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Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus

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Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus viruses Communication Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus Edson R. A. Oliveira , Lenong Li and Marlene Bouvier * Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL 60612, USA; [email protected] (E.R.A.O.); [email protected] (L.L.) * Correspondence: [email protected] Abstract: The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins. Citation: Oliveira, E.R.A.; Li, L.; Keywords: adenoviruses; adenovirus species F; viral tropism; gut immune system; enteric viruses; Bouvier, M. Intracellular immune evasion; NK cells; MIC A and MIC B Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus. Viruses 2021, 13, 1289. https:// doi.org/10.3390/v13071289 1. Introduction HAdVs represents a large family of genetically diverse pathogens. To date, more Academic Editor: Glen R. Nemerow than 100 different HAdVs have been identified and classified into seven species, A to G(http://hadvwg.gmu.edu/ (accessed on 22 November 2019)). HAdVs cause partially Received: 14 May 2021 overlapping, species-specific diseases associated with infections of the respiratory (species Accepted: 25 June 2021 Published: 1 July 2021 B, C, and E), urinary (species B), gastrointestinal (species A and F), and ocular (species D) systems [1]. HAdVs are highly contagious and can cause severe local outbreaks. Al- Publisher’s Note: MDPI stays neutral though healthy adults can generally control the virus, HAdV infections in children and with regard to jurisdictional claims in immunocompromised individuals can be fatal [2–5]. HAdV devotes a considerable portion published maps and institutional affil- of its genome to modulation of host immune functions, which presumably enables some iations. species to establish and maintain lifelong asymptomatic infections. The vast majority of HAdV genes involved in the modulation of host immune functions are grouped in the E3 region [6,7]. The E3 region is not essential for HAdV replication in cultured cells, but the fact that this transcription unit is always maintained in natural isolates strongly suggests that E3 gene products are critical for natural infections in humans [6,7]. Notably, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. E3 is one of the most divergent gene regions between species (see Figure1). This genetic This article is an open access article variability is not well understood, but it strongly suggests that E3 proteins play a role in distributed under the terms and the manifestation of species-specific tissue tropism and diseases [6]. The 19K protein of conditions of the Creative Commons HAdV-C binds to and retains MHC class I molecules in the endoplasmic reticulum, thereby Attribution (CC BY) license (https:// rendering HAdV-C-infected cells less efficient at presenting viral antigens and less sensitive creativecommons.org/licenses/by/ to lysis by CD8+ T cells [8–22]. That this 19K gene is maintained in HAdV-B, -D, and -E (see 4.0/). Figure1) underscores the critical need for these species to retain a MHC I-binding function. Viruses 2021, 13, 1289. https://doi.org/10.3390/v13071289 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 1289 2 of 11 Viruses 2021, 13, 1289 2 of 11 to lysis by CD8+ T cells [8–22]. That this 19K gene is maintained in HAdV-B, -D, and -E (see Figure 1) underscores the critical need for these species to retain a MHC I-binding function. The x-ray crystal structures of AdV-C2 and AdV-E4 E3-19K bound to HLA-A2 providedThe x-ray insights crystal structuresinto the mechanism of AdV-C2 of and immune AdV-E4 modulation E3-19K bound [23,24 to]. HLA-A2Other E3 provided proteins wereinsights shown into to the function mechanism by inhibiting of immune tumor modulation necrosis [23 factor,24]. activities Other E3 proteinsand interfering were shown with apoptoticto function cell by death inhibiting processes tumor and necrosis leukocyt factore activation, activities and ultimately interfering suppressing with apoptotic the lysis cell ofdeath infected processes cells by and NK leukocyte cells [25 activation,] and references ultimately therein. suppressing the lysis of infected cells by NKThe cells enteric [25] andHAdV references-F, which therein. comprises HAdV-F40 and HAdV-F41, shows a narrow The enteric HAdV-F, which comprises HAdV-F40 and HAdV-F41, shows a narrow tropism for epithelial cells of the GI tract and is a leading etiologic agent of acute gastro- tropism for epithelial cells of the GI tract and is a leading etiologic agent of acute gas- enteritis in infants and young children worldwide [26–29]. Notably, there are marked dif- troenteritis in infants and young children worldwide [26–29]. Notably, there are marked ferences in the E3 region of HAdV-F compared to the other species (see Figure 1): HAdV- differences in the E3 region of HAdV-F compared to the other species (see Figure1): HAdV- F lacks the common E3-19K gene and has two genes, 19.4K and 31.6K, that are unique to F lacks the common E3-19K gene and has two genes, 19.4K and 31.6K, that are unique to that species [30–32]. To date, E3-19.4K and E3-31.6K proteins have not been characterized that species [30–32]. To date, E3-19.4K and E3-31.6K proteins have not been characterized and we have no knowledge of their functions. The study of HAdV-F thus offers a unique and we have no knowledge of their functions. The study of HAdV-F thus offers a unique opportunity to study how interactions between E3 proteins and the immune microenvi- opportunity to study how interactions between E3 proteins and the immune microenvi- ronment at the site of infection contributes to viral tropism and pathogenicity. We suggest ronment at the site of infection contributes to viral tropism and pathogenicity. We suggest that the selective pressure on HAdV-F40 and HAdV-F41 by the immune system of the GI that the selective pressure on HAdV-F40 and HAdV-F41 by the immune system of the GI tracttract has has led led these these viruses viruses to to adapt adapt in in order order to replicate effectively in in gut cells, and that E3E3-19.4K-19.4K and/or E3 E3-31.6K-31.6K proteinsproteins playplay an an important important role role in in this this process. process. More More specifically, specifi- cally,we suggest we suggest that HAdVs-F that HAdVs have-F evolved have evolved a function a function directed directed at suppressing at suppressing the expression the ex- pressof MICion A of and MIC MIC A and B molecules MIC B molecules on infected on cells.infected MIC cells. A and MIC MIC A and B are MIC stress-inducible B are stress- induciblesurface ligands surface that ligands are recognized that are recognized by the NKG2D by the NKG2D activating activating receptor receptor expressed expressed on NK oncells NK to cells eliminate to eliminate stressed stressed cells. Given cells. Given that the that distribution the distribution of MIC of activating MIC activating ligands lig- is andslargely is restrictedlargely restricted to intestinal to intestinal epithelial epithelial cells under cells normal under conditions, normal conditions, and that HAdVs-Fand that HAdVsare exquisitely-F are exquisitely adapted to adapted replicate to in replicate the intestinal in the epithelium intestinal [epithelium33] and references [33] and therein, refer- encesit might therein, not be it surprisingmight not thatbe surprising these viruses that interferethese viruses with interfere MIC A and wit MICh MIC B toA and suppress MIC Bimmune to suppress surveillance immune by surveillance NK cells. by NK cells. ToTo advance ourour understandingunderstanding of of HAdVs-F, HAdVs-F, and and given given the the significance significance of these of these viruses vi- rusesas pathogens, as pathogens, we have we have initiated initiated a study a study to examine to examine the the effects effects of HAdV-Fof HAdV infection-F infection on oncell cell surface surface expression expressio ofn of MIC MIC ligands. ligands. We We have have established established anan inin vitrovitro culture system basedbased on on infection infection of of human human intestinal intestinal HCT116 HCT116 cells cells with with HAdVs HAdVs-F-F from from which we show thatthat HAdV HAdV-F41-F41 causes the the intracellular intracellular sequestration sequestration of of MIC MIC B. B. These These preliminary preliminary results results supportsupport the the hypoth hypothesisesis that that interferences interferences with NKG2D MIC ligands is a mechanism used byby HAdVs HAdVs-F-F to to evade evade immune immune surveillance surveillance in the inthe gut gutand and may may be a bedeterminant a determinant of viral of tropism.viral tropism.
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