Collectin-mediated antiviral host defense of the lung: evidence from influenza virus infection of mice

Abstract

Collagenous lectins (collectins) present in mammalian serum and pulmonary fluids bind to influenza virus and display antiviral activity in vitro, but their role in vivo has yet to be determined. We have used early and late isolates of H3N2 subtype influenza viruses that differ in their degree of glycosylation to examine the relationship between sensitivity to murine serum and pulmonary lectins in vitro and the ability of a virus to replicate in the respiratory tract of mice. A marked inverse correlation was found between these two parameters. Early H3 isolates (1968 to 1972) bear 7 potential glycosylation sites on hemagglutinin (HA), whereas later strains carry 9 or 10. Late isolates were shown to be much more sensitive than early strains to neutralization by the mouse serum mannose-binding lectin (MBL) and rat lung surfactant protein D (SP-D) and bound greater levels of these lectins in enzyme-linked immunosorbent assays and Western blot analyses. They also replicated very poorly in mouse lungs compared to the earlier strains. Growth in the lungs was greatly enhanced, however, if saccharide inhibitors of the collectins were included in the virus inoculum. The level of SP-D in bronchoalveolar lavage fluids increased on influenza virus infection. MBL was absent from lavage fluids of normal mice but could be detected in fluids from mice 3 days after infection with the virulent strain A/PR/8/34 (H1N1). The results implicate SP-D and possibly MBL as important components of the innate defense of the respiratory tract against influenza virus and indicate that the degree or pattern of glycosylation of a virus can be an important factor in its virulence.

Virus glycosylation: role in virulence and immune interactions

“…Similarly, SP-A and SP-D can both interact with influenza to prevent the association of the HA with its receptor. Binding of MMR, MBL or SP-D to influenza A virus involves the carbohydrate recognition domain of the molecule and high-mannose oligosaccharides of the viral proteins hemagglutinin and neuraminidase [63][64][65][66] and can potentially lead to internalization of the lectin-virus complex and delivery of complexed virus to degradative compartments for processing and presentation by the immune system (Figure 2b). MMR and SP-D can additionally bind to HIV and prevent entry and replication [67].…”

No association between mannose-binding lectin deficiency and H1N1 2009 infection observed during the first season of this novel pandemic influenza virus

“…Having bound to microbial pathogens, MBL mediates killing through lectin complement pathway activation and opsonophagocytosis. MBL has been observed to bind to and neutralize the influenza virus in studies involving nonpandemic H3N2 strains [3]. In this study, the efficacy of MBL-mediated inhibition of these influenza strains that have multiple exposed glycosylation sites on the hemagglutinin head was proportional to the number of glycosylation sites available for MBL binding.…”

“…The obvious conclusion is that MBL is not involved in innate immune responses to influenza or other respiratory viruses. This is countered, however, by the in vitro evidence of MBL's inhibition of influenza virus [3,18], recent evidence of MBL's role in the development of humoral immunity to influenza [19], and clinical association studies that demonstrate that MBL deficiency predisposes not only to respiratory tract infection in general, but also to respiratory tract infections with viral pathogens like severe acute respiratory syndrome in particular [7].…”

Alveolar Epithelium and Pulmonary Surfactant

“…162,163,163a,163b It is interesting to note that the annual severity of influenza infections is related to the ability of SP-D to bind to the circulating strains of influenza. 163,164 Strains with less SP-D binding such as the 1918 H1N1 strain and the pandemic 2009 strain are clinically more virulent. Although studies on the interaction of SP-D with viruses have been reported for only a few viruses, it is likely that SP-D binds to many respiratory viruses.…”