Altered <i>α</i>‐defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour‐permissive microenvironment

Hubert, Pascale; Herman, Ludivine; Roncarati, Patrick; Maillard, Catherine; Renoux, Virginie; Demoulin, Stéphanie; Erpicum, Charlotte; Foidart, Jean‐Michel; Boniver, Jacques; Noël, Agnès; Delvenne, Philippe; Herfs, Michaël

doi:10.1002/path.4435

Cited by 35 publications

(28 citation statements)

References 41 publications

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“…New data suggest that cervical carcinoma originates at cells of the squamocolumnar junction (57). Recent evidence for reduced HD5 expression at these sites could render them more permissive to HPV infection (58). Moreover, ␣-defensins are known to act as cytokines and chemokines, and immune responses to HPV at these sites could be attenuated (6,59,60).…”

Section: Discussionmentioning

confidence: 99%

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Wiens

Smith

2015

J Virol

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Human papillomavirus (HPV) is a significant oncogenic virus, but the innate immune response to HPV is poorly understood. Human ␣-defensin 5 (HD5) is an innate immune effector peptide secreted by epithelial cells in the genitourinary tract. HD5 is broadly antimicrobial, exhibiting potent antiviral activity against HPV at physiologic concentrations; however, the specific mechanism of HD5-mediated inhibition against HPV is unknown. During infection, the HPV capsid undergoes several critical cell-mediated viral protein processing steps, including unfolding and cleavage of the minor capsid protein L2 by host cyclophilin B and furin. Using HPV16 pseudovirus, we show that HD5 interacts directly with the virus and inhibits the furin-mediated cleavage of L2 at the cell surface during infection at a step downstream of the cyclophilin B-mediated unfolding of L2. Importantly, HD5 does not affect the enzymatic activity of furin directly. Thus, our data support a model in which HD5 prevents furin from accessing L2 by occluding the furin cleavage site via direct binding to the viral capsid. IMPORTANCEOur study elucidates a new antiviral action for ␣-defensins against nonenveloped viruses in which HD5 directly interferes with a critical host-mediated viral processing step, furin cleavage of L2, at the cell surface. Blocking this key event has deleterious effects on the intracellular steps of virus infection. Thus, in addition to informing the antiviral mechanisms of ␣-defensins, our studies highlight the critical role of furin cleavage in HPV entry. Innate immune control, mediated in part by ␣-defensins expressed in the genital mucosa, may influence susceptibility to HPV infections that lead to cervical cancer. Moreover, understanding the mechanism of these natural antivirals may inform the design of therapeutics to limit HPV infection. Defensins are effector peptides of the human innate immune system. They are divided into two classes, ␣-and ␤-defensins, based on the pattern of disulfide bonds that stabilize their tertiary structure (1, 2). HD5 is one of six human ␣-defensins and is constitutively expressed and secreted in the female and male genitourinary tracts (3-5). Concentrations of HD5 in vaginal lavage fluid of healthy women have been reported to be 16.5 Ϯ 10.5 M (3). Although originally discovered due to their antibacterial activity, defensin antiviral activity against both enveloped and nonenveloped viruses has also been described. Neutralization of enveloped viruses, such as human immunodeficiency virus 1 (HIV-1), herpes simplex virus (HSV), and respiratory syncytial virus (RSV), is largely dependent on direct interactions of defensins with both viral attachment proteins and cellular receptors, as well as envelope damage, fusion inhibition, and modulation of host responses (6). Inhibition of these viruses may be due to multiple defensin actions rather than a single overriding inhibitory mechanism. While less is known about the mechanisms of defensin antiviral activity against nonenveloped viruses, human adeno...

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Section: Discussionmentioning

confidence: 99%

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Wiens

Smith

2015

J Virol

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“…HD5 is expressed in the ectocervix but not in the squamocolumnar junction or endocervix. It is possible that the absence of HD5 at this site allows for more HPV infection and therefore a greater possibility of cervical cancer progression (11). However, the squamocolumnar junction is also thought to be more permissive to HPV infection due to a surfaceexposed population of stem cells (13).…”

Section: ␣-Defensin Immunomodulatory Activity May Be More Important Tmentioning

confidence: 99%

“…Thus, direct antiviral activity in vivo is plausible. In the case of HPV, there has been interest in examining HD5 expression in cervical tissue, the site of HPV infection that leads to cancer (11). More than 90% of high-grade cervical intraepithelial neoplasias are thought to be due to HPV infection of a population of cells at the squamocolumnar junction, the region between the ectocervix and endocervix (12).…”

Section: ␣-Defensin Immunomodulatory Activity May Be More Important Tmentioning

confidence: 99%

Defensins at the Mucosal Surface: Latest Insights into Defensin-Virus Interactions

Wilson

Wiens

Holly

et al. 2016

J Virol

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Defensins are innate immune effector peptides expressed at mucosal surfaces throughout the human body and are potently antiviral in vitro. The role of defensins in viral pathogenesis in vivo is poorly understood; however, recent studies have revealed that defensin-virus interactions in vivo are complicated and distinct from their proposed antiviral mechanisms in vitro. These findings highlight the need for additional research that connects defensin neutralization of viruses in cell culture to in vivo antiviral mechanisms.

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“…These observations suggest that defensins play a role in the local immune response to HPV. In addition, Hubert et al (28) noted a regional disparity in the expression of human ␣-defensin 5, which was readily detectable in ectocervical, vaginal, and vulvar neoplasia but nearly absent from the cervical squamocolumnar junction, and suggested that this absence of ␣-defensin 5 may contribute to the unique susceptibility of the squamocolumnar junction to HPV infection and progressive disease.…”

Section: Hpv Infection and Disease Progressionmentioning

confidence: 99%

“…Defensins can block HPV infection (25,26) and potentially influence adaptive immunity by recruiting immune cells (27,28). Greater expression of ␤-defensins has been reported in HPV-associated genital warts than in uninfected tissue (29) and in anal intraepithelial neoplasia than in nonlesional tissue in men who have sex with men (30).…”

Section: Hpv Infection and Disease Progressionmentioning

confidence: 99%

Early Defensive Mechanisms against Human Papillomavirus Infection

Moerman-Herzog

Nakagawa

2015

Clin Vaccine Immunol

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Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process. Human papillomavirus (HPV) infects epithelial cells of the skin and mucosal tissues and is best known for its causal role in cervical cancer (1, 2), the fourth most common cancer in women worldwide (3). HPV remains a serious public health problem despite the availability of effective prophylactic vaccines such as Gardasil (Merck, Whitehouse Station, NJ, USA) and Cervarix (GlaxoSmithKline Biologicals, Rixensart, Belgium). In the United States in 2009, cervical cancer represented 53.4% of the newly diagnosed HPV-associated cancers in women and oropharyngeal cancer represented 78.2% of the newly diagnosed HPV-associated cancers in men (4). The incidence rates of HPV-associated anal and oropharyngeal cancers in both men and women increased between 2000 and 2009 (4). In addition, adoption of prophylactic vaccines has been slow. Therefore, understanding of early events that occur upon HPV infection would be important in developing additional modalities for preventing HPV-associated malignancies. This review presents recent advances in our knowledge of the impact of epithelial danger sensing and cytokine responses on the clearance of HPV infections and the emerging role of keratinocytes (KC) as initiators of and partners in the amplification of anti-HPV immunity. HPV INFECTION AND DISEASE PROGRESSIONThe site of infection matters. HPV can be divided into cutaneous and mucosal types based on their tropism for the epithelium of different tissues (5). Mucosal HPV types are further divided into low-and high-risk categories, depending on oncogenicity. Highrisk HPV types cause virtually all cases of cervical cancer (1, 2) and are commonly associated with cancer and high-grade precursor lesions in other mucosal tissues (5-7). HPV16 and -18 cause approximately 70% of cervical cancers, while low-risk HPV6 and -11 cause 90% of anogenital warts. Although HPV broadly infects proliferative cells of cutaneous and mucosal epithelia (2), the risk of HPV-associated disease progression is much higher in the metaplastic transformation zones of the cervix, anus, and oropharynx (8). Active metaplasi...

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Altered α‐defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour‐permissive microenvironment

Cited by 35 publications

References 41 publications

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Defensins at the Mucosal Surface: Latest Insights into Defensin-Virus Interactions

Early Defensive Mechanisms against Human Papillomavirus Infection

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