Tut 4- Interferon and Viral Infection Flashcards
(15 cards)
What are type 1 interferons and how do they signal from cell to cell?
Type I interferons act in a paracrine manner and have numerous effects on the surrounding cells, preparing them to ward off possible infection.
The primary function is to induce protection against viruses in neighboring, non-infected cells. This can be induced directly by virus infections and also induced by viral nuclei acids and proteins acting on cellular signalling molecules to stimulation of an array of transmembrane or cytosolic receptors which in turn regulate the immune response.
(They do this by binding to IFNG receptor on both infected and nearby uninfected cells. Signalling form the IFNR induces transcription of serval genes encoding proteins which ultimately inhibit virus replication).
Provide 3 ways in which INF induce expression of enzymes that block viral replication.
- PKR kinase phosphorylates eukaryotic synthesis initiation factor eIF-2 and thereby inhibiting viral protein synthesis
- 2. synthase activates endonuclease which degrade viral RNA. - Mx proteins inhibit viral gene expression and virions assembly of some RNA viruses but not DNA viruses.
How many interferon types are there and what subtypes and associated proteins do they interact with?
IFNs are classified into three types of IFNs, Type I, II and III, (alpha, beta, and gamma) based on the structure of their receptors on the cell membrane surface.
IFN’s also consists of IFNAR1 and IFNAR2 subunits that are associated with tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1) respectively.
Type I, II and III IFNs bind to their specific receptors on the cell membrane and trigger JAK-STAT signaling pathway.
While Type I and III can phosphorylate both STAT1 and STAT2 to form ISGF3 and GAF that binds to ISRE and GAS respectively in the promoter region of responding genes,
Type II IFN can only phosphorylate STAT1 and induce expression of genes with GAS in the promoter region.
What cells induce IFNβ and which ones induce IFNα?
IFNβ is induced in most cell types
IFNα shows a more restricted pattern of induction notably, plasmacytoid dendritic cells (pDCs)
What is the interferon response?
- Induce resistance to viral replication in all cells
- IFNα/β up-regulates surface expression of MHC class I and II
- Increase expression of ligand for receptors on NK cells
- Activate dendritic cells
- Activate NK cells to kill virus-infected cells
- Influence T cell function
What is the role of RIG-1?
Preferentially binds to ssRNA containing a terminal 5” triphosphate and short dsRNA motifs for negative sense RNA viruses e.g. measles, rabies, Ebola, influenza, RSV
What is the role of MDA5?
A. Detect long dsRNA segments of positive sense viruses e.g. picoronaviruses
Which viruses activate RIG-1 and MDA5?
DENV, JEV, and HCV.
What conditions are type 1 interferons licensed for by health authorities?
Interferon alphas are used for treating cancers and viral infections;
Hairy cell leukaemia, AIDS-related Kaposi’s sarcoma, chronic myelogenous leukemia, malignant melanoma, condylomata acuminata, AIDS-related Kaposi’s sarcoma, chronic hepatitis C, and chronic hepatitis B.
interferon betas are used for treating multiple sclerosis;
interferon gamma is used for treating chronic granulomatous disease and severe, malignant osteopetrosis and multiple sclerosis.
What are the anti-viral mechanisms of type 1 interferon action?
Type I IFN induces an array of proteins that interfere with virus replication in order to restrict and limit viral spread from cell to cell.
2’–5’-oligoadenylate synthetase (OAS) is an enzyme induced by Type I IFN that activates latent nuclease RNaseL which then mediates viral RNA degradation.
Another induced enzyme, protein kinase RNA-activated (PKR), a member of the eukaryotic initiation factor 2α family, prevents the recycling of guanidine diphosphate which in turns blocks viral RNA translation.
Other notable antiviral proteins induced by Type I IFN are myxovirus resistance (Mx) GTPases which restrict viral nucleocapsid localization, interferon stimulated gene 15 (ISG15) and tripartite motif (TRIM) protein which interfere with the release of viral particles as well as APOBEC3, a protein that induces hypermutation of viral DNA.
To confine and localize the infection, Type I IFNs also can activate the apoptosis mechanism to eliminate virus infected cells by up regulating Fas ligand (FasL), PDL-1 and TRAIL.
In addition to activating the antiviral mechanism in the infected cells, Type I IFN can also limit virus infection by modulating both innate and adaptive immunity.
Type I IFNs directly activate NK cells to enhance their cytotoxicity to eliminate infected cells and confine the infection. However, complete elimination of intracellular infection by pathogens requires activation of the adaptive immune response and the Type I IFNs have an active role in this activation process.
Type I IFNs promote the maturation of dendritic cells (DCs) that facilitate CD4+ T cell differentiation into either Th1 or Th2 cells.
Studies have shown that Type I IFN experienced APCs are capable of cross-presentation and stimulate naïve CD8+ T cells, resulting in clonal expansion and proliferation. These Type I IFN experienced DCs have increased expression of chemokines that recruit NK, T and B cells to the site of infection, and IL-15 which is important in NK and CD8+ memory cell maintenance.
How are type 1 interferons administered clinically?
Unfortunately, interferons administered in pharmacological doses produce considerable toxicity that is dose-related and that may require cessation of therapy. The administration of interferon has been carried out mostly by intravenous and intramuscular routes.
Will type 1 interferons be useful against ASF and CV?
No. There is no vaccine available right now to protect against swine flu or covid 19.
IFNα and β were systematically relatively efficient in vitro and succeeded in certain animal models but generally failed to significantly improve the disease in humans. For example, a combination of IFNβ with lopinavir/ritonavir against MERS-CoV improved pulmonary function but did not significantly reduce virus replication or lung pathology severity. while a combination of IFNα2a with ribavirin delayed mortality without decreasing it on the long run. Similarly, the combination of IFNα2b with ribavirin gave excellent results in the rhesus macaque but was inconclusive in human..
In 2019, a group of Spanish researchers injected a number of domestic pigs with a weak strain of ASFV genotype 2 that had been isolated from a wild boar captured in Latvia. The vaccine caused mild, transient symptoms involving fever and joint swelling in some animals, but they all survived after being exposed to pigs that carried the virulent genotype 2 strain Georgia 2007. Although they’re effective, safety is still a significant concern.
Why are there so few effective antivirals?
Unfortunately, confidence in the potential benefits of antivirals is tempered by the possibility of their improper use (and potentially their overuse), which could perhaps result in lessened benefit to the individual, and pose an enhanced risk that a resistant virus will emerge in the population. If more were known about how antivirals would work in a pandemic, it would be possible to make sensitive risk–benefit analyses of how to deploy antivirals, and thus answer many questions that are difficult, if not impossible, to answer in the current circumstances. Should a limited supply of antivirals be used for treatment only, or a combination of treatment and prophylaxis? If a combination of the two uses is desired what should be the proportion of each? What types of prophylaxis should be implemented, and what groups should be targeted? Scenarios A, B, and C answer these questions in very different ways. They represent different assumptions about the available supply of antiviral drugs, as well as drugs about the risks associated with certain of their uses. They also factor in unknowns differently. These unknowns include, What will be the effect of community mitigation in terms of attack rate and mortality rate? Will the stockpiled antivirals be effective against the pandemic virus? What is the potential that the virus will become drug resistant and how rapidly and how extensively will resistance develop? How will limited shelf-life of antivirals impact the supply at any given time? How, in the absence of a timely and accurate diagnostic test, will demand for treatment antivirals be affected by the presence of other influenza-like illnesses? What will be the potential for restocking antivirals, should this be affordable and the best policy objective?
The greatest risk appears to be that overprescribing (e.g., to patients who do not actually have the pandemic influenza strain) and misuse of antivirals may not only deplete the supply but also may promote resistance, undermining the effectiveness of both treatment and prophylaxis. Scenario C poses the greatest risk in this regard. Scenario B runs the calculated risk that prophylaxis for workers providing critical societal functions (e.g., health care, utilities) does not risk over-use and misuse to the same extent. For the same reasons as the broad prophylaxis associated with scenario C, and because of its focus on health care and emergency services personnel, scenario B promises health care, public safety, and social order benefits for the population as a whole.
What other antivirals are available for use in infected pigs/people?
Influenza antiviral drugs can be used to treat influenza infections, including human infections with influenza viruses that normally circulate in swine (swine influenza). There are four different antiviral drugs that are recommended for use in the United States for the treatment of influenza: oseltamivir, peramivir, zanamivir, and baloxavir.
What are the predominant approaches used by Health Authorities to control the ASF and Coronavirus outbreaks?
Veterinary and Public Health Authorities have instituted strong quarantine, culling and travel restriction procedures. Each disease requires a different set of health interventions with the objectives of reducing (a) transmission, (b) severe morbidity and mortality (c) the impact on health systems and also on the political and other sector.
Health care workers collecting NP and OP swab specimens from suspected or confirmed COVID-19 patients should be well-trained on the procedure and should wear a clean, non-sterile, long-sleeve gown, a medical mask, eye protection (i.e., googles or face shield), and gloves. Procedure should be conducted in a separate/isolation room, and during NP specimen collection health care workers should request the patients to cover their mouth with a medical mask or tissue. Although collection of NP and OP swabs have the potential to induce fits of coughing from the patient undergoing the procedure, there is no currently available evidence that cough generated via NP/OP specimen collection leads to increased risk of COVID-19 transmission via aerosols.
