Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans

Abstract

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection in infants, causing significant morbidity and mortality. No vaccine or specific, effective treatment is currently available. A more complete understanding of the key components of effective host response to RSV and novel preventative and therapeutic interventions are urgently required. Cathelicidins are host defense peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defense against infection. In this article, we demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on RSV by inducing direct damage to the viral envelope, disrupting viral particles and decreasing virus binding to, and infection of, human epithelial cells in vitro. In addition, exogenously applied LL-37 is protective against RSV-mediated disease in vivo, in a murine model of pulmonary RSV infection, demonstrating maximal efficacy when applied concomitantly with virus. Furthermore, endogenous murine cathelicidin, induced by infection, has a fundamental role in protection against disease in vivo postinfection with RSV. Finally, higher nasal levels of LL-37 are associated with protection in a healthy human adult RSV infection model. These data lead us to propose that cathelicidins are a key, nonredundant component of host defense against pulmonary infection with RSV, functioning as a first point of contact antiviral shield and having additional later-phase roles in minimizing the severity of disease outcome. Consequently, cathelicidins represent an inducible target for preventative strategies against RSV infection and may inform the design of novel therapeutic analogs for use in established infection.

Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection

“…It is known that 1,25(OH) 2 D 3 enhances antimicrobial activity via interaction with VDR to up-regulate the synthesis of antimicrobial peptides such as cathelicidin and β-defensin [55,56]. Cathelicidin is produced by neutrophils, monocytes, and macrophages and has broad antimicrobial activity against bacteria, as well as viruses, such as respiratory syncytial virus (RSV) [57,58]. Moreover, under subclinical inflammatory conditions, vitamin D may be less able to control inflammatory responses in otherwise healthy individuals [59].…”

Antimicrobial peptides alter early immune response to influenza A virus infection in C57BL/6 mice

“…Differences in Bpifa1 levels after IAV infection in our study suggests that early expression may be necessary in host defense and its reduction may be associated with damage to the epithelia. Human LL-37 was recently shown to have direct antiviral properties against respiratory syncytial virus and mouse CAMP reduced viral infectivity (Currie et al, 2016). While we did not use CAMP as a therapeutic in this study, we noted increased Camp expression in response to IAV that remained elevated throughout the infection perhaps indicative of a role for CAMP in antiviral responses to IAV.…”

Antiviral immunity is impaired in COPD patients with frequent exacerbations

“…In the current study, we showed trends toward increased baseline production of inflammatory cytokines TNF-␣ and CCL5/RANTES, hinting that chronic airway inflammation could contribute to defective antiviral responses upon infection observed in some patients. A previous study in airway epithelial cell cultures demonstrated that proinflammatory cytokine exposure impaired epithelial expression of cathelicidin (29), an antimicrobial peptide that has antibacterial and antiviral properties (4,7). Exposure to proinflammatory cytokines can induce persistent epigenetic changes that modify innate immune responses.…”