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
- Were significantly less susceptible to RSV infection than CX3CR1-expressing mice
- www.ncbi.nlm.nih.gov/pmc/articles/PMC8495404/
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
- 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
- By binding to RSV F protein
- 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)
- Receptor of RSV
- www.ncbi.nlm.nih.gov/pmc/articles/PMC8495404/
