syncytial virus protein and a cytokine

2001 ◽  
Vol 82 (9) ◽  
pp. 2107-2116 ◽  
Author(s):  
Teresa R. Johnson ◽  
Julie E. Fischer ◽  
Barney S. Graham
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Antigen Expression ◽  
Virus Protein ◽  
Recombinant Vaccinia ◽  
Vaccinia Viruses ◽  
Ifn Γ ◽  
Syncytial Virus ◽  
The Impact

Recombinant vaccinia viruses are well-characterized tools that can be used to define novel approaches to vaccine formulation and delivery. While vector co-expression of immune mediators has enormous potential for optimizing the composition of vaccine-induced immune responses, the impact on antigen expression and vector antigenicity must also be considered. Co-expression of IL-4 increased vaccinia virus vector titres, while IFN-γ co-expression reduced vaccinia virus replication in BALB/c mice and in C57BL/6 mice infected with some recombinant viruses. Protection against respiratory syncytial virus (RSV) challenge was similar in mice immunized with vaccinia virus expressing RSV G glycoprotein and IFN-γ, even though the replication efficiency of the vector was diminished. These data demonstrate the ability of vector-expressed cytokine to influence the virulence of the vector and to direct the development of selected immune responses. This suggests that the co-expression of cytokines and other immunomodulators has the potential to improve the safety of vaccine vectors while improving the immunogenicity of vaccine antigens.

scholarly journals Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials

2020 ◽  
Vol 21 (18) ◽  
pp. 6838 ◽  
Author(s):  
Laurie Spehner ◽  
Stefano Kim ◽  
Angélique Vienot ◽  
Eric François ◽  
Bruno Buecher ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Immune Responses ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Adaptive Immune Responses ◽  
Anal Squamous Cell Carcinoma ◽  
Adaptive Immune ◽  
Immunosuppressive Cells ◽  
The Impact

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients’ clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients’ survival.

A MATHEMATICAL STUDY OF THE IMPLICIT ROLE OF INNATE AND ADAPTIVE IMMUNE RESPONSES ON WITHIN-HUMAN PLASMODIUM FALCIPARUM PARASITE LEVELS

2020 ◽  
Vol 28 (02) ◽  
pp. 377-429
Author(s):  
GIDEON A. NGWA ◽  
WOLDEGEBRIEL A. WOLDEGERIMA ◽  
MIRANDA I. TEBOH-EWUNGKEM
Keyword(s):  
Immune Responses ◽  
Parasite Development ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Plasmodium Falciparum Parasite ◽  
Number Formula ◽  
Parameter Measuring ◽  
System Variables ◽  
The Impact

A within-human-host malaria parasite model, integrating key variables that influence parasite evolution-progression-advancement, under innate and adaptive immune responses, is analyzed. The implicit role of immunity on the steady state parasite loads and parasitemia reproduction number ([Formula: see text]), a threshold parameter measuring the parasite’s annexing ability of healthy red blood cells (HRBCs), eventually rendering a human infectious to mosquitoes, is investigated. The impact of the type of recruitment function used to model HRBC growth is also investigated. The model steady states and [Formula: see text], both obtained as functions of immune system variables, are analyzed at snapshots of immune sizes. Model results indicate that the more the immune cells, innate and adaptive, the more efficient they are at inhibiting parasite development and progression; consequently, the less severe the malaria disease in a patient. Our analysis also illustrates the existence of a Hopf bifurcation leading to a limit cycle, observable only for the nonlinear recruitment functions, at reasonably large [Formula: see text].

scholarly journals The immunology of Zika Virus

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 203 ◽  
Author(s):  
Abigail Culshaw ◽  
Juthathip Mongkolsapaya ◽  
Gavin Screaton
Keyword(s):  
Immune Responses ◽  
Zika Virus ◽  
Effective Vaccine ◽  
Comprehensive Understanding ◽  
Adaptive Immune Responses ◽  
Zikv Infection ◽  
Virus Identification ◽  
Adaptive Immune ◽  
Poor Outcomes ◽  
The Impact

Zika virus (ZIKV) was initially thought to cause only mild, self-limiting symptoms. However, recent outbreaks have been associated with the autoimmune disease Guillain-Barré syndrome and causally linked to a congenital malformation known as microcephaly. This has led to an urgent need for a safe and effective vaccine. A comprehensive understanding of the immunology of ZIKV infection is required to aid in the design of such a vaccine. Whilst details of both innate and adaptive immune responses to ZIKV are emerging, further research is needed. As immunopathogenesis has been implicated in poor outcomes following infection with the related dengue virus, identification of cross-reactive immune responses between flaviviruses and the impact they may have on disease progression is also of high importance.

scholarly journals Lack of Activation Marker Induction and Chemokine Receptor Switch in Human Neonatal Myeloid Dendritic Cells in Response to Human Respiratory Syncytial Virus

2019 ◽  
Vol 93 (22) ◽  
Author(s):  
Cyril Le Nouën ◽  
Philippa Hillyer ◽  
Eric Levenson ◽  
Craig Martens ◽  
Ronald L. Rabin ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Cord Blood ◽  
Influenza A ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Young Infants ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) infects and causes disease in infants and reinfects with reduced disease throughout life without significant antigenic change. In contrast, reinfection by influenza A virus (IAV) largely requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC), which may be too immature in young infants to induce a fully protective immune response against RSV reinfections. We therefore compared the ability of RSV and IAV to activate primary human cord blood (CB) and adult blood (AB) myeloid DC (mDC). While RSV and IAV infected with similar efficiencies, RSV poorly induced maturation and cytokine production in CB and AB mDC. This difference between RSV and IAV was more profound in CB mDC. While IAV activated CB mDC to some extent, RSV did not induce CB mDC to increase the maturation markers CD38 and CD86 or CCR7, which directs DC migration to lymphatic tissue. Low CCR7 surface expression was associated with high expression of CCR5, which keeps DC in inflamed peripheral tissues. To evaluate a possible inhibition by RSV, we subjected RSV-inoculated AB mDC to secondary IAV inoculation. While RSV-inoculated AB mDC responded to secondary IAV inoculation by efficiently upregulating activation markers and cytokine production, IAV-induced CCR5 downregulation was slightly inhibited in cells exhibiting robust RSV infection. Thus, suboptimal stimulation and weak and mostly reversible inhibition seem to be responsible for inefficient mDC activation by RSV. The inefficient mDC stimulation and immunological immaturity in young infants may contribute to reduced immune responses and incomplete protection against RSV reinfection. IMPORTANCE Respiratory syncytial virus (RSV) causes disease early in life and can reinfect symptomatically throughout life without undergoing significant antigenic change. In contrast, reinfection by influenza A virus (IAV) requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC). We used myeloid DC (mDC) from cord blood and adult blood donors to evaluate whether immunological immaturity contributes to the inability to mount a fully protective immune response to RSV. While IAV induced some activation and chemokine receptor switching in cord blood mDC, RSV did not. This appeared to be due to a lack of activation and a weak and mostly reversible inhibition of DC functions. Both viruses induced a stronger activation of mDC from adults than mDC from cord blood. Thus, inefficient stimulation of mDC by RSV and immunological immaturity may contribute to reduced immune responses and increased susceptibility to RSV disease and reinfection in young infants.

Sign in / Sign up

Export Citation Format

Share Document