Advances in Influenza Research

Seasonal influenza virus infections are a significant clinical threat in the world today. In the United States alone, it is estimated that approximately 114,000 hospitalizations and 36,000 deaths can be attributed to influenza on an annual basis. Furthermore, there is always the possibility that pandemic strains of the virus can emerge that can be responsible for much higher levels of mortality. It was just 100 years ago that such a pandemic strain emerged and killed millions of people worldwide. In the current issue of Viral Immunology, several articles discuss research progress in different aspects of influenza virus biology and vaccine development. Klonoski et al. point out that although the influenza virus is the primary invader, the majority of influenza virus-related deaths arise from secondary bacterial infections. However, the nature of host–pathogen interactions that result in survival versus lethal outcomes is undefined. The authors propose that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. In this regard, they show that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection. The likely mechanism is the modulation of host proinflammatory responses. These findings advance our understanding of the molecular mechanisms underlying influenza virus and bacterial superinfections, and the factors that contribute to morbidity and mortality.

Influenza can also be exacerbated by underlying disease. Roberts et al. note that influenza virus infections are associated with enhanced pathology in individuals with sickle cell disease (SCD). Despite being a high priority group for annual influenza vaccination, little is known about long-term responses to influenza vaccination in this patient population. Using a mouse model, the authors show that both wild-type and SCD mice were fully protected from infection after vaccination. They conclude that influenza vaccination is effective in SCD mice and supports regular flu vaccination in SCD patients.

A key aspect of the host response to influenza virus infection is innate immunity. Type 1 interferons (IFNs) and proinflammatory mediators play leading roles in the response, and double-stranded RNA (dsRNA) has been shown to act as a trigger for IFN production. To better understand the role of dsRNA in the immune response, Ahmed-Hassan et al. have studied the antiviral response against a low pathogenic avian influenza virus. Their data suggest that dsRNA in the context of infection increases the expression of Toll-like receptor-3, IFN-α, and IFN-32β and interleukin (IL)-1β. They note that further studies are needed to determine the role of other innate immune mediators in the dsRNA-mediated antiviral responses to influenza viruses. Jantaratrirat et al. also investigate the role of innate immunity in influenza virus infections. The authors show that microparticles are released from some cell lines upon influenza virus infection and that these microparticles could exhibit anti-influenza activity. The level of antiviral activity correlated with the surface levels of sialic acid, the receptor for the influenza virus. Interestingly, methyl-β-cyclodextrin efficiently activated microparticle release from some cell lines and might be a candidate for the treatment of mucosal viral infections in general.

Other articles in this issue of Viral Immunology investigate immunity to persistent infections. Hepatitis C virus (HCV) causes a persistent infection that attacks the liver and can result in cirrhosis (scarring of the liver) and liver cancer. Zafar et al. investigate the epidemiological distribution of HCV genotypes in different districts of Punjab, Pakistan, with an emphasis on the prevalence of diagnostically untypable subtypes of the virus. Importantly, they show that patients infected with untypable HCV variants could be effectively treated with standard IFN-based antiviral regimens. Saleem et al. report on five HCV-infected patients that exhibited an unusual response to antivirals. These patients experienced unusually high viral loads during therapy followed by a sudden decline of viral titers after completion of the treatment. The authors note that clinicians and policy makers should consider these unusual responders in the development of treatment guidelines. Zhang et al. have investigated the immunomodulatory activity of IL-7 to T follicular helper (Tfh) cells and their contribution to the pathogenesis of chronic HCV infection. Their data suggest that IL-7-regulated HCV-specific and nonspecific-activated Tfh cells contribute to viral clearance, and that IL-7 could be a potential therapeutic agent for treatment of chronic hepatitis C.

Another persistent viral infection is mediated by the cytomegalovirus (CMV). This virus infects more than half of the adult U.S. population and can cause serious health problems for people with weakened immune systems. Ariyanto et al. note that altered T cell profiles have been linked with persistent CMV infections in older HIV patients whose condition has been stabilized on antiretroviral therapy. Here, the authors confirm that CMV-reactive antibody is a simple and stable metric of the CMV burden, and link elevated CMV antibodies to the depletion of naive T cells and expanded pools of memory T cells expressing CD57.

In the veterinary field, avian leukosis virus (ALV-J) can cause cancer in chickens and results in significant economic losses in the global poultry industry. Jing et al. have developed a vaccine based on the secretory recombinant ALV-J gp85 protein with a CpG-oligodeoxynucleotide adjuvant. The authors report that their vaccine protects chickens against ALV-J infection. This vaccine shows significant commercial promise for the poultry industry.

I would like to thank all of the authors for the excellent contributions to the Journal and all of the reviewers who work tirelessly to ensure high quality of the published articles.