Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome

David K Meyerholz, Allyn M Lambertz, Paul B McCray Jr, David K Meyerholz, Allyn M Lambertz, Paul B McCray Jr

Abstract

Dipeptidyl peptidase 4 (DPP4, CD26), a type II transmembrane ectopeptidase, is the receptor for the Middle Eastern respiratory syndrome coronavirus (MERS-CoV). MERS emerged in 2012 and has a high mortality associated with severe lung disease. A lack of autopsy studies from MERS fatalities has hindered understanding of MERS-CoV pathogenesis. We investigated the spatial and cellular localization of DPP4 to evaluate an association MERS clinical disease. DPP4 was rarely detected in the surface epithelium from nasal cavity to conducting airways with a slightly increased incidence in distal airways. DPP4 was also found in a subset of mononuclear leukocytes and in serous cells of submucosal glands. In the parenchyma, DPP4 was found principally in type I and II cells and alveolar macrophages and was also detected in vascular endothelium (eg, lymphatics) and pleural mesothelia. Patients with chronic lung disease, such as chronic obstructive pulmonary disease and cystic fibrosis, exhibited increased DPP4 immunostaining in alveolar epithelia (type I and II cells) and alveolar macrophages with similar trends in reactive mesothelia. This finding suggests that preexisting pulmonary disease could increase MERS-CoV receptor abundance and predispose individuals to MERS morbidity and mortality, which is consistent with current clinical observations. We speculate that the preferential spatial localization of DPP4 in alveolar regions may explain why MERS is characterized by lower respiratory tract disease.

Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Dipeptidyl peptidase 4 (DPP4) immunostaining in nasal mucosa. A: Surface epithelial cells lack DPP4 immunostaining but scattered mononuclear cells in the subepithelial connective tissue have cytoplasmic staining (arrows). B: In contrast, the apical surface of serous cells (arrows) in submucosal glands commonly have robust DPP4 immunostaining. Original magnification, ×400 (A and B).
Figure 2
Figure 2
Dipeptidyl peptidase 4 (DPP4) immunostaining in airways. A: In the trachea, DPP4 is observed in scattered mononuclear cells (arrows and inset) within the epithelium and in the subepithelial connective tissue, and DPP4 is sometimes seen in the apical cytoplasm of goblet cells (arrowheads). B: Submucosal glands have apical to cytoplasmic immunostaining in serous cells (arrows), but mucous cells (asterisks) lack immunostaining. Gland lumens also stain positive (arrowheads). C: In bronchus, apical staining is seen in scattered to solitary nonciliated cells (arrowheads), and apical immunostaining is seen in uncommon submucosal gland ducts (arrows). D and E: Bronchioles have robust solitary apical immunostaining in scattered to solitary nonciliated cells (D, inset) or less commonly apical border of ciliated cells including cilia (E, inset). F: Cytoplasmic staining is also uncommonly seen in select nonciliated cells that appear to be undergoing extrusion from the epithelial surface (F, insets). Original magnification: ×600 (A and D–F); ×2100 (A, inset); ×400 (B); ×200 (C); ×100 (D–F); ×225 (D–F, insets).
Figure 3
Figure 3
Dipeptidyl peptidase 4 immunostaining in lung. A: Immunostaining is detected in alveolar macrophages (red arrows) and in type II cells (black arrows). B–D: Vascular lining cells have multifocal immunostaining (arrows, B and D). C: A pulmonary vein with preferential immunostaining on vessel valves. D: Pulmonary lymph node with abundant immunostaining of the vascular cells in the medullary sinus (arrows). Original magnifications: ×600 (A); ×400 (B); ×200 (C); ×100 (D).
Figure 4
Figure 4
Differential dipeptidyl peptidase 4 (DPP4) immunostaining in relatively healthy (top) and remodeled (bottom) regions of the same cystic fibrosis lung. A and C: DPP4 is detected in the visceral pleura (arrow, inset, A) and has more intense staining in remodeled areas with plump reactive mesothelial cells (arrows, inset, C). B and D: Weak to moderate immunostaining is common in alveolar macrophages (arrows, B) in nominally affected lung. However, in areas of remodeling, activated alveolar macrophages (macrophages with larger, foamier cytoplasm and sometimes multinucleate cells) have more robust immunostaining (arrows, D). Original magnification: ×600 (A–D); ×1500 (A and C, insets).
Figure 5
Figure 5
Dipeptidyl peptidase 4 (DPP4) immunostaining increases in activated alveolar macrophages near sites of disease (eg, remodeling). A semiquantitative scoring was used to compare group 1 (healthy) and group 2 (diseased) tissues. Data are expressed as means ± SD. ∗P < 0.05, paired t-test.
Figure 6
Figure 6
Alveoli of a control (A) and chronic obstructive pulmonary disease (COPD) lung (B and C). A: Dipeptidyl peptidase 4 (DPP4) immunostaining is detected in scattered alveolar type II cells (arrows) in control lungs. B: DPP4 immunostaining increases in intensity in type II cells (arrows) and also in type I cells along septal walls (arrowhead). C: Inflammation in a COPD lung airway. Note the immunostaining in macrophages (arrowheads) but absence of immunostaining in neutrophils (arrows). D and E: Assessment of sex differences in DPP4 expression in healthy (group 1) and diseased (group 2) tissues. No significant sex-related differences in DPP4 expression are found in alveolar type II cells or alveolar macrophages. Data are expressed as means ± SD (D and E). Original magnification: ×600 (A and B); ×400 (C).

References

    1. Zaki A.M., van Boheemen S., Bestebroer T.M., Osterhaus A.D., Fouchier R.A. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814–1820.
    1. Arabi Y.M., Arifi A.A., Balkhy H.H., Najm H., Aldawood A.S., Ghabashi A., Hawa H., Alothman A., Khaldi A., Al Raiy B. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160:389–397.
    1. Kapoor M., Pringle K., Kumar A., Dearth S., Liu L., Lovchik J., Perez O., Pontones P., Richards S., Yeadon-Fagbohun J., Breakwell L., Chea N., Cohen N.J., Schneider E., Erdman D., Haynes L., Pallansch M., Tao Y., Tong S., Gerber S., Swerdlow D., Feikin D.R. Clinical and laboratory findings of the first imported case of Middle East respiratory syndrome coronavirus to the United States. Clin Infect Dis. 2014;59:1511–1518.
    1. Saad M., Omrani A.S., Baig K., Bahloul A., Elzein F., Matin M.A., Selim M.A., Al Mutairi M., Al Nakhli D., Al Aidaroos A.Y., Al Sherbeeni N., Al-Khashan H.I., Memish Z.A., Albarrak A.M. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis. 2014;29:301–306.
    1. Assiri A., McGeer A., Perl T.M., Price C.S., Al Rabeeah A.A., Cummings D.A., Alabdullatif Z.N., Assad M., Almulhim A., Makhdoom H., Madani H., Alhakeem R., Al-Tawfiq J.A., Cotten M., Watson S.J., Kellam P., Zumla A.I., Memish Z.A., Team KM-CI Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013;369:407–416.
    1. Hui D.S., Perlman S., Zumla A. Spread of MERS to South Korea and China. Lancet Respir Med. 2015;3:509–510.
    1. Al-Hameed F., Wahla A.S., Siddiqui S., Ghabashi A., Al-Shomrani M., Al-Thaqafi A., Tashkandi Y. Characteristics and outcomes of Middle East respiratory syndrome coronavirus patients admitted to an intensive care unit in Jeddah, Saudi Arabia. J Intensive Care Med. 2015 [Epub ahead of print]
    1. Ajlan A.M., Ahyad R.A., Jamjoom L.G., Alharthy A., Madani T.A. Middle East respiratory syndrome coronavirus (MERS-CoV) infection: chest CT findings. AJR Am J Roentgenol. 2014;203:782–787.
    1. Arabi Y.M., Harthi A., Hussein J., Bouchama A., Johani S., Hajeer A.H., Saeed B.T., Wahbi A., Saedy A., AlDabbagh T., Okaili R., Sadat M., Balkhy H. Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV) Infection. 2015;43:495–501.
    1. Yusof M.F., Eltahir Y.M., Serhan W.S., Hashem F.M., Elsayed E.A., Marzoug B.A., Abdelazim A.S., Bensalah O.K., Al Muhairi S.S. Prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels in Abu Dhabi Emirate, United Arab Emirates. Virus Genes. 2015;50:509–513.
    1. Chan R.W., Hemida M.G., Kayali G., Chu D.K., Poon L.L., Alnaeem A., Ali M.A., Tao K.P., Ng H.Y., Chan M.C., Guan Y., Nicholls J.M., Peiris J.S. Tropism and replication of Middle East respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: an in-vitro and ex-vivo study. Lancet Respir Med. 2014;2:813–822.
    1. Wernery U., Corman V.M., Wong E.Y., Tsang A.K., Muth D., Lau S.K., Khazanehdari K., Zirkel F., Ali M., Nagy P., Juhasz J., Wernery R., Joseph S., Syriac G., Elizabeth S.K., Patteril N.A., Woo P.C., Drosten C. Acute middle East respiratory syndrome coronavirus infection in livestock dromedaries, Dubai, 2014. Emerg Infect Dis. 2015;21:1019–1022.
    1. Azhar E.I., El-Kafrawy S.A., Farraj S.A., Hassan A.M., Al-Saeed M.S., Hashem A.M., Madani T.A. Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med. 2014;370:2499–2505.
    1. Yu I.T., Li Y., Wong T.W., Tam W., Chan A.T., Lee J.H., Leung D.Y., Ho T. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med. 2004;350:1731–1739.
    1. Wang Sh X., Li Y.M., Sun B.C., Zhang S.W., Zhao W.H., Wei M.T., Chen K.X., Zhao X.L., Zhang Z.L., Krahn M., Cheung A.C., Wang P.P. The SARS outbreak in a general hospital in Tianjin, China – the case of super-spreader. Epidemiol Infect. 2006;134:786–791.
    1. Perlman S., McCray P.B., Jr. Person-to-person spread of the MERS coronavirus–an evolving picture. N Engl J Med. 2013;369:466–467.
    1. Breban R., Riou J., Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet. 2013;382:694–699.
    1. Memish Z.A., Assiri A.M., Al-Tawfiq J.A. Middle East respiratory syndrome coronavirus (MERS-CoV) viral shedding in the respiratory tract: an observational analysis with infection control implications. Int J Infect Dis. 2014;29:307–308.
    1. Memish Z.A., Zumla A.I., Al-Hakeem R.F., Al-Rabeeah A.A., Stephens G.M. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med. 2013;368:2487–2494.
    1. Memish Z.A., Al-Tawfiq J.A., Assiri A., AlRabiah F.A., Al Hajjar S., Albarrak A., Flemban H., Alhakeem R.F., Makhdoom H.Q., Alsubaie S., Al-Rabeeah A.A. Middle East respiratory syndrome coronavirus disease in children. Pediatr Infect Dis J. 2014;33:904–906.
    1. Madani T.A. Case definition and management of patients with MERS coronavirus in Saudi Arabia. Lancet Infect Dis. 2014;14:911–913.
    1. Raj V.S., Mou H., Smits S.L., Dekkers D.H., Muller M.A., Dijkman R., Muth D., Demmers J.A., Zaki A., Fouchier R.A., Thiel V., Drosten C., Rottier P.J., Osterhaus A.D., Bosch B.J., Haagmans B.L. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495:251–254.
    1. Lu G., Hu Y., Wang Q., Qi J., Gao F., Li Y., Zhang Y., Zhang W., Yuan Y., Bao J., Zhang B., Shi Y., Yan J., Gao G.F. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013;500:227–231.
    1. Lambeir A.M., Durinx C., Scharpe S., De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40:209–294.
    1. Juillerat-Jeanneret L., Aubert J.D., Leuenberger P. Peptidases in human bronchoalveolar lining fluid, macrophages, and epithelial cells: dipeptidyl (amino)peptidase IV, aminopeptidase N, and dipeptidyl (carboxy)peptidase (angiotensin-converting enzyme) J Lab Clin Med. 1997;130:603–614.
    1. Mentzel S., Dijkman H.B., Van Son J.P., Koene R.A., Assmann K.J. Organ distribution of aminopeptidase A and dipeptidyl peptidase IV in normal mice. J Histochem Cytochem. 1996;44:445–461.
    1. van der Velden V.H., Wierenga-Wolf A.F., Adriaansen-Soeting P.W., Overbeek S.E., Moller G.M., Hoogsteden H.C., Versnel M.A. Expression of aminopeptidase N and dipeptidyl peptidase IV in the healthy and asthmatic bronchus. Clin Exp Allergy. 1998;28:110–120.
    1. Gibson-Corley K.N., Olivier A.K., Meyerholz D.K. Principles for valid histopathologic scoring in research. Vet Pathol. 2013;50:1007–1015.
    1. Zhao J., Li K., Wohlford-Lenane C., Agnihothram S.S., Fett C., Zhao J., Gale M.J., Jr., Baric R.S., Enjuanes L., Gallagher T., McCray P.B., Jr., Perlman S. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A. 2014;111:4970–4975.
    1. Agrawal A.S., Garron T., Tao X., Peng B.H., Wakamiya M., Chan T.S., Couch R.B., Tseng C.T. Generation of transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol. 2015;89:3659–3670.
    1. Rohrborn D., Eckel J., Sell H. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett. 2014;588:3870–3877.
    1. Sanchez-Otero N., Rodriguez-Berrocal F.J., de la Cadena M.P., Botana-Rial M.I., Cordero O.J. Evaluation of pleural effusion sCD26 and DPP-IV as diagnostic biomarkers in lung disease. Sci Rep. 2014;4:3999.
    1. van der Velden V.H., Naber B.A., Van Hal P.T., Overbeek S.E., Hoogsteden H.C., Versnel M.A. Peptidase activities in serum and bronchoalveolar lavage fluid from allergic asthmatics–comparison with healthy non-smokers and smokers and effects of inhaled glucocorticoids. Clin Exp Allergy. 1999;29:813–823.
    1. Schmiedl A., Krainski J., Schwichtenhovel F., Schade J., Klemann C., Raber K.A., Zscheppang K., Beekmann T., Acevedo C., Glaab T., Wedekind D., Pabst R., von Horsten S., Stephan M. Reduced airway inflammation in CD26/DPP4-deficient F344 rats is associated with altered recruitment patterns of regulatory T cells and expression of pulmonary surfactant proteins. Clin Exp Allergy. 2010;40:1794–1808.
    1. Zhou J., Chu H., Li C., Wong B.H., Cheng Z.S., Poon V.K., Sun T., Lau C.C., Wong K.K., Chan J.Y., Chan J.F., To K.K., Chan K.H., Zheng B.J., Yuen K.Y. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis. 2014;209:1331–1342.
    1. Chu H., Zhou J., Wong B.H., Li C., Cheng Z.S., Lin X., Poon V.K., Sun T., Lau C.C., Chan J.F., To K.K., Chan K.H., Lu L., Zheng B.J., Yuen K.Y. Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology. 2014;454–455:197–205.
    1. Scheuplein V.A., Seifried J., Malczyk A.H., Miller L., Hocker L., Vergara-Alert J., Dolnik O., Zielecki F., Becker B., Spreitzer I., Konig R., Becker S., Waibler Z., Muhlebach M.D. High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus. J Virol. 2015;89:3859–3869.
    1. Chu H., Zhou J., Wong B.H., Li C., Chan J.F., Cheng Z.S., Yang D., Wang D., Lee A.C., Li C., Yeung M.L., Cai J.P., Chan I.H., Ho W.K., To K.K., Zheng B.J., Yao Y., Qin C., Yuen K.Y. Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates both the extrinsic and intrinsic apoptosis pathways. J Infect Dis. 2015 [Epub ahead of print]
    1. Ying T., Li W., Dimitrov D.S. Discovery of T cell infection and apoptosis by MERS Coronavirus. J Infect Dis. 2015 [Epub ahead of print]
    1. de Meester I., Lambeir A.M., Proost P., Scharpe S. Dipeptidyl peptidase IV substrates: an update on in vitro peptide hydrolysis by human DPPIV. Adv Exp Med Biol. 2003;524:3–17.
    1. Chan R.W., Chan M.C., Agnihothram S., Chan L.L., Kuok D.I., Fong J.H., Guan Y., Poon L.L., Baric R.S., Nicholls J.M., Peiris J.S. Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J Virol. 2013;87:6604–6614.
    1. Shin J.W., Jurisic G., Detmar M. Lymphatic-specific expression of dipeptidyl peptidase IV and its dual role in lymphatic endothelial function. Exp Cell Res. 2008;314:3048–3056.
    1. Kajiyama H., Kikkawa F., Maeda O., Suzuki T., Ino K., Mizutani S. Increased expression of dipeptidyl peptidase IV in human mesothelial cells by malignant ascites from ovarian carcinoma patients. Oncology. 2002;63:158–165.
    1. Casrouge A., Decalf J., Ahloulay M., Lababidi C., Mansour H., Vallet-Pichard A., Mallet V., Mottez E., Mapes J., Fontanet A., Pol S., Albert M.L. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest. 2011;121:308–317.
    1. Wronkowitz N., Gorgens S.W., Romacho T., Villalobos L.A., Sanchez-Ferrer C.F., Peiro C., Sell H., Eckel J. Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta. 2014;1842:1613–1621.
    1. Ikeda T., Kumagai E., Iwata S., Yamakawa A. Soluble CD26/dipeptidyl peptidase IV enhances the transcription of IL-6 and TNF-alpha in THP-1 cells and monocytes. PLoS One. 2013;8:e66520.
    1. Hocke A.C., Becher A., Knepper J., Peter A., Holland G., Tonnies M., Bauer T.T., Schneider P., Neudecker J., Muth D., Wendtner C.M., Ruckert J.C., Drosten C., Gruber A.D., Laue M., Suttorp N., Hippenstiel S., Wolff T. Emerging human middle East respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs. Am J Respir Crit Care Med. 2013;188:882–886.
    1. Josset L., Menachery V.D., Gralinski L.E., Agnihothram S., Sova P., Carter V.S., Yount B.L., Graham R.L., Baric R.S., Katze M.G. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. MBio. 2013;4:e00165-13.
    1. Selinger C., Tisoncik-Go J., Menachery V.D., Agnihothram S., Law G.L., Chang J., Kelly S.M., Sova P., Baric R.S., Katze M.G. Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates. BMC Genomics. 2014;15:1161.
    1. Menachery V.D., Eisfeld A.J., Schafer A., Josset L., Sims A.C., Proll S., Fan S., Li C., Neumann G., Tilton S.C., Chang J., Gralinski L.E., Long C., Green R., Williams C.M., Weiss J., Matzke M.M., Webb-Robertson B.J., Schepmoes A.A., Shukla A.K., Metz T.O., Smith R.D., Waters K.M., Katze M.G., Kawaoka Y., Baric R.S. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. MBio. 2014;5:e01174-14.
    1. Jornot L., Grouzmann E., Lacroix J.S., Rochat T. BDNF and DPP-IV in polyps and middle turbinates epithelial cells. Rhinology. 2007;45:129–133.
    1. Chan J.F., Chan K.H., Choi G.K., To K.K., Tse H., Cai J.P., Yeung M.L., Cheng V.C., Chen H., Che X.Y., Lau S.K., Woo P.C., Yuen K.Y. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications for disease pathogenesis and clinical manifestation. J Infect Dis. 2013;207:1743–1752.
    1. Tao X., Hill T.E., Morimoto C., Peters C.J., Ksiazek T.G., Tseng C.T. Bilateral entry and release of Middle East respiratory syndrome coronavirus induces profound apoptosis of human bronchial epithelial cells. J Virol. 2013;87:9953–9958.
    1. Zhou Y., Vedantham P., Lu K., Agudelo J., Carrion R., Jr., Nunneley J.W., Barnard D., Pohlmann S., McKerrow J.H., Renslo A.R., Simmons G. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76–84.

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