What actually prevents viral lung infection?
The immune system is complex and multi-faceted. We know what individual components do to prevent infection, but how they act together is unclear.
The protection provided by our immune system against infection is multi-layered. Each individual cell has a degree of self-defence where it is able to recognise and kill infectious pathogens, this is called intrinsic immunity. Then there is a rapid response called the innate immune system that recognises infection in general. Finally there is a pathogen specific response tailored to each individual virus subtype called adaptive immunity. In turn the adaptive immunity has several elements to it there is a cellular arm made up of two flavours of T cells (CD4 and CD8) and an antibody arm which is also divided into 5 different subtypes based on the structures of the immunoglobulin molecule produced, these are called IgA, IgD, IgE, IgG and IgM. Why they are not called IgA,B,C,D and E is unclear to me, but then again much of immunology nomenclature is opaque (think of the HLA/MHC gene numbering system – or don’t): some might say is deliberately difficult to keep out interlopers from other fields.
Whilst we know that these different components exist, what produces them and how they work to kill infections, we don’t have a complete picture of the relative contributions each component makes. Thanks to studies performed in the 1970’s in the common cold unit, Porton Down (in the rolling Wiltshire countryside of the UK), we do know that antibodies in the blood protect against influenza infection. In these studies, volunteers were deliberately infected with influenza and the rate of infection compared with antibody levels in the blood. The researchers found that volunteers whose blood scored greater than 40 on a particular test called Haemagglutination inhibition (HAI), which measures the functional activity of antibodies, were significantly less likely to get infected. This benchmark number of 1:40, is now used to assess new vaccines. However, the HAI test only assesses one of the arms of the immune system – IgG. We were interested in the role of other components.
In order to assess the role of another antibody subtype, IgA, in our recently published study we went back to human challenge studies. Working with a biotech company – Altimmune – volunteers were deliberately infected with influenza. However in this study, individuals were deliberately selected who had a sub-protective HAI titre. This enabled us to look at the role of other components without the masking effect of blood IgG. Having screened the patients to have low levels of functional antibody in the blood, one prediction might be that they should all get infected. However of the 47 volunteers infected, fifteen had no recoverable virus or symptoms of infection. This suggests that there are indeed other factors that can protect against infection. We measured influenza specific antibody and found that volunteers with high levels of flu binding IgA antibody in their nose or their blood produced less virus over the course of the study. This suggests that IgA can also protect against flu.
However, there were patients with low IgA and low IgG who didn’t get infected, suggesting that there are additional factors contributing to protection. We have data that suggest that CD8 T cells could also be playing a role. CD8 T cells are also called cytotoxic T cells, they work by recognising little bits of virus that are displayed on the surface of infected cells as little flags of infection. Recently it has been shown that there is a special population of T cells that live in the lungs and are primed to recognise and prevent infections. We found high levels of these cells in the lung after a viral infection (Respiratory Syncytial Virus: RSV, which has a very large burden of disease in children). What was really striking was that by transferring these cells alone from one animal that had been exposed to RSV to another animal who hadn’t we could also transfer protection against infection. This means that CD8 T cells are also able to protect against infection, the full study is described in our paper in Mucosal Immunology.
So where does this leave us? We think there is a layered defence against infection. IgA, which is mostly found in the upper airway, forms a barrier to the virus getting into cells in the first place. If this barrier is breached, then the IgG prevents the virus from moving from the upper to the lower airway. If the IgG fails to prevent infection of the lungs, CD8 T cells resident in the lungs rapidly kill the infected cells reducing the burden of disease. What this means is that when designing vaccines for these infections, we need to target all three components of the immune response for the best protection.