Host-microbe interactions in coxsackievirus infection : Focus on innate immunity
Sammanfattning: Coxsackievirus group B (CVB) is a common virus that usually causes only mild symptoms in humans. However, occasionally these infections result in severe diseases like meningitis, myocarditis and pancreatitis. In addition, CVB infections have been suggested to be involved in the etiology of chronic diseases such as dilated cardiomyopathy and type 1 diabetes (T1D). Why the outcome of a CVB infection can vary so greatly is not entirely clear. Besides virusintrinsic factors it has been hypothesized that the ability to mount an adequate immune response is important in regulating damage after CVB infection. The innate immune response is essential for the control of virus replication early after infection and for initiating the adaptive immune response, which is needed to clear the infection. If the host fails to initiate a suitable immune response, damage may arise as a result of uncontrolled virus replication or excessive inflammation. The aim of this thesis was to increase our understanding of how the innate immune response is initiated after CVB infections and how it may help to control the virus. In paper I, we showed that the intracellular virus sensor melanoma differentiationdifferentiation protein-5 (MDA-5) plays an important role in the immune response to CVB. Lack of MDA-5 weakened the host s ability to limit virus replication during the first days after infection, which lead to increased tissue damage. In addition, we found that the genetic background determines how heavily the host relies on MDA-5 for survival. Mice lacking MDA-5 on a C57/BL6 background rapidly succumbed to CVB infection while 129/SvJ mice survived and eventually cleared the virus even in the absence of MDA-5. Surprisingly, production of type I interferons (IFNs) was not significantly compromised by a lack of MDA-5. Type I IFNs produced by infected cells can stimulate immune cells like natural killer (NK) cells that have been demonstrated to be important in the host response to CVB infections. In paper II, we established that CVB infection modulates the cell surface expression of NK cell receptor ligands. The downregulation of inhibitory class I HLA alleles and the activating NKG2D ligand MICA did not result in increased NK cell mediated killing of the infected cells. However, after encountering infected cells, NK cells responded with enhanced secretion of IFN-gamma, a cytokine with well-described antiviral and immuno-modulatory properties. Type I and II IFNs secreted by infected cells and/or immune cells are an indispensable part of the immune response to virus infections. In paper III, it was demonstrated that human pancreatic islet cells respond to IFN stimulation by upregulating the expression of genes involved in virus recognition, limiting virus replication and shaping of the adaptive immune response. This so-called antiviral state reduced the permissiveness of human islet cells to CVB infection. Patients suffering from cystic fibrosis (CF) have a well-described defect in their antimicrobial immune response, leaving them especially vulnerable to respiratory tract infections. Using a mouse model for CF in paper IV, it was shown that a defective cystic fibrosis transmembrane conductance regulator (cftr) gene, the genetic cause for CF, renders mice susceptible to systemic CVB infection. Mice lacking CFTR succumbed to CVB at a dose that was not lethal for their wild type counterparts. In conclusion, the studies included in this thesis add to our understanding of how the innate immune response recognizes and responds to CVB infections. Interestingly, MDA-5, NK cells and IFNs, while important in the immune response to CVB, have also been implicated to play a role in the development of T1D. This supports the notion that the immune response mounted by the host may influence the outcome of an infection with CVB. Hopefully, a better understanding of the host immune response can help to prevent the severe outcomes sometimes associated with CVB infection.
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