Collectins, H-ficolin and LL-37 reduce influence viral replication in human monocytes and modulate virus-induced cytokine production

White, Mitchell R.; Tripathi, Shweta; Verma, Anamika; Kingma, Paul S.; Takahashi, Kazue; Jensenius, Jens C.; Thiel, Steffen; Wang, Guangshun; Crouch, Erika C.; Hartshorn, Kevan L.

doi:10.1177/1753425916678470

Cited by 24 publications

(17 citation statements)

References 53 publications

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“…The activity of the native LL-37 was significantly greater than scrLL-37, leading us to conclude that LL-37 had a structure-dependent antiviral activity against KSHV. This ability of the native primary structure of LL-37 to inhibit viral infections as opposed to a scrambled version of the peptide has also been observed with a number of other viruses—including DENV (Alagarasu et al, 2017), HAdV19 (Gordon et al, 2005), HCV (Matsumura et al, 2016), HRV (Sousa et al, 2017), HSV-1 (Gordon et al, 2005; Lee et al, 2014), influenza A virus (Barlow et al, 2011; Tripathi et al, 2015a, 2013 White et al, 2017), and RSV (Currie et al, 2013; Harcourt et al, 2016)—suggesting the specific structure, and not simply the charge, of LL-37 is important in its antiviral activity.…”

Section: Discussionmentioning

confidence: 61%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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Oral epithelial cells (OECs) represent the first line of defense against viruses that are spread via saliva, including Kaposi's sarcoma-associated herpesvirus (KSHV). Infection of humans by KSHV and viral pathogenesis begins by infecting OECs. One method OECs use to limit viral infections in the oral cavity is the production of antimicrobial peptides (AMPs), or host defense peptides (HDPs). However, no studies have investigated the antiviral activities of any HDP against KSHV. The goal of this study was to determine the antiviral activity of one HDP, LL-37, against KSHV in the context of infecting OECs. Our results show that LL-37 significantly decreased KSHV's ability to infect OECs in both a structure- and dose-dependent manner. However, this activity does not stem from affecting OECs, but instead the virions themselves. We found that LL-37 exerts its antiviral activity against KSHV by disrupting the viral envelope, which can inhibit viral entry into OECs. Our data suggest that LL-37 exhibits a marked antiviral activity against KSHV during infection of oral epithelial cells, which can play an important role in host defense against oral KSHV infection. Thus, we propose that inducing LL-37 expression endogenously in oral epithelial cells, or potentially introducing as a therapy, may help restrict oral KSHV infection and ultimately KSHV-associated diseases.

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Section: Discussionmentioning

confidence: 61%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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“…SP-D and other collectins modify responses to neutrophils, monocytes and macrophages to IAV or other stimuli. SP-D and MBL promote phagocytosis of IAV by human neutrophils and monocytes in vitro and increases neutrophil respiratory burst responses to the virus (Hartshorn et al, 1993(Hartshorn et al, , 1994White et al, 2017). In the absence of other ligands collectins bind to macrophages through SIRPalpha and down-regulate activation of these cells, presumably contributing to an antiinflammatory environment in the lung (Gardai et al, 2003).…”

Section: Interaction Of Sp-d and Antimicrobial Peptides With Myeloid mentioning

confidence: 99%

“…The ability of LL-37 to potentiate IAV induced neutrophil respiratory burst responses is mediated through binding to formyl peptide type 2 receptors (Tripathi et al, 2015b). Note, however, that in vitro LL-37 downregulates IAV-induced monocyte inflammatory cytokine production (White et al, 2017) and in vivo it also downregulates cytokines during IAV infection in vivo (Barlow et al, 2011). Defensins have also been found to be anti-inflammatory (Miles et al, 2009;Semple et al, 2010).…”

Section: Interaction Of Sp-d and Antimicrobial Peptides With Myeloid mentioning

confidence: 99%

Innate Immunity and Influenza A Virus Pathogenesis: Lessons for COVID-19

Hartshorn

2020

Front. Cell. Infect. Microbiol.

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There is abundant evidence that the innate immune response to influenza A virus (IAV) is highly complex and plays a key role in protection against IAV induced infection and illness. Unfortunately it also clear that aspects of innate immunity can lead to severe morbidity or mortality from IAV, including inflammatory lung injury, bacterial superinfection, and exacerbation of reactive airways disease. We review broadly the virus and host factors that result in adverse outcomes from IAV and show evidence that inflammatory responses can become damaging even apart from changes in viral replication per se, with special focus on the positive and adverse effects of neutrophils and monocytes. We then evaluate in detail the role of soluble innate inhibitors including surfactant protein D and antimicrobial peptides that have a potential dual capacity for down-regulating viral replication and also inhibiting excessive inflammatory responses and how these innate host factors could possibly be harnessed to treat IAV infection. Where appropriate we draw comparisons and contrasts the SARS-CoV viruses and IAV in an effort to point out where the extensive knowledge existing regarding severe IAV infection could help guide research into severe COVID 19 illness or vice versa.

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“…The ability of SP-D to aggregate IAV is related not only to its antiviral activity but also to its ability to promote uptake of the virus or bacteria by phagocytes ( 52 – 55 ). The collagen domain per se was not found to be critical for increasing viral uptake by neutrophils or monocytes as long as the molecule can form multimers ( 56 , 57 ). The neck and carbohydrate recognition domains (NCRDs) of collectins can be expressed as small separate trimers as illustrated in Figure 1 B.…”

Section: Determining the Molecular Mechanisms Of Antiviral Activity Omentioning

confidence: 97%

“…Alternatively, SP-D could independently act on inflammatory cells to limit their activity. We recently found that SP-D inhibits replication of seasonal IAV in human monocytes and reduces monocyte tumor necrosis factor (TNF) responses to the virus ( 56 ). In that study, reduction of the TNF response could be demonstrated even when viral replication was not reduced.…”

Section: Future Directionsmentioning

confidence: 99%

The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza A Virus

et al. 2018

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Influenza A viruses (IAVs) continue to pose major risks of morbidity and mortality during yearly epidemics and periodic pandemics. The genomic instability of IAV allows it to evade adaptive immune responses developed during prior infection. Of particular concern are pandemics which result from wholesale incorporation of viral genome sections from animal sources. These pandemic strains are radically different from circulating human strains and pose great risk for the human population. For these reasons, innate immunity plays a strong role in the initial containment of IAV infection. Soluble inhibitors present in respiratory lining fluids and blood provide a level of early protection against IAV. In general, these inhibitors act by binding to the viral hemagglutinin (HA). Surfactant protein D (SP-D) and mannose-binding lectin (MBL) attach to mannosylated glycans on the HA in a calcium dependent manner. In contrast, surfactant protein A, ficolins, and other inhibitors present sialic acid rich ligands to which the HA can bind. Among these inhibitors, SP-D seems to be the most potent due to its specific mode of binding to viral carbohydrates and its ability to strongly aggregate viral particles. We have studied specific properties of the N-terminal and collagen domain of SP-D that enable formation of highly multimerized molecules and cooperative binding among the multiple trimeric lectin domains in the protein. In addition, we have studied in depth the lectin activity of SP-D through expression of isolated lectin domains and targeted mutations of the SP-D lectin binding site. Through modifying specific residues around the saccharide binding pocket, antiviral activity of isolated lectin domains of SP-D can be markedly increased for seasonal strains of IAV. Wild-type SP-D causes little inhibition of pandemic IAV, but mutated versions of SP-D were able to inhibit pandemic IAV through enhanced binding to the reduced number of mannosylated glycans present on the HA of these strains. Through collaborative studies involving crystallography of isolated lectin domains of SP-D, glycomics analysis of the HA, and molecular modeling, the mechanism of binding of wild type and mutant forms of SP-D have been determined. These studies could guide investigation of the interactions of SP-D with other pathogens.

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Collectins, H-ficolin and LL-37 reduce influence viral replication in human monocytes and modulate virus-induced cytokine production

Cited by 24 publications

References 53 publications

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

Innate Immunity and Influenza A Virus Pathogenesis: Lessons for COVID-19

The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza A Virus

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