Friday, May 3, 2013

Interferon, Always Messing Stuff Up

Persistent viral infection such as those from HIV, Hepatitis B and Hepatitis C can lead to continuous pain and suffering in infected individuals. Persistent viruses are able to avoid clearance by down-regulating the immune system and suppressing the activation of antiviral CD4 and CD8 T cells. After persistent infection, a hyperimmune response is often observed characterized by elevated pro-inflammatory mediators and a constant interferon signature. Type 1 interferon (IFN-1) signaling is upstream of many immune responses such as activation of T cells, B cells and natural killer cells as well as inflammatory genes. Interferon is a protein that cells display during the presence of pathogens to communicate to other cells and initiate the innate immune system. Interferon signaling is necessary for host defense against viral infection and viral immunity during acute infections.(1) Because of this it is suspected that IFN-1 is responsible for the hyperimmune activity in persistent viral infection.

         To understand the role of IFN-1 in persistent viral infection the authors used the Armstrong (Arm) and clone 13 (Cl13) strains of lymphocytic choriomeningitis virus. The Arm strain is characterized by an acute infection, while the Cl13 strain is characterized by a systemic viral infection. Through the use of IFN-β-yellow fluorescent protein tagging in plasmacytoid dendritic cells (pDCs) it was determined that IFN-β was produced during Cl13 infection and not during Arm infection. Fluorescent protein tagging works by attaching an antibody to a cell surface protein receptor. Then an additional molecule that contains the fluorescent tag binds to the antibody attached to the protein of interest thereby allowing you to observe the expression of the target protein, in this case IFN-β .By replacing the glycoproteins of Arm and Cl13 viruses with green fluorescent protein, the authors confirmed that Cl13 infection preferentially targets pDCs. Green fluorescent protein is a protein that is found in jellyfish. We can insert the gene for the green fluorescent protein into the coding sequence of our target protein, then when the protein of interest gets transcribed the green fluorescent protein will be transcribed as well and we can measure target protein levels by measuring the level of green fluorescent protein. pDCs showed increased green fluorescent protein expression when infected with the Cl13 viruses marked with the protein compared to when infected with the Arm viruses marked with the green fluorescent protein.

To confirm that the pro-inflammatory substrates produced during Cl13 infection were caused by IFN-1 signaling, the authors treated mice with an antibody against interferon alpha-beta-receptor 1 (anti-IFNAR1) prior to infection. Pro-inflammatory substrate levels were reduced in infections after anti-IFNAR1 treatment. Pro-inflammatory substrates such as cytokines and chemokines play an important role in acute immune responses.(2) They seem, however, to have a negative effect in persistent viral infection. Blocking IFN-1 signaling in Cl13 infection also led to increased splenocyte, a white blood cell precursor, levels as well as increased B cells, CD4 and CD8 T cells, natural killer cells, DCs and macrophages. Lymphoid architecture is important for the activation and maintenance of immune responses. Lymphoid tissue destruction is usually present in persistent infection, and when IFN-1 signaling was blocked lymphoid architecture was preserved. Although Cl13 levels were higher 10 days postinfection after IFN-1 blockade, by 50 days postinfection virus levels were virtually undetectable after IFN-1 blockade while much higher in control mice signifying that IFN-1 blockade increases the clearance of Cl13 infection. In Arm infection, however, IFN-1 blockade led to higher viral loads at 20 days postinfection compared to control mice. This is because the clearance of acute infection is controlled by CD8 T cell response, which is inactivated when IFN-1 signaling is blocked. Blockade of IFN-1 also enhanced virus-specific CD4 T cell responses. To determine whether CD4 T cell responses were necessary for virus control after IFN-1 blockade the authors depleted CD4 T cells and observed viral levels. Although CD4 T cell depletion had little effect on viral levels 20 days postinfection, by 40 days postinfection CD4 depletion led to increased viral levels in anti-IFNAR1-treated mice. This indicates that CD4 T cells are necessary for persistent viral control after IFN-1 blockade. CD4 T cell levels can control the progression of persistent infection and could be used in future therapies.(3) Previous studies have shown that persistent viral infection is associated with decreased T cell levels which leads to greater susceptibility to future viral infections.(4)

The findings of this study are important because persistent infections such as those from HIV infection continuously harm infected individuals. By determining that blocking the IFN-1 pathway can reduce viral load levels during persistent infections, we could understand a way to alleviate pathologies in infected individuals. There is the potential therapeutic benefit of IFN-1 signaling blockade for persistent viral infections. Future studies could address how to increase CD4 T cell levels in presisntently infected individuals to fight infection in addition to IFN-1 blockade. Also, IFN-1 signaling plays a role in many physiological process, many of which are not fully understood. The mechanisms of IFN-1 in immune modulation or antiviral activity could by studied.

I was not sure of the significance of the suppression of interleukin-10 and programmed cell death 1 ligand 1 in the study. I think that the authors should have gone more into depth on its importance. I also did not understand how the authors came to their conclusion about the T cell localization saying that CD4 T cells levels increased while CD8 level remained the same after IFN-1 blockade.


Primary Source:
Teijaro, John R., Cherie Ng, et al. "Persistent LCMV Infection Is Controlled by Blockade of Type 1 Interferon Signaling." Science. 340. (2013): 207-211. Web. 3 May. 2013. 

Secondary Sources:
1. Dionne, KR, JM Glavin, et al. "Type 1 interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection." Journal of Neurovirology. 17.4 (2011): 314-26. Web. 3 May. 2013.

2. Zhong, X, C Bai, et al. "Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger."International Immunology. 16.8 (2004): 1181-8. Web. 3 May. 2013.

3. Stamm, A, L Valentine, et al. "An intermediate dose of LCMV clone 13 causes prolonged morbidity that is maintained by CD4 T cells." Virology. 425.2 (2012): 122-32. Web. 3 May. 2013.

4. Smithey, MJ, G Li, et al. "Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life." Journal of Immunology. 189.11 (2012): 5356-66. Web. 3 May. 2013.

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