Antimicrobial peptide LL‐37 attenuates infection of hepatitis C virus

Matsumura, Takuya; Sugiyama, Nao; Murayama, Asako; Yamada, Noriko; Shiina, Masaaki; Asabe, Shinichi; Wakita, Takaji; Imawari, Michio; Kato, Takanobu

doi:10.1111/hepr.12627

Cited by 49 publications

(33 citation statements)

References 44 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%

“…The ability of LL-37 to directly inhibit a number of viruses has been reviewed previously (Barlow et al, 2014b), with further activities found against Aichi virus A (Vilas Boas et al, 2017), human adenoviruses 8 and 19 (HAdV-8 and HAdV-19) (Gordon et al, 2005; Uchio et al, 2013), hepatitis C virus (HCV) (Matsumura et al, 2016), human papillomavirus 16 (HPV16) (Buck et al, 2006), human rhinovirus (HRV) (Findlay et al, 2017; Schögler et al, 2016; Sousa et al, 2017), and varicella zoster virus (VZV) (Crack et al, 2012). While LL-37 has only been measured at 0.5 μg/ml in saliva (Bachrach et al, 2006; Takeuchi et al, 2012) and 10 μg/ml in gingival crevicular fluid 29 , the actual physiological concentration may be much higher at sites closer to the oral epithelial cells themselves due to the diffusion of the peptides once released from cells.…”

Section: Discussionmentioning

confidence: 99%

“…While the antiviral activities of adrenomedullin have not been characterized, beta-defensins 1-3 and LL-37 were shown to exhibit antiviral activities (Barlow et al, 2014a; Klotman and Chang, 2006). Of these HDPs, LL-37, a 37-amino acid cationic peptide present in both saliva and gingival crevicular fluid (Murakami et al, 2002; Türkoğlu et al, 2009), has been the most widely studied in the context of antiviral activities, with defined mechanisms against dengue type 2 virus (DENV2) (Alagarasu et al, 2017), hepatitis C virus (HCV) (Matsumura et al, 2016), human immunodeficiency virus (HIV) (Wong et al, 2011), influenza A virus (Tripathi et al, 2015b, 2014, 2013), respiratory syncytial virus (RSV) (Currie et al, 2016, 2013), vaccinia virus (VV) (Dean et al, 2010; Ulaeto et al, 2016), and herpes simplex virus type 1 (HSV-1) (Lee et al, 2014; Takiguchi et al, 2014). In contrast, no HDP has been studied with respect to KSHV infection.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2018

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“…Indeed, pretreatment of Huh‐7 cells with different concentrations of LL37 (2‐20 μg/mL) attenuated HCV infection approximately 2 to 10‐fold as shown by decreased intra‐ and extracellular levels of HCV core antigen. Supplementation with vitamin D is thought to induce elevated levels of LL37, which might improve the efficacy of treatment when used in combination with IFN‐based therapy . However, further studies are required to confirm if LL37 exerts its anti‐viral effect independently or in combination with other intrinsic defense factors.…”

Section: Introductionmentioning

confidence: 99%

The interplay between vitamin D and viral infections

Teymoori‐Rad

Shokri

Salimi

et al. 2019

Reviews in Medical Virology

242

230

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Summary The pleiotropic role of vitamin D has been explored over the past decades and there is compelling evidence for an epidemiological association between poor vitamin D status and a variety of diseases. While the potential anti‐viral effect of vitamin D has recently been described, the underlying mechanisms by which vitamin D deficiency could contribute to viral disease development remain poorly understood. The possible interactions between viral infections and vitamin D appear to be more complex than previously thought. Recent findings indicate a complex interplay between viral infections and vitamin D, including the induction of anti‐viral state, functional immunoregulatory features, interaction with cellular and viral factors, induction of autophagy and apoptosis, and genetic and epigenetic alterations. While crosstalk between vitamin D and intracellular signalling pathways may provide an essential modulatory effect on viral gene transcription, the immunomodulatory effect of vitamin D on viral infections appears to be transient. The interplay between viral infections and vitamin D remains an intriguing concept, and the global imprint that vitamin D can have on the immune signature in the context of viral infections is an area of growing interest.

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“…CAMP has also been reported to have antiviral activity against human immunodeficiency virus, influenza A virus, respiratory syncytial virus, and vaccinia virus (62) as well as several other functions in the immune system, such as chemotactic and angiogenic roles (63). Very recently, it was reported that preincubation of cells or HCV with LL-37 attenuates the infectivity of HCV (64), in contrast to our observation here that the exogenous expression of CAMP and LL-37 promotes infectious particle production in BE-KO cells. Although direct comparison is difficult, the discrepancy of the effects of LL-37 on HCV propagation might be attributable to the concentration of LL-37 used in the experiments.…”

Section: Discussionmentioning

confidence: 99%

Human Cathelicidin Compensates for the Role of Apolipoproteins in Hepatitis C Virus Infectious Particle Formation

Puig-Basagoiti

Fukuhara

Tamura

et al. 2016

J Virol

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Exchangeable apolipoproteins (ApoA, -C, and -E) have been shown to redundantly participate in the formation of infectious hepatitis C virus (HCV) particles during the assembly process, although their precise role in the viral life cycle is not well understood. Recently, it was shown that the exogenous expression of only short sequences containing amphipathic ␣-helices from various apolipoproteins is sufficient to restore the formation of infectious HCV particles in ApoB and ApoE double-gene-knockout Huh7 (BE-KO) cells. In this study, through the expression of a small library of human secretory proteins containing amphipathic ␣-helix structures, we identified the human cathelicidin antimicrobial peptide (CAMP), the only known member of the cathelicidin family of antimicrobial peptides (AMPs) in humans and expressed mainly in bone marrow and leukocytes. We showed that CAMP is able to rescue HCV infectious particle formation in BE-KO cells. In addition, we revealed that the LL-37 domain in CAMP containing amphipathic ␣-helices is crucial for the compensation of infectivity in BE-KO cells, and the expression of CAMP in nonhepatic 293T cells expressing claudin 1 and microRNA miR-122 confers complete propagation of HCV. These results suggest the possibility of extrahepatic propagation of HCV in cells with low-level or no expression of apolipoproteins but expressing secretory proteins containing amphipathic ␣-helices such as CAMP. IMPORTANCEVarious exchangeable apolipoproteins play a pivotal role in the formation of infectious HCV during the assembly of viral particles, and amphipathic ␣-helix motifs in the apolipoproteins have been shown to be a key factor. To the best of our knowledge, we have identified for the first time the human cathelicidin CAMP as a cellular protein that can compensate for the role of apolipoproteins in the life cycle of HCV. We have also identified the domain in CAMP that contains amphipathic ␣-helices crucial for compensation and show that the expression of CAMP in nonhepatic cells expressing claudin 1 and miR-122 confers complete propagation of HCV. We speculate that low levels of HCV propagation might be possible in extrahepatic tissues expressing secretory proteins containing amphipathic ␣-helices without the expression of apolipoproteins. According to recent estimates, more than 160 million people worldwide are chronically infected with hepatitis C virus (HCV) (1), which causes liver-related pathologies that can result in life-threatening diseases such as cirrhosis and hepatocellular carcinoma (2). Chronic HCV infection is also associated with several extrahepatic manifestations, including immunological disorders such as cryoglobulinemia and B-cell non-Hodgkin lymphoma (3). A vaccine is not yet available, but recent advances in antiviral treatment, improving upon what was for many years the standard therapy of pegylated interferon alpha plus ribavirin, now include several direct-acting antivirals (DAAs) that have increased the rate of sustained virological response (SVR) up to 80 ...

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Antimicrobial peptide LL‐37 attenuates infection of hepatitis C virus

Abstract: The VD-associated antimicrobial peptide LL-37 attenuated the infectivity of HCV. This anti-HCV effect of LL-37 may explain the contribution of VD to the improved efficacy of interferon-based therapy.

Cited by 49 publications

References 44 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

The interplay between vitamin D and viral infections

Human Cathelicidin Compensates for the Role of Apolipoproteins in Hepatitis C Virus Infectious Particle Formation

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