Hey Virus: Replicate Here!

The innate immune system, that part of the immune system that responds to non-specific signs of pathogen infection, faces a quandary when mounting a response against a pathogen. On one hand, it must limit the replication of the pathogen to prevent spread throughout the body. On the other, it must facilitate the development of a specific adaptive immune response, which can clear the pathogen from the body and lead to immunologic memory. It might seem like both of these are reasonable tasks, but the quandary lies in the fact that the adaptive immune system must be activated by a certain amount of antigen (proteins derived from the pathogen that can be effectively targeted by the immune system) in order to elicit an effective response. Low levels of antigen lead to weak responses, whereas high amounts of antigen induce strong responses. Thus, if the innate immune system does the first part of its job too well and largely prevents virus replication, there will not be enough viral antigen present to stimulate a robust adaptive response. So how does the immune system get around this predicament? A new paper in Nature Immunology by Nadine Honke and her colleagues sheds some light on this question (1).

            The major weapons in the innate immune system’s arsenal are small, secreted proteins called interferons. When cells in the body detect a pathogen, they produce interferons, which alert the surrounding cells to the impending danger. These “warning flags” bind to interferon receptors found on the surface of all cells, and induce the expression of a large number of genes, termed interferon stimulated genes (ISGs), which can combat the pathogen through various means. Interferons also initiate mechanisms that facilitate the adaptive immune response, by increasing the presentation of specific antigens to the T cells and B cells that comprise the adaptive immune system. To effectively stimulate T cells, however, requires a sufficient dose of antigen: prior studies have indicated that over 20,000 copies of the antigen are required for an antigen-presenting cell to induce a robust T cell response (2). So, how can the innate immune system effectively prevent the spread of a pathogen while still providing enough “grist” to be presented to naïve T cells? Honke et al began to answer this by examining a particular subset of innate immune cells, metallophilic macrophages.

IRF-1 is Essential for Immunity Against West Nile Virus Infection in Mice

The West Nile Virus (WNV) is spread via mosquitoes and has been affecting humans in the United States since 1999 (1). Current research by immunologist further dissects antiviral immunity, in hopes of understanding WNV infectivity and how it can be combated or prevented. Previous research in mice has identified several immune mechanisms of control against WNV including cytokines, chemokines, complement, B CD4+ and CD8+ T cells (reviewed in [1]). These are all various aspects of the innate and adaptive immune system that aid in fighting against pathogens. More specifically, type 1 IFN (IFN-αβ) has been given special attention, as mice deficient in it, rapidly succumb to WNV infection (2). Further, it was determined that IFN induction is dependent on certain transcriptional signals. Past research pointed Brien et al. (2011) in the direction of IRF-1, as it has been reported to contribute to IFN-β induction. For example, it was found that IRF-1 transcription factor activated IFN-β gene transcription and regulated genes that directly impeded replication of several viruses. Further roles of IRF-1 have been found in controlling herpes virus, even though mice lacking IRF-1 did not have defects in their type I IFN response. This would suggest that IRF-1 regulates IFN genes “in a pathogen and cell type-dependent manner” (1). Further research has also identified IRF-1 as a tumor suppressing gene and a regulator of the adaptive immune response (3).
To understand the role of IRF-1, Brien et al. (2011) assessed WNF infectivity in IRF-1 normal and IRF-1 deficient mice (1). As previously mentioned, they chose to manipulate IRF-1 because mice lacking it (IRF-1-/- ) were vulnerable to WNV infection. First, it was confirmed that IRF-1 is required for control of lethal WNV infection. After infection with WNV, Wild-type (WT) mice had a 65% survival rate and a mean time to death of 11 days, whereas IRF-1-/- mice had a 0% survival rate and a mean time to death of 9.5 days.
To better understand how IRF-1 deficiency is a disadvantage for mice with WNV infection, the ‘viral burden’ was measured at various points post infection in serum, several peripheral organs, and the central nervous system (CNS). Indeed, increased levels of viral RNA were found in the serum and lymph nodes in IRF-1-/- mice compared to the WT. Therefore, IRF-1 controls the early stages of WNV infection. Additionally, WNV infected the spleen more rapidly and clearance was delayed in IRF-1-/- mice. WNV was also detected sooner in the kidneys of IRF-1-/- mice, further suggesting that IRF-1 normally functions to control infection in peripheral tissues.

A Chronic Viral Infection May Affect Ability to Fight Off Bacteria

The prevalence of viruses like HIV and Hepatitis C, which cause chronic infections, raises questions about the long-term effects of infection on the immune system. These questions include: How does the immune system’s composition change in response to a chronic infection? How do the immune system’s effector functions change? How is a defense mounted against other simultaneous infections? In a recent PLoS Pathogens article, Zajac and coworkers address some of these questions. They describe a population of cells, called exhausted T cells, which develop from chronic viral infection and have a reduced ability to fight bacteria.

The presence of an intracellular pathogen, like a virus, rallies a population of T cells to combat the virus. Among the cells produced are effector and memory CD8+ T cells. Effector CD8+ T cells are capable of lysing (killing) cells infected with the same virus that induced their production. Memory CD8+ T cells, on the other hand, wait for further stimulation (a second infection with the same virus) to proliferate and produce the next generation of effector cells. These functions constitute an adaptive response, where T cells respond to one antigen (the virus) specifically.

In addition, effector and memory CD8+ T cells can mount a broader innate-like response that does not require the presence of the specific antigen that induced their production. For example, if effector or memory CD8+ T cells receive cytokines (molecular signals) IL-12, IL-18, and IL-21, produced in response to an infection, they can secrete a cytokine called IFN-gamma that helps other cells take action against the infection. Here the memory and effector cells are responding not to one antigen, but any antigen that induces production of IL-12, IL-18, and IL-21.

While it was already known that exhausted T cells, produced from persistent viral infection (think: less effective versions of effector/memory cells), mount weaker adaptive responses than normal effector or memory T cells (2), Zajac and coworkers found that exhausted T cells mount weaker innate-like responses, as well.

Toll-like Receptor 7 is the Retrovirus Sensing Receptor in Mice

Retroviruses tend to be of great interest to the general public, because of all the media attention given to widely problematic ones, such as the Human Immunodeficiency Virus (HIV). Before effective vaccines against retroviruses like HIV can be produced, a basic understanding of how the immune system responds to them is imperative. When a retrovirus enters the human body, many are known to overcome the immune system, and possibly inhabit the host long-term. However, some animals have developed very efficient immune responses, which allow them to essentially evade or kill the virus. Scientists can study animals with this ability, like mice, to better understand the specificities of their immune systems that facilitate its advantage over the retrovirus, in hopes of relating their findings back to humans.

The first line of defense in the immune response is the innate immune system. The innate immune system is often thought of as “natural,” and provides non-specific protection against foreign invaders (1). Innate defenses are found all over the body, and include physical barriers like skin and mucus. Additionally, the innate immune system responds to pathogens in a generic way and has multiple mechanisms for killing and removing invaders. Most times, the innate defenses are successful. However, if the innate immune system is unsuccessful, it is responsible for triggering the secondary reaction of the adaptive immune system. The adaptive immune response is a specific response to a particular pathogen (foreign invader) and is usually only triggered by those entities that successfully overcome the innate immune response (1). Previous research has shown that in some strains of mice, the innate immune system senses the virus and triggers the appropriate adaptive immune response specific to the virus (2). So although the adaptive immune response is responsible for controlling retroviruses in mice, the first, critical innate virus-sensing step is still not confirmed.

Viruses are unique because they are recognized by endocytic pattern recognition receptors (PRR) on host leukocytes (white blood cells) that detect replication intermediates (nucleic acids) produced by the virus (2). However, it is unknown whether these viral sensors play a vital role in virus sensing in vivo, which is why animal models are very helpful. A recent paper by Kane et al. (2011) is therefore broadly asking whether retroviral replication intermediates are recognized by the innate immune system and further, if they are critical components for the adaptive immune response.