Influenza - putting the Trojan into the horse but should you open it?

A trojan horse (dendritic cell) filled with virus

Inspired by a recent journal club article:

A number of pathogens infect via one organ but are able to move to another. Think of the likes of the initial HIV infection of cells within the reproductive tract followed by its transfer to the immune system (see my earlier post here). This transfer of viruses, bacteria or other parasites is responsible for the induction of an effective immune response but also it can lead to some of the more serious disease symptoms during infection, but how is it controlled?

A now classic example is that of the measles virus: this virus is inhaled inside your lungs whereby certain sentinel immune cells (types of dendritic cells and macrophages) capture it and become infected themselves. Here, these migrating cells transport the infection into the lymph nodes nearby where these organs are jam-packed full of the kinds of cells measles really likes to infect: T cells. From here the infection spreads throughout the body resulting in the classic symptoms you see as measles: rash, immunosuppression and it even allows for it's exit out of the body. This very same mechanism may be used by the deadly and re-emerging virus: nipah.

On the the other hand, these same cells - dendritic cells - also control our response to infection. This discovery was even recognized this year by the Nobel Prize committee. Through capturing of pathogens they can act as potent antigen presenting cells when they travel to the draining lymph nodes. Here - as in the case of measles - they come across T cells but in this instance no infection is transferred; the pathogen-laden cells cause the proliferation of virus-specific T cells, which act to eliminate virally infected cells throughout the body.

But just how is this possible? What controls the difference between viral infection of dendritic cells and them just passing on antigen? How come they allow themselves to be infected by the virus? Can we use this to our advantage? And, do any other pathogens use this 'Trojan Horse' strategy? Well, a paper out recently in the journal PLoS Pathogens uncovers the mechanism behind this kind of interaction between another kind of virus: influenza virus and these lung dendritic cells. They show their role in potentially inducing a good immune response but may also shine light on the use of these cells by other pathogens to move around the body.

The model out forward: only one kind of lung dendritic cell supports influenza virus replication

The Mount Sinai School of Medicine team followed the involvement of two dendritic cell (DC) sub-types (for immunology experts: CD103⁺ DCs and CD11b^high DCs) following influenza infection in mice. They discovered that oddly, both types allowed for viral infection with one in particular being many, many times more infectable than the other. Recently a number of molecules expressed on the surface of these cells have been thought to facilitate influenza entry. This difference in flu replication was based on the difference in interferon-response, i.e. the more resistant cell type responded more strongly to innate immune signals resulting in a block on viral replication; the other had no such block. Before this, influenza was really only thought to infect the cells lining your respiratory tract, so what were they doing in these dendritic cells leaving the lungs?

Influenza virus replicates (as shown by flu nucleocapsid protein in red) in one kind of dendritic cell (CD103+s) See antigen inside nucleus, a hallmark for productive flu infection.

This work shows influenza virus infecting certain types of migratory dendritic cells that are leaving the infected lungs - these cells would allow for influenza-specific priming of adaptive immunity. Influenza does not usually spread further than the lungs, suggesting that it may not be able to escape the lymph nodes containing these infected dendritic cells and associated T cells. However, other viruses may not have that problem. For example: the aforementioned Measles virus uses this same method to reach it's target cells, the T cells. In the case of measles the dendritic cells act as a Trojan horse bringing the pathogen through the host's defenses inside the lung. 

While it is not known exactly how it does this, it wouldn't be a stretch of the imagination to suggest that it hijacks these very dendritic cell subtypes. It is not understood what controls viral spread once it reaches the lymph nodes (measles versus infuenza) but it may have something to do with the measles affinity - and flu's lack of - for nearby T cells.

And, finally: this may also be harnessed in our development of new vaccine strategies: targeting of antigen to these specific migratory cells may allow for a much more potent immune response. But we will have to wait and see.

Moltedo, B., Li, W., Yount, J., & Moran, T. (2011). Unique Type I Interferon Responses Determine the Functional Fate of Migratory Lung Dendritic Cells during Influenza Virus Infection PLoS Pathogens, 7 (11) DOI: 10.1371/journal.ppat.1002345