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Editorial: Mannose‐binding lectin in fighting influenza: promise or peril?

Seasonal and pandemic influenza continue to be a major cause of morbidity and mortality globally. Each year in the United States, 5–20% of the population are infected, 200,000 are hospitalized, and 36,000 die as a result of influenza virus infection, making it the leading infectious cause of death [1]. The most challenging difficulty that we face in combating influenza is that antigenic drift and shift lead to a mismatch between the vaccine virus strain and the circulating virus strain. In addition, vaccine efficacy is suboptimal in certain populations. For example, although vaccination rates of individuals over age 65 increased significantly after 1980, the rate of influenzarelated deaths did not change [2]. Thus, current vaccine strategies focusing on the adaptive immune system are insufficient to combat influenza mortality. Therefore, more information about the response of the innate immune system to influenza virus is needed. The patterns of innate immune responses in patients with virus infection have not been well-characterized. The key puzzle is whether severe illness is the result of enhanced virus replication, broader cellular receptor binding, viralmediated immunosuppression of the host, or a massive cytokine storm. The term “cytokine storm” refers to the concept of an excessive or uncontrolled release of proinflammatory cytokines during the innate response against the invading microorganism. The innate immune responses to viruses are triggered by recognition of specific structures on invading pathogens, called PAMPs. Influenza virus triggers intraand extracellular receptors, called PRRs, during infection that elicit an innate immune response that serves as a first line of protection against infection. Recently, three families of PRRs have been found: TLRs, RIG-I like helicases, and nucleotide-binding domain and leucinerich repeat-containing proteins. All three families are involved in recognition of influenza virus, and studies in cell culture and mouse models show that they cooperatively operate to coordinate the response to the virus. It is clear that there are two types of innate immune cytokine responses to infection with influenza virus—the antiviral response and proinflammatory response. The first type of response is an antiviral cytokine response, which facilitates intracellular control of viral replication through induction of IFNs, IFN-mediated antiviral signaling, and 300 IFNstimulated genes. Rapid production of type I IFN is an essential component of the antiviral response [3]. The proinflammatory cytokine response is likely responsible for recruiting immune effector cells that help to clear the virus and cells that participate in adaptive immunity. Inflammation is responsible for activating innate and adaptive immune responses so that the damage can be resolved and homeostasis restored. However, an aberrant inflammatory response may contribute to severe lung viral pneumonia that results in the serious complications of infection. The exposure of monkeys to a genetically reconstructed 1918 influenza virus resulted in a prolonged inflammatory response and produced a fatal outcome [4]. Extremely high levels of cytokines have been observed in patients who died of pandemic influenza and animals infected with these viruses [5]. The ancient defense pathways mediated by soluble molecules, such as collectins, are also integral components of innate immune defense. Soluble mediators inhibit viral replication in the respiratory tract and modulate the immune response to influenza. MBL belongs to the collectin family of proteins, which are characterized by extended collagenlike domains and calcium-dependent carbohydrate-recognition domains homologous to the large C-type lectin superfamily. The collectin family also includes lung SP-A and SP-D. Many in vitro studies have described the antiviral functions of MBL, including viral aggregation, inhibition of viral HA, and opsonization of virus. MBL also activates complement via the lectin pathway, which requires MASPs. For the most part, there is evidence that MBL and other collectins are protective during influenza virus infection. An in vivo study using rMBL in knockout mice showed that MBL decreases inflammation, increases viral clearance, and maintains lung homeostasis [6]. MBL deficiency, as a result of gene polymorphism in humans, has been associated with infection susceptibility. Similarly, there are polymorphisms of SP-D that are associated with reduced serum levels of the protein and decreased in vitro activity against influenza virus, but the role of these polymorphisms in susceptibility to influenza virus infection in vivo has not yet been studied.