The outcomes of viral infections are the result of dynamic interplays between infecting viruses and induced host responses. They can be categorized as either acute or persistent depending on temporal virus-host relationships. A multitude of viral and host factors are known to influence acute or persistent infection outcomes. An example is Type I IFNs (IFN-I), a cytokine produced early after the infection. IFN-I plays a critical role in shaping the antiviral immune response, however, the dynamics by which different immune cell subsets regulate the IFN-I response during the early stage of infection are not completely understood.
The aim of my project is to understand better how type I IFN regulation during the early stage of infection influences the infection fate. We used Lymphocytic Choriomeningitis Virus (LCMV)-infection of mice as a model system and through RNA sequencing we obtained spleen-specific transcriptomes from acutely and chronically infected mice. We generated co-expression weighted gene networks that lead to the identification of modules containing highly co-expressed genes that represent relevant biological pathways. Among these, we identified modules related to the IFN-I signaling and observed that they follow different expression behaviors during acute and chronic infections. Importantly, IFN-I genes in acute infection were co-expressed with genes related to inflammatory macrophages, suggesting that IFN-I signaling pathway might participate in the induction of these cells during acute LCMV infection. Moreover, we hypothesized that lack of inflammatory macrophages in chronic infection is a critical event that influence infection fate.
Phenotypic and transcriptomic analysis lead us to identify macrophages from acutely infected mice as more polarized towards a pro-inflammatory phenotype compared to those from chronically infected mice. Moreover, we identified macrophages as an important source of IFN-I during acute but not chronic infection, altogether suggesting that this innate immune cell subset plays an important role in the resolution of an acute infection. Indeed, depletion of macrophages by Clodronate-loaded liposomes affected the virus-specific T cells response and the clearance of the virus.
Altogether these results demonstrate the contribution of macrophages in the production of IFN-I early during an acute infection, which results in the induction of an inflammatory response that likely contributes to infection resolution. Further studies are necessary to understand the mechanisms and specific macrophage cell subsets that participate in these early events during acute infection, as well as the regulatory pathways that prevent the induction of this innate immune response during a chronic infection. We expect that the results from this project will elucidate universal concepts related to infection fate decision that are also relevant for persistent human infections such as HIV or HCV.