Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.
Studies of the host response to virus infection typically focus on protein-coding genes. However, non-protein-coding RNAs (ncRNAs) are transcribed in mammalian cells, and the roles of many of these ncRNAs remain enigmas. Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross. We observed differential expression of approximately 500 annotated, long ncRNAs and 1,000 nonannotated genomic regions during infection. Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment. These findings represent the first discovery of the widespread differential expression of long ncRNAs in response to virus infection and suggest that ncRNAs are involved in regulating the host response, including innate immunity. At the same time, virus infection models provide a unique platform for studying the biology and regulation of ncRNAs.
Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.
Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.
IntroductionCytomegalovirus (CMV) viremia and disease are a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). 1,2 The most feared complication is CMV pneumonia, which is still associated with high mortality. 3 Preemptive therapy using antiviral drugs can reduce the incidence of early-onset CMV disease but is associated with substantial toxicity and development of late-onset CMV disease. 4,5 In addition, drugresistant virus strains might develop. 6 CMV replication in patients who underwent transplantation arises as a result of lack of immune control. Thus, bridging the period of immunodeficiency by passive transfer of the most important immune functions is a goal in transplantation medicine. Reports from the murine CMV model (MCMV) had established the importance of CD8 T cells for control of primary infection as well as latency. 7,8 Based on these findings, clinical protocols were developed whereby CD8 T-cell clones were cultured from the transplant donor and transferred to the patient after transplantation. [9][10][11] This strategy has proved effective in the prevention of reactivation and treatment of CMV infection that is unresponsive to antiviral therapy. 12 However, the MHC restriction of CD8 lymphocytes and the need to expand these cells in vitro makes this procedure cumbersome, and a limited number of patients has been treated so far. In addition, CD4 ϩ cells seem to be important for the long-term survival of the transferred CD8 cells. 9 More recently, CMV-specific CD8 ϩ T cells have been purified from the blood of stem cell transplant donors and infused directly into patients. 13 Measures have also been taken to support the humoral arm of the immune system. Again, data from the murine model of CMV have clearly demonstrated an important role of antibodies in protecting against a primary infection as well as reactivation or reinfection. 14,15 In contrast to T-cell transfer, support of the humoral immune system in patients has been limited to application of intravenous immune globulin (IVIG) or hyperimmune products. However, even after more than 20 years of extensive use of this treatment either prophylactically and/or therapeutically, uncertainty about benefits for the prevention of CMV infection and disease is evident. 16 Reasons are manifold but might include, among others, use of different products, 17 dosing regimens, and schedule. To our knowledge, cell-based strategies to support the humoral immune response in patients who underwent bone marrow transplantation (BMT) or HSCT have not been explored.In a mouse model, we have recently shown that virus-specific B cells that are adoptively transferred into immunodeficient hosts can be stimulated to antibody production by antigen alone; T-cell help is not required. 18 This finding suggested the possibility of prophylaxis and/or therapy of viral infections in T-celldeficient hosts by transfer of specific memory B cells. Here, we examine the protective capacity of adoptively transferred memory For personal use on...
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