Abstract
The COVID-19 situation we are currently facing will have lasting effects on society and the way we live and interact as a species. It will be years before we fully appreciate and understand the effects this situation has already had, and will continue to have, on the way we live our lives. People tend to educate themselves on diseases that have affected them or someone close to them. When a member of a family has cancer, suddenly everyone in that family wants to know more about cancer. Some viruses are only of interest to certain groups of people, for example, due to a limited geographical range or due to an association with a particular behavior or lifestyle, meaning not everyone will feel the need to understand that virus or the disease it can cause. SARS-CoV-2 and COVID-19 are unique in this regard because everyone wants to know more about this virus and its disease because we are all targets regardless of where or how we live. As we learn to live with this virus and begin to see the second wave coming toward us, we find ourselves looking for silver linings. One such unexpected benefit is the noticeable increase in immunology and virology knowledge in the general public. I never thought I would see the day when friends and family members who are not in science or research would be asking me about neutralizing antibodies and cytokine storms! Another topic that is receiving even more attention than usual because of COVID-19 is inflammation, which is somewhat of a theme for this current issue.
Inflammation is one of the body's many defenses against pathogens. It is an intricate and complex orchestra of immune cells and inflammatory mediators working together to respond to many types of infection. However, we also know that inflammation can be detrimental to the host in such cases as arthritis, diabetes, cancer, as well as in many acute and chronic viral infections. Three of the studies presented in this current issue are focused on inflammatory cytokines or signaling in the context of a virus infection. Tao et al. analyzed metabolic profiles in cell lines infected with canine influenza virus (CIV) to investigate changes in energy metabolism and small molecule metabolism. They found that numerous positive and negative ions were either up- or downregulated, and using a Kyoto Encyclopedia of Genes and Genomes enrichment analysis, they observed that most of these differentially regulated molecules were concentrated in pathways involved in energy metabolism and nucleic acid or protein synthesis, which are all essential for virus replication. The authors proposed that their findings are important for identification and development of antiviral agents, and also help to understand the pathogenesis of CIV.
In another article, Manzoor et al. address the topic of profibrotic microenvironments and inflammatory signaling in chronic hepatitis C virus (HCV) infection with the goal of elucidating the role of the TLR4-induced immune response in chronic inflammation observed in chronic HCV patients. The team found increased expression of proinflammatory and profibrotic genes induced by the TLR4/MyD88-dependent pathway in peripheral blood mononuclear cells (PBMCs) isolated from treatment-naive subjects compared with uninfected controls. No such differences were observed in treatment responders versus uninfected controls, but both TLR4/MyD88-dependent and -independent pathways were functional in patients who did not respond to interferon. The authors conclude that these results strengthen the importance of the TLR4/MyD88-dependent and -independent pathways in maintenance of chronic inflammation.
Finally, in a brief report by Preeyaa et al., the authors studied peripheral T follicular helper (pTfh) cells and mucosal-associated invariant T (MAIT) cells and found that these subsets represent activated phenotypes in the febrile phase of acute Dengue virus infection. Using a multiparametric flow cytometry-based approach, they investigated signatures of immune activation and found that dengue virus (DENV) infection induced expansion and activation of pTfh cells and circulating MAIT cells. These results, along with those of the other articles mentioned earlier highlight the delicate balance between the positive and negative impacts of virus-induced inflammation.
In line with the theme of virus-induced pathogenesis, an article by Niklasson et al. addresses the etiology of type 1 diabetes (T1D) and the frequently challenged notion that a virus might be the etiological agent for this disease. This group has previously reported that antiviral therapy significantly delayed the onset of diabetes in diabetes prone (DP) bio breeding (BB) rats. In this article, they now report a significant clinical response in DP-BB rats after treatment with clinically available antiviral agents. They also report the presence of Ljungan virus picornavirus antigen in islets of Langerhans in both human and T1D rat model tissue. Based on these findings the authors propose to try treating newly diagnosed individuals with T1D with antiviral agents.
Still with the theme of liver inflammation, Viera-Segura et al. studied the contribution of hepatitis E virus (HEV) in perpetuating the cytokine-mediated inflammatory setting related to liver damage in the context of obesity. Using a retrospective analysis of serum samples from individuals characterized as normal weight, overweight, obese, or high alcohol consuming, the authors tested for IgM and IgG anti-HEV antibodies. Interestingly, they observed a strong association between HEV serology and obesity. Subsequent cytokine profiling revealed significantly higher levels of proinflammatory cytokines (interleukin [IL]-12, interferon-γ, and IL-1β) in IgG anti-HEV-positive obese patients compared with obese patients negative for anti-HEV IgG. The authors also reported that a high proportion of patients with positive serology also displayed advanced liver pathology. Based on these finding the group concluded that the high prevalence of anti-HEV antibodies and vial RNA in the presence of excess weight, along with high levels of proinflammatory cytokines and severe liver disease, supports a potential interplay between HEV infection and obesity.
In conclusion, the articles published in this issue highlight the role of inflammation in viral pathogenesis and emphasize the need to better understand the relationship between viruses and the inflammatory response.