Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

Bertram, Kirstie M.; Truong, Naomi R.; Smith, Jacinta B.; Kim, Min; Sandgren, Kerrie J.; Feng, Konrad L.; Herbert, Jason J.; Rana, Hafsa; Danastas, Kevin; Miranda-Saksena, Monica; Rhodes, Jake W.; Patrick, Ellis; Cohen, Richard. D.; Lim, Jake; Merten, Steven; Harman, Andrew N.; Cunningham, Anthony L.

doi:10.1371/journal.ppat.1009536

Cited by 17 publications

(16 citation statements)

References 74 publications

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“…Explants were next inoculated in a polarized manner with non-infected or HIV-1-infected PBMCs for 4 h. Epidermal cell suspensions were then immediately prepared and the percentages of high forward scatter (FSC) conjugates between LCs and T-cells were determined by flow cytometry. Of note, we focused on CD1a high cells that represent the LC1 population, as CD1a + cells in the inner foreskin include both the LC2 population and epidermal dendritic cells (27)(28)(29). In agreement with our previous results (11,12), polarized exposure to HIV-1-infected PBMCs increased the percentages of FSC high CD1a high CD3 + CD8conjugates (Figure 6B).…”

Section: Cgrp and Sax Inhibit Mucosal Hiv-1 Transmission In Human Mucosal Tissues Ex-vivosupporting

confidence: 88%

Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

et al. 2021

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BackgroundThe vasodilator neuropeptide calcitonin gene-related peptide (CGRP) plays both detrimental and protective roles in different pathologies. CGRP is also an essential component of the neuro-immune dialogue between nociceptors and mucosal immune cells. We previously discovered that CGRP is endowed with anti-viral activity and strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suppressing Langerhans cells (LCs)-mediated HIV-1 trans-infection in-vitro and mucosal HIV-1 transmission ex-vivo. This inhibition is mediated via activation of the CGRP receptor non-canonical NFκB/STAT4 signaling pathway that induces a variety of cooperative mechanisms. These include CGRP-mediated increase in the expression of the LC-specific pathogen recognition C-type lectin langerin and decrease in LC-T-cell conjugates formation. The clinical utility of CGRP and modalities of CGRP receptor activation, for inhibition of mucosal HIV-1 transmission, remain elusive.MethodsWe tested the capacity of CGRP to inhibit HIV-1 infection in-vivo in humanized mice. We further compared the anti-HIV-1 activities of full-length native CGRP, its metabolically stable analogue SAX, and several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. These agonists were evaluated for their capacity to inhibit LCs-mediated HIV-1 trans-infection in-vitro and mucosal HIV-1 transmission in human mucosal tissues ex-vivo.ResultsA single CGRP intravaginal topical treatment of humanized mice, followed by HIV-1 vaginal challenge, transiently restricts the increase in HIV-1 plasma viral loads but maintains long-lasting higher CD4+ T-cell counts. Similarly to CGRP, SAX inhibits LCs-mediated HIV-1 trans-infection in-vitro, but with lower potency. This inhibition is mediated via CGRP receptor activation, leading to increased expression of both langerin and STAT4 in LCs. In contrast, several N-terminal and N+C-terminal bivalent CGRP peptide fragments fail to increase langerin and STAT4, and accordingly lack anti-HIV-1 activities. Finally, like CGRP, treatment of human inner foreskin tissue explants with SAX, followed by polarized inoculation with cell-associated HIV-1, completely blocks formation of LC-T-cell conjugates and HIV-1 infection of T-cells.ConclusionOur results show that CGRP receptor activation by full-length CGRP or SAX is required for efficient inhibition of LCs-mediated mucosal HIV-1 transmission. These findings suggest that formulations containing CGRP, SAX and/or their optimized agonists/analogues could be harnessed for HIV-1 prevention.

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Section: Cgrp and Sax Inhibit Mucosal Hiv-1 Transmission In Human Mucosal Tissues Ex-vivosupporting

confidence: 88%

Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

et al. 2021

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“…Our results not only show that LCs are permissive to USUV, but also that they support productive viral replication. This is a surprising observation, since LCs are notoriously refractory to most viruses, with only a few exceptions, including HSV-1 46,47 and DENV 25–27 . Among the viral strains that we tested, USUV EU2 showed the fastest and most efficient replication in both DCs and LCs, and also triggered the most intense innate immune response.…”

Section: Discussionmentioning

confidence: 98%

Usutu virus escapes langerin-induced restriction to productively infect human Langerhans cells, unlike West Nile virus

Martin

Maarifi

Abiven

et al. 2021

Preprint

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Usutu virus (USUV) and West Nile virus (WNV) are emerging flaviviruses transmitted by mosquitoes. Although they differ in their endemicity, with WNV present throughout much of the world and USUV currently limited to Africa and Europe, both constitute a global public health threat. Since they are directly inoculated in the epidermis and the dermis during mosquito bites, the skin constitutes the initial site of viral replication and immune response. The skin is equipped with a unique network of dendritic cells, which represent an essential outpost of immune defenses. These skin-resident DCs comprise Langerhans cells (LCs) in the epidermis and dermal DCs in the dermis, which capture pathogens through the C-type lectin receptors (CLR) langerin and DC-SIGN, respectively. Despite the key role of these cells in the body's antiviral defenses, their implication in the immune control and replication of WNV and USUV is not known. Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism, since WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV compared with WNV and that this correlates with a more intense innate immune response to USUV compared with WNV. Next, we show that ectopic expression of langerin in non-permissive cells rendered them permissive to USUV, but not to WNV. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that this specific CLR allows USUV to enter and productively infect LCs. Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favors its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.

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“…Our results not only show that LCs are permissive to USUV, but also that they support productive viral replication. This is a surprising observation, since LCs are notoriously refractory to most viruses, with only a few exceptions, including HSV-1 [ 46 , 47 ] and DENV [ 25–27 ]. Among the viral strains that we tested, USUV EU2 showed the fastest and most efficient replication in both DCs and LCs, and also triggered the most intense innate immune response.…”

Section: Discussionmentioning

confidence: 99%

Usutu Virus escapes langerin-induced restriction to productively infect human Langerhans cells, unlike West Nile virus

Martin

Maarifi

Abiven

et al. 2022

Emerging Microbes & Infections

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Usutu virus (USUV) and West Nile virus (WNV) are phylogenetically close emerging arboviruses and constitute a global public health threat. Since USUV and WNV are transmitted by mosquitoes, the first immune cells they encounter are skin-resident dendritic cells, the most peripheral outpost of immune defense. This unique network is composed of Langerhans cells (LCs) and dermal DCs, which reside in the epidermis and the dermis, respectively. Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism: WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV than WNV and that this correlates with a more intense innate immune response to USUV compared with WNV. Next, we show that ectopic expression of the LC-specific C-type lectin receptor (CLR), langerin, in HEK293T cells allows WNV and USUV to bind and enter, but supports the subsequent replication of USUV only. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that USUV uses langerin to enter and replicate in LCs. Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favours its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.

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Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

Cited by 17 publications

References 74 publications

Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

Usutu virus escapes langerin-induced restriction to productively infect human Langerhans cells, unlike West Nile virus

Usutu Virus escapes langerin-induced restriction to productively infect human Langerhans cells, unlike West Nile virus

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