What do interferons activate

This collection of data and knowledge will not only facilitate our search for new antiviral compounds and vaccines, but will also be useful in related areas, such as microbial pathogenesis, immunity and cell biology. This effort deserves the attention of the scientific community and requires proper cooperation and coordination of the research programmes at many institutions, both public and private, academic and industrial.

An emerging theme in the interferon IFN field is the cross-talk that occurs between the main cellular regulatory pathways. TLRs are a family of innate immune-recognition receptors that recognize molecular patterns that are associated with microbial pathogens, and they induce anti-microbial immune responses This indicates that there are further pathways possibly through TLRs for viral recognition by host cells It will be interesting to monitor the infection of TLR3-deficient mice with various viral pathogens.

A recent report concerning TLR4 is also of note. Horng et al. Most of the components of these complex signalling pathways have been targeted for disruption in experiments using knockout mice , These mouse experiments have validated the importance of these host pathways in fighting virus infection. Of the influenza viruses, type A viruses cause the most illness and have caused three important worldwide outbreaks during the past century The influenza pandemic of was remarkable for many reasons.

Twenty-eight per cent of the world's population million people were potentially infected during the pandemic. Estimates of the total mortality that resulted from this pandemic range from 20 million to 40 million people It was proposed — in retrospect, in a somewhat naive way — that the ability of viral non-structural protein NS1 to combat the interferon IFN response was the main determinant of virus pathogenicity in — Although it is still too early to completely discount this theory, it seems that the pandemic-type NS1 in a WSN-influenza-virus background actually attenuates virulence in vivo However, the studies were carried out in mice and the WSN virus that was used in these studies was mouse adapted.

Studies using a better animal model preferably a non-human primate such as the Asian macaque are required to fully understand the role of NS1 in pandemic influenza.

Therefore, the hunt continues for the cause of this great pandemic, looking at both viral and host factors that might have affected virus replication and virulence DNA shuffling, pioneered by Maxygen, Inc.

It is a method for quickly evolving genes, operons and whole viruses for the acquisition of any desired properties. This has been accomplished for the generation of new retroviruses that have altered tropisms , but more relevant to this review, also for the generation of new cytokines.

There is minimal cross-species reactivity of these IFNs, except perhaps at very high concentrations. Sequence analysis of the chimaeras showed that the sequence of the carboxy-terminal residues — correlates with the unusually high activity in mouse cells, which is consistent with previous site-directed mutagenesis studies The implications of this approach are profound.

It will be of great interest to determine why the shuffled IFNs are so much more potent. Is it only due to enhanced receptor interactions? It will be interesting to carry out DNA-microarray analysis of cells that have been treated with these highly evolved cytokines. It will also be important to test whether these IFNs are active against hepatitis C virus in a replicon assay based on human liver Huh-7 cells, as these IFNs have only been tested so far against mouse encephalomyocarditis virus EMCV , which is a particularly IFN-sensitive virus.

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Lee, T. The 58,dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase PKR is a member of the tetratricopeptide-repeat family of proteins. Jr et al. Melville, M. The cellular inhibitor of the PKR protein kinase, P58 IPK , is an influenza virus-activated co-chaperone that modulates heat-shock protein 70 activity.

Polyak, S. The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity. Wang, X. Geiss, G. Cellular transcriptional profiling in influenza virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza.

This study examined the effects of NS1 protein expression during influenza A virus infection on global cellular mRNA levels using high-density microarrays. It indicated that the cellular IFN response to influenza A virus infection in lung epithelial cells is influenced markedly by the sequence of the NS1 gene, and it characterized a virus that contains the pandemic influenza NS1 gene.

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Pore-forming activity and structural autoinhibition of the gasdermin family. The mechanisms underlying this protective effect have not been fully elucidated but were found to be STAT1, STAT2 and STAT3 independent in macrophages, and were associated with polarization towards a classically activated M1 macrophage phenotype and the induction of iNOS expression Typhimurium and reduced the invasion of their intestinal epithelial cells in vivo , as well as the invasion of fibroblasts in vitro , By contrast, type I IFNs have been shown to have adverse effects in colon ascendens stent peritonitis, which is a model of peritoneal sepsis In the case of the immune response to group B streptococcus, E.

These differences were associated with decreased levels of CXC-chemokine ligand 10 CXCL10 and with reduced neutrophil numbers and function. Conversely, during subcutaneous S. These pathogens are intracellular, preferentially infect macrophages and require broadly similar immune responses for their control. Infection with L. During infection with pathogens such as L. Infection with M. However, these changes have not been universally observed , and there has not always been concordance between studies regarding bacterial load and survival data.

It is likely that the differences between studies result from differences in experimental protocols, and in the genetics of the host and the M. The importance of type I IFNs as a potentially detrimental factor during tuberculosis was suggested by studies of patient cohorts from the United Kingdom and South Africa Studies of infection with hyper-virulent M. Finally, concurrent co-infection of mice with influenza A virus and M.

Data from investigations of hyper-virulent M. The production of other pro-inflammatory cytokines such as TNF and IL is also negatively affected , , K. Moreover, investigating the effects of prostaglandin E2 during M. Similarly to the findings in L. Ewbank and A. Infection with Francisella tularensis and Francisella tularensis subsp.

The facultative intracellular bacterium F. Similarly to infection with L. Infection with other bacteria. This resistance was associated with an increased number of neutrophils and enhanced function of phagocytic cells Typhimurium infection Protection in these mice was associated with macrophage resistance to necroptosis rather than to alterations in cytokine production or inflammasome activation.

Typhimurium infection. This activation resulted in macrophage cell death that was injurious to the host, but only in the absence of caspase 1, which was required for the antibacterial function of neutrophils For each process, the organisms that cause infections in which IFN-mediated effects may occur are shown.

Typhimurium, Salmonella enterica subsp. Bacterial infection subsequent to or together with viral infection has long been known to be a significant cause of mortality and morbidity in humans, particularly following influenza virus infection Intensive research has therefore gone into understanding how viral infection sensitizes the host to bacterial infection.

Similar results were reported with Staphylococcus aureus secondary infection when poly I:C was administered as a surrogate for viral infection Negative effects on granulocyte generation in the bone marrow were also implicated in a model of lymphocytic choriomeningitis virus— Listeria monocytogenes superinfection Finally, viral infection or poly I:C administration together with Escherichia coli or M.

Parasitic infection. More recent work with different strains of Leishmania spp. An interesting recent report has shown that during the liver stage of infection, P. Studies of infection with the protozoan parasite T.

Finally, the relative balance between the effects on the innate immune response and the adaptive immune response seems to be important. Fungal infection. Interestingly, another study of C. The reason for these opposing findings is unclear; however, given the very similar infection protocols used, it is possible that the differences are due to variations in the microbiota at different animal facilities.

Whole exome sequencing and genome-wide association studies looking for the genetic aetiologies of chronic mucocutaneous candidiasis have identified mutations in STAT1 in some patients , reviewed in Ref.

The same STAT1 mutations were also found in patients with disseminated disease caused by other fungal pathogens such as H. Type I IFNs are among the first cytokines whose production is induced by a plethora of cells during infection. Such knowledge will allow researchers to uncover mechanisms to harness the immune response for maximum host protection with minimum damage.

The ability of the resident microbial flora to influence the homeostasis and function of the host immune system has attracted growing attention in recent years Both Ganal et al. In both cases, antiviral immunity was severely compromised, as mononuclear phagocytes had a defective response to viral challenge, with an abrogated ability both to limit viral replication and to prime other aspects of the antiviral response such as natural killer cell activation.

A recent study suggests that an absence of type I IFN receptor IFNAR signalling in intestinal epithelial cells leads to the proliferation of Paneth cells and consequently to an alteration in the intestinal microbiota composition Pestka, S.

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Crotta, S. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. This study demonstrates the redundant roles of type I and type III IFN signalling in epithelial cells in the anti-influenza virus response, clarifying the confusion arising from earlier literature over protection against influenza virus infection. Casanova, J. Immunity 36 , — Zhang, S.

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Zhang, Y. Interferon-induced transmembrane protein-3 genetic variant rsC is associated with severe influenza in Chinese individuals. Nature Commun. This is a follow-up study to reference 38, showing that IFITM3 variants that contribute to the severity of influenza virus infection are predominant in the Chinese population. Google Scholar. Staeheli, P. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Horisberger, M. Effects of Interferons All interferons share several common effects; they are antiviral agents and can fight tumors.

IFNs activate immune cells natural killer cells and macrophages , increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus. Key Terms Interferons : Interferons IFNs are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells.

They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors. The host may be an animal including humans , a plant, or even another microorganism.