Why the sequel is always worse than the original

One would like to think that pneumonia is like a classic film. If all goes well, the story resolves with the patient having conquered the infectious threat, changed for the better, and more capable to take on the next challenge. However, recent work from Roquilly and colleagues suggests that when it comes to severe infections, the happy ending may presage the sequel. The investigators began their studies examining how E.coli pneumonia differed if it followed a previously cured episode of E.coli or viral pneumonia, as compared with its course in naïve animals. They found that in secondary infections, the mice developed more severe disease, with a higher bacterial burden and longer duration of illness. The investigators were able to tie the increased disease severity to impaired activity of antigen presenting cells (APCs) and enhanced production of T regulatory cells (T_regs) in the lungs. The ability of APCs to prime T cells was reduced for weeks after primary infection, and the APCs expressed reduced levels of proinflammatory cytokines, like interleukin-12 (IL-12), and increased transforming growth factor-β (TGF-β). TGF-β was central to the reduced immunogenic function of the DCs and macrophages, as blocking TGF-β restored antigen presentation, cytokine production, abundance of T_regs, and bacterial burden to levels seen in a primary infection. Similarly, depleting T_regs and restoring IL-12 reversed the enhanced sensitivity to infection. Transcriptional profiling showed that dendritic cells (DCs) that develop in the lung microenvironment post-infection had decreased expression of IRF4, which is a transcription factor associated with antigen presentation, and increased expression of Blimp1, a transcription factor that induces tolerogenic functions. Circulating DCs from patients with secondary E.coli infection after sepsis or with severe trauma showed enhanced expression of Blimp1, suggesting a similar immunosuppressive environment. Thus, blocking TGF-β or supplying IL-12 might be useful prophylaxis against secondary infection. Of course, timing and patient selection would be critical, as presumably the shift in phenotype of the APCs post-infection is important in resolving host-damaging inflammation. It will also be interesting to see whether this immunosuppressive environment can contribute to reactivation of latent infections, such as tuberculosis. Overall, the work by Roquilly and colleagues reveals that APCs, the heroes of the first conflict, can provide the set-up for the second episode.