MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/VIROLOGIE/rs-virus/patofyziologie

Host CX3CR1 and RSV G

A non-neutralizing monoclonal antibody (mAb) against the CX3C motif of the viral G protein

  • Could inhibit the effective infection of RSV in culture.

CX3CR1-deficient mice

RSV cell entry

  • Activates ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1) in an RSV G protein-dependent manner
  • Causes tyrosine kinase c-Src to transactivate EGFR
    • Through phosphorylation at EGFR Tyr845
  • Downstream signals of EGFR
    • Lead to actin rearrangement,
    • Wrinkles on the plasma membrane
    • Phagocytosis of liquid RSV via macropinosomes upon extension of the plasma membrane
  • RSV is introduced into large liquid-filled macropinosomes in the form of the viral envelope
    • Promotes the fusion of RSV and host membranes
  • Binding of RSV to cholesterol-rich plasma membrane components
    • Promote the semifusion of the RSV envelope and the plasma membrane
  • Interaction between the RSV F protein and EGFR
    • That activates the signal cascade
      • Phosphatidylinositol 3-kinase (PI3K),
      • P21-activated kinase 1 (PAK1)
        • Downstream effectors in host cells triggering macrophage-mediated endocytosis
  • Rab5 functions,
  • RSV F protein is cleaved acid-independent furin-like enzyme
  • Inhibition of PKCzeta significantly reduced RSV infection
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8495404/

Life cycle of RSV

  • Enters a host cell
  • Internal viral components are released
  • Viral ribonucleoprotein (RNP) complex
    • Assembled by L polymerase
    • Viral genomic RNA wrapped by P, M2-1 and N proteins
      • Is replicated, transcribed and translated
  • Cytoplasmic protein inclusion body (IB) near the intima
  • IB contains
    • Host proteins
      • Antiviral protein MDA5
      • Chaperone protein HSP70
      • Poly(A)-binding protein (PABP)
      • Eukaryotic translation initiation factor 4G (EIF4G)
  • RSV is a negative sense RNA virus
    • Contains noncoding regions
      • Leader region and tailer region, at the 3' and 5' ends
      • RdRp
        • Replicates and synthesizes full-length and positive-sense antigenomes
        • Transcribes viral subgenomic mRNA
          • Polymerase complex switches between replication and transcription
            • Switching may be related to the M2-2 protein
  • RNP complex
    • Use the trailer region as a promoter to replicate the full-length negative-sense genome at the 3' end of the positive-sense antigenome for the assembly of progeny viruses
    • RSV polymerase
      • Binds a sequence from the polymerase starting point of the leader region (nucleotides 1 to 15)
      • Moves along the RNA genome from the 3' end to the 5' end
      • Produce all 10 subgenomic mRNAs
      • Gene start (GS) and gene end (GE) signals on both sides of the template gene region
      • Corresponding to each newly synthesized mRNA
      • GS signal guides the polymerase to initiate mRNA synthesis and adds a methylated guanosine cap structure to the 5' end of the newly synthesized mRNA
        • GE signal guides the addition of a poly A sequence at the 3' end
        • Induces the release of the mRNA
      • Polymerase continues to slide along the gene sequence after the GE signal
        • Until the next GS signal is activated to synthesize the next subgenomic mRNA
  • Both genomic and antigenomic RNA are directly encapsulated by nuclear protein (N) in the process of synthesis, and each N protein binds 7 nucleotides.
  • RSV glycoproteins are initially translated into the endoplasmic reticulum
  • Then transported to the Golgi apparatus
    • Glycosylated
    • Rapidly expanded along microtubules to form filaments through dynein-dependent vesicles
  • The RNP complex loaded with the RSV RNA genome is assembled into filaments after their formation
    • Ultimately transferred to the plasma membrane to sprout new RSV virus particles
  • Assembly of RSV virions occurred at the plasma membrane
  • RSV is newly released from infected cells
    • Is filamentous regardless of virus strain

Metabolism

  • RSV infection can induce microtubule-/dynein-dependent mitochondria to gather around the nucleus
    • And translocate to the center of the microtubule tissue
  • Impairment of mitochondrial respiratory function
    • Loss of mitochondrial membrane potential
      • Elevation of mitochondrial reactive oxygen species (ROS)
        • Increase the replication and titer of RSV
  • RSV infection can stabilize the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in infected cells
    • Facilitate glycolysis
    • Pentose phosphate pathway activation
    • Enhance the replication ability of RSV
  • Main cell to be infected by RSV is the respiratory epithelial cell (AEC)
    • RSV F inhibits the production of interferon-lambda (IFN-lambda)
      • Induced by interferon regulatory factor (IRF) - most critical type III IFN in the antiviral immune response to RSV infection
    • Inducing EGFR activation
      • Leads to a continuous increase in viral infection
  • Transcription of viral genes should encode NS1 and NS2 proteins initially
    • Essential for host infection
    • Inhibit the type gamma interferon response and other components of the immune system
  • NS1 is a major participant in immunosuppression.
    • Can bind and inhibit various molecules in the signal cascade of IFN-gamma response in
      • Retinoic acid-inducible gene I (RIG-I)
      • Toll-like receptor (TLR) pathway
  • NS1 and NS2 complexes are transported to mitochondria
    • To form degradosome
      • Degrade a variety of proteins in the IFN-gamma pathway
        • STAT2, TRAF3 (TNF receptor-associated factor 3)
        • TBK1 (TANK-binding kinase 1)
        • RIG-I
  • NS1 protein also plays a role in altering CD4+/CD8+ cells
    • NS1 inhibits the activation and proliferation of CD103+ CD8+ T cells
      • Which CD103 is a molecule that guides CD8+ T cells to respiratory mucosal epithelial cells triggers cytolytic activity
    • NS1 also inhibited the activation and proliferation of Th17 cells with antiviral effect
    • NS1 increased the expression of IL-4 in CD4+ T cells
    • Promoted the response of Th2 (T helper cells) by antagonizing IFN-I
  • IL-33 signaling
    • Important role in airway inflammation caused by RSV infection
  • Neutralizing IL-33 can significantly reduce the occurrence of allergic inflammatory events
  • IL-6 and tumor necrosis factor-alpha
    • Lead to the secretion of tissue mucus
    • Recruits a large number of granulocytes (such as neutrophils) to the infected site
  • Neutrophils
    • Could significantly regulate RSV latent infection
    • Reduce the exacerbation of asthma in children
      • Through phagocytosis facilitated by the carcinoembryonic antigen-associated cell adhesion molecule 3 (CEACAM3) protein
    • MPO is a powerful bactericidal protein
      • Selectively binds to and quickly kills bacteria such as
        • Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes in the presence of Streptococcus pneumoniae
  • BPI
    • Independent antimicrobial activity against gram-negative bacteria, such as Escherichia coli
    • Can neutralize bacterial endotoxins
  • IL-33 can increase the expression of thymic stromal lymphopoietin (TLSP) in DC cells
    • Change the differentiation of T cells to favor CD4+ T cells expressing Th2 characteristic cytokines
    • Induce type II congenital lymphoid cells (ILC2 cells) the increased secretion of IL-4 and IL-13 levels
      • Further promote mucus secretion
  • IL-13-induced Th2 cellular immune response
    • Closely related to chitinase 3-like 1 protein (CHI3L1)
      • Proposed to enhance airway hyperreactivity (AHR)
      • Inflammatory cell recruitment
      • Mucus production in RSV-infected hosts
  • Excessive mucus secretion and exfoliated airway cilia and airway epithelial cells caused by RSV infection together with neutrophils and lymphocytes in the airway lead to airway obstruction.
  • Severe RSV disease is associated with
    • Inadequate immune response and a low viral load
  • Infants with severe disease showed
    • Lower RSV viral load and lower concentrations of IFN-gamma and CCL5/RANTES
      • Compared with infants with moderate disease
  • Children with mild disease
    • Had high expression of plasma cell and inflammatory genes
    • Lower activation of neutrophil and monocyte gene expression
    • Reduced inhibition of T cell and NK cell gene expression
  • RSV inhibited the humoral immune response of B cells
    • By negatively regulating the expression of IL-21R on the surface of T follicular helper (TFH) cells and IL-21 in immature B cells.
  • Infants with severe respiratory tract infection
    • IFN-? by NK cells induced by specific antibodies to RSV was significantly lower
      • Activation of these NK cells seemed to be related to Fc fucosylation of RSV-specific antibodies
  • Severity of bronchiolitis and wheezing disease
    • Related to other factors, such as respiratory bacteria
  • Nasal mucus samples obtained from children with mild and severe RSV diseases were analyzed
    • All five major bacterial communities showed the characteristics of being the dominant bacteria types.
    • RSV infection and hospitalization were positively correlated with an abundance of
      • Haemophilus influenzae
      • Streptococcus
    • Negatively correlated with an abundance of
      • Staphylococcus aureus
  • Streptococcus pneumoniae (gram positive) and Haemophilus influenzae (gram negative)
    • Were also found to be the most common bacterial isolates in other studies of lower respiratory tract bacterial coinfections in hospitalized patients with RSV infection
  • These results suggest that airways damaged by RSV infection
    • May be more vulnerable to secondary bacterial infection.
  • The expression of some bacterial receptors
    • Intercellular adhesion molecule-1 (ICAM-1),
    • Platelet activating factor-receptor (PAF-r)
    • Carcinoembryonic antigen-associated cellular adhesion molecule 1 (CEACAM1)
    • Was induced during RSV infection
      • Enhances the binding of bacteria to prolong lower respiratory tract infection (LRTI).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8495404/

F protein

  • Major glycoprotein on the surface of RSV
  • Class I fusion protein
  • Anchored on the surface of the RSV membrane
    • By a transmembrane domain
  • 'spring-loaded' trimer

Toll-like receptor 4 (TLR4)

    • Sensitive receptor of gram-negative lipopolysaccharide (LPS)
  • RSV replicating in higher concentrations in TLR4-deficient mice
    • Persisted longer than that replicating in normal mice
  • Expression of TLR4 plays an important role in controlling RSV replication in vivo
    • Mediates the innate immune response of monocytes to produce IL-6
      • Upon exposure to the RSV F protein

Intercellular adhesion molecule-1 (ICAM-1)

  • Promotes the entry and infection of RSV in human epithelial cells
  • Important for viral replication and infection

Epidermal growth factor receptor (EGFR)

  • Expressed on the apical surface of differentiated bronchial epithelial cells
    • Can interact with the RSV F protein
      • Promote fusion of host-virus membrane

Nucleolin (NCL) of host cells

  • Via the F protein
  • Specifically bound to NCL on the surface of apical cells in vitro
  • NCL and RSV virions were colocalized at the surface of the cultured cells

NCL-specific antibodies

  • Colocalization of RSV and NCL proteins on the cell surface decreased significantly

Levels of NCL and TLR4

  • Colocalized with the F protein
  • Increased in the early stage of infection and then decreased
  • Nlc interact with many other viruses, including
    • HIV-1 35, human parainfluenza virus type 3 36, enterovirus71 37, human influenza A 38 and rabbit hemorrhagic disease virus
  • NCL may act as a cofactor of the RSV F protein

Insulin-like growth factor 1 receptor (IGF1R)

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Poslední aktualizace: 29. 12. 2022 22:46:52