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Respiratory Research
Published in: Respiratory Research 1/2024

Open Access 01-12-2024 | Influenza | Research

Cooperation of immune regulators Tollip and surfactant protein A inhibits influenza A virus infection in mice

Authors: Niccolette Schaunaman, Diana Cervantes, Taylor Nichols, Mari Numata, Julie G. Ledford, Monica Kraft, Hong Wei Chu

Published in: Respiratory Research | Issue 1/2024

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Abstract

Background

Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated.

Methods

Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h.

Results

Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling.

Conclusions

Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.
Appendix
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Literature
1.
Shrestha SS, Swerdlow DL, Borse RH, Prabhu VS, Finelli L, Atkins CY, et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis. 2011;52 Suppl 1:S75-82.PubMedCrossRef
2.
3.
LeMessurier KS, Rooney R, Ghoneim HE, Liu B, Li K, Smallwood HS, et al. Influenza A virus directly modulates mouse eosinophil responses. J Leukoc Biol. 2020;108(1):151–68.PubMedCrossRef
4.
Liu B, Li NL, Shen Y, Bao X, Fabrizio T, Elbahesh H, et al. The C-terminal tail of TRIM56 dictates antiviral restriction of influenza A and B viruses by impeding viral RNA synthesis. J Virol. 2016;90(9):4369–82.PubMedPubMedCentralCrossRef
5.
Li X, Goobie GC, Gregory AD, Kass DJ, Zhang Y. Toll-interacting protein in pulmonary diseases. Abiding by the goldilocks principle. Am J Respir Cell Mol Biol. 2021;64(5):536–46.PubMedPubMedCentralCrossRef
6.
Colotta F, Lampugnani MG, Polentarutti N, Dejana E, Mantovani A. Interleukin-1 induces c-fos protooncogene expression in cultured human endothelial cells. Biochem Biophys Res Commun. 1988;152(3):1104–10.PubMedCrossRef
7.
Schaunaman N, Dimasuay KG, Cervantes D, Li L, Numata M, Kraft M, et al. Tollip inhibits IL-33 release and inflammation in influenza A virus-infected mouse airways. J Innate Immun. 2023;15(1):66–7.CrossRef
8.
Schaunaman N, Dimasuay KG, Kraft M, Chu HW. Tollip interaction with STAT3: a novel mechanism to regulate human airway epithelial responses to type 2 cytokines. Respir Res. 2022;23(1):31.PubMedPubMedCentralCrossRef
9.
Ito Y, Schaefer N, Sanchez A, Francisco D, Alam R, Martin RJ, et al. Toll-Interacting protein, Tollip, inhibits IL-13-mediated pulmonary eosinophilic inflammation in mice. J Innate Immun. 2018;10(2):106–18.PubMedPubMedCentralCrossRef
10.
Dakhama A, Al Mubarak R, Pavelka N, Voelker D, Seibold M, Ledford JG, et al. Tollip inhibits ST2 signaling in airway epithelial cells exposed to type 2 cytokines and rhinovirus. J Innate Immun. 2020;12(1):103–15.PubMedCrossRef
11.
Huang C, Jiang D, Francisco D, Berman R, Wu Q, Ledford JG, et al. Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection. Clin Exp Allergy. 2016;46(12):1549–63.PubMedPubMedCentralCrossRef
12.
Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.PubMedCrossRef
13.
Didierlaurent A, Brissoni B, Velin D, Aebi N, Tardivel A, Kaslin E, et al. Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide. Mol Cell Biol. 2006;26(3):735–42.PubMedPubMedCentralCrossRef
14.
Zhang G, Ghosh S. Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem. 2002;277(9):7059–65.PubMedCrossRef
15.
Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol. 2000;2(6):346–51.PubMedCrossRef
16.
Nayak A, Dodagatta-Marri E, Tsolaki AG, Kishore U. An insight into the diverse roles of surfactant proteins, SP-A and SP-D in innate and adaptive immunity. Front Immunol. 2012;3:131.PubMedPubMedCentralCrossRef
17.
Khubchandani KR, Snyder JM. Surfactant protein A (SP-A): the alveolus and beyond. FASEB J. 2001;15(1):59–69.PubMedCrossRef
18.
Benne CA, Kraaijeveld CA, van Strijp JA, Brouwer E, Harmsen M, Verhoef J, et al. Interactions of surfactant protein A with influenza A viruses: binding and neutralization. J Infect Dis. 1995;171(2):335–41.PubMedCrossRef
19.
Al-Qahtani AA, Murugaiah V, Bashir HA, Pathan AA, Abozaid SM, Makarov E, et al. Full-length human surfactant protein A inhibits influenza A virus infection of A549 lung epithelial cells: A recombinant form containing neck and lectin domains promotes infectivity. Immunobiology. 2019;224(3):408–18.PubMedCrossRef
20.
Wang Y, Voelker DR, Lugogo NL, Wang G, Floros J, Ingram JL, et al. Surfactant protein A is defective in abrogating inflammation in asthma. Am J Physiol Lung Cell Mol Physiol. 2011;301(4):L598-606.PubMedPubMedCentralCrossRef
21.
Benne CA, Benaissa-Trouw B, van Strijp JA, Kraaijeveld CA, van Iwaarden JF. Surfactant protein A, but not surfactant protein D, is an opsonin for influenza A virus phagocytosis by rat alveolar macrophages. Eur J Immunol. 1997;27(4):886–90.PubMedCrossRef
22.
Lugogo N, Francisco D, Addison KJ, Manne A, Pederson W, Ingram JL, et al. Obese asthmatic patients have decreased surfactant protein A levels: mechanisms and implications. J Allergy Clin Immunol. 2018;141(3):918-26 e3.PubMedCrossRef
23.
Herrera-Ramos E, Lopez-Rodriguez M, Ruiz-Hernandez JJ, Horcajada JP, Borderias L, Lerma E, et al. Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection. Crit Care. 2014;18(3):R127.PubMedPubMedCentralCrossRef
24.
LeVine AM, Hartshorn K, Elliott J, Whitsett J, Korfhagen T. Absence of SP-A modulates innate and adaptive defense responses to pulmonary influenza infection. Am J Physiol Lung Cell Mol Physiol. 2002;282(3):L563–72.PubMedCrossRef
25.
Li G, Siddiqui J, Hendry M, Akiyama J, Edmondson J, Brown C, et al. Surfactant protein-A–deficient mice display an exaggerated early inflammatory response to a beta-resistant strain of influenza A virus. Am J Respir Cell Mol Biol. 2002;26(3):277–82.PubMedCrossRef
26.
Chroneos ZC, Sever-Chroneos Z, Shepherd VL. Pulmonary surfactant: an immunological perspective. Cell Physiol Biochem. 2010;25(1):13–26.PubMedCrossRef
27.
Daly K, Nguyen P, Woodland DL, Blackman MA. Immunodominance of major histocompatibility complex class I-restricted influenza virus epitopes can be influenced by the T-cell receptor repertoire. J Virol. 1995;69(12):7416–22.PubMedPubMedCentralCrossRef
28.
Hartshorn KL, White MR, Tecle T, Holmskov U, Crouch EC. Innate defense against influenza A virus: activity of human neutrophil defensins and interactions of defensins with surfactant protein D. J Immunol. 2006;176(11):6962–72.PubMedCrossRef
29.
Numata M, Mitchell JR, Tipper JL, Brand JD, Trombley JE, Nagashima Y, et al. Pulmonary surfactant lipids inhibit infections with the pandemic H1N1 influenza virus in several animal models. J Biol Chem. 2020;295(6):1704–15.PubMedCrossRef
30.
Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis. 2009;9(8):493–504.PubMedPubMedCentralCrossRef
31.
Chan RW, Yuen KM, Yu WC, Ho CC, Nicholls JM, Peiris JS, et al. Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation. PLoS One. 2010;5(1):e8713.PubMedPubMedCentralCrossRef
32.
Chen K, Yuan R, Zhang Y, Geng S, Li L. Tollip deficiency alters atherosclerosis and steatosis by disrupting lipophagy. J Am Heart Assoc. 2017;6(4):e004078.PubMedPubMedCentralCrossRef
33.
Francisco D, Wang Y, Conway M, Hurbon AN, Dy ABC, Addison KJ, et al. Surfactant Protein-A protects against IL-13-Induced inflammation in asthma. J Immunol. 2020;204(10):2829–39.PubMedCrossRef
34.
Korfhagen TR, Bruno MD, Ross GF, Huelsman KM, Ikegami M, Jobe AH, et al. Altered surfactant function and structure in SP-A gene targeted mice. Proc Natl Acad Sci U S A. 1996;93(18):9594–9.PubMedPubMedCentralCrossRef
35.
Nouri HR, Schaunaman N, Kraft M, Li L, Numata M, Chu HW. Tollip deficiency exaggerates airway type 2 inflammation in mice exposed to allergen and influenza A virus: role of the ATP/IL-33 signaling axis. Front Immunol. 2023;14:1304758.PubMedPubMedCentralCrossRef
36.
Dimasuay KG, Berg B, Schaunaman N, Chu HW. Role of myeloid cell-specific TLR9 in mitochondrial DNA-induced lung inflammation in mice. Int J Mol Sci. 2023;24(2):939.PubMedPubMedCentralCrossRef
37.
Somerville L, Cardani A, Braciale TJ. Alveolar macrophages in influenza A infection guarding the castle with sleeping dragons. Infect Dis Ther (San Antonio). 2020;1(1):1–3.
38.
Jacob IB, Gemmiti A, Xiong W, Reynolds E, Nicholas B, Thangamani S, et al. Human surfactant protein A alleviates SARS-CoV-2 infectivity in human lung epithelial cells. Front Immunol. 2024;15:1370511.PubMedPubMedCentralCrossRef
39.
Agraval H, Crue T, Schaunaman N, Numata M, Day BJ, Chu HW. Electronic cigarette exposure increases the severity of influenza a virus infection via TRAIL dysregulation in human precision-cut lung slices. Int J Mol Sci. 2023;24(5):4295.PubMedPubMedCentralCrossRef
40.
Chen Y, Cui D, Zheng S, Yang S, Tong J, Yang D, et al. Simultaneous detection of influenza A, influenza B, and respiratory syncytial viruses and subtyping of influenza A H3N2 virus and H1N1 (2009) virus by multiplex real-time PCR. J Clin Microbiol. 2011;49(4):1653–6.PubMedPubMedCentralCrossRef
41.
da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.PubMedCrossRef
42.
da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1):1–13.PubMedCrossRef
43.
Todd EM, Zhou JY, Szasz TP, Deady LE, D’Angelo JA, Cheung MD, et al. Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli. Blood. 2016;128(24):2785–96.PubMedPubMedCentralCrossRef
44.
45.
Dewhurst JA, Lea S, Hardaker E, Dungwa JV, Ravi AK, Singh D. Characterisation of lung macrophage subpopulations in COPD patients and controls. Sci Rep. 2017;7(1):7143.PubMedPubMedCentralCrossRef
46.
Berkebile AR, Bartlett JA, Abou Alaiwa M, Varga SM, Power UF, McCray PB Jr. Airway surface liquid has innate antiviral activity that is reduced in cystic fibrosis. Am J Respir Cell Mol Biol. 2020;62(1):104–11.PubMedPubMedCentralCrossRef
47.
Campione E, Lanna C, Cosio T, Rosa L, Conte MP, Iacovelli F, et al. Lactoferrin as antiviral treatment in COVID-19 management: preliminary evidence. Int J Environ Res Public Health. 2021;18(20):10985.PubMedPubMedCentralCrossRef
48.
Malaczewska J, Kaczorek-Lukowska E, Wojcik R, Siwicki AK. Antiviral effects of nisin, lysozyme, lactoferrin and their mixtures against bovine viral diarrhoea virus. BMC Vet Res. 2019;15(1):318.PubMedPubMedCentralCrossRef
49.
Hashimoto Y, Moki T, Takizawa T, Shiratsuchi A, Nakanishi Y. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol. 2007;178(4):2448–57.PubMedCrossRef
50.
51.
Shibayama N, Imai K, Morimoto H, Saigo S. Oxygen equilibrium properties of nickel(II)-iron(II) hybrid hemoglobins cross-linked between 82 beta 1 and 82 beta 2 lysyl residues by bis(3,5-dibromosalicyl)fumarate: determination of the first two-step microscopic Adair constants for human hemoglobin. Biochemistry. 1995;34(14):4773–80.PubMedCrossRef
52.
Mattner J, Schindler H, Diefenbach A, Rollinghoff M, Gresser I, Bogdan C. Regulation of type 2 nitric oxide synthase by type 1 interferons in macrophages infected with Leishmania major. Eur J Immunol. 2000;30(8):2257–67.PubMedCrossRef
53.
Perrone LA, Belser JA, Wadford DA, Katz JM, Tumpey TM. Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice. J Infect Dis. 2013;207(10):1576–84.PubMedCrossRef
54.
Yau E, Yang L, Chen Y, Umstead TM, Atkins H, Katz ZE, et al. Surfactant protein A alters endosomal trafficking of influenza A virus in macrophages. Front Immunol. 2023;14:919800.PubMedPubMedCentralCrossRef
55.
Siakaeva E, Pylaeva E, Spyra I, Bordbari S, Hoing B, Kurten C, et al. Neutrophil maturation and survival is controlled by IFN-dependent regulation of NAMPT signaling. Int J Mol Sci. 2019;20(22):5584.PubMedPubMedCentralCrossRef
56.
Schultz BM, Acevedo OA, Kalergis AM, Bueno SM. Role of extracellular trap release during bacterial and viral infection. Front Microbiol. 2022;13:798853.PubMedPubMedCentralCrossRef
57.
Higgins P, Runnegar N, Bird RJ, Markey KA. Rates of neutropenia in adults with influenza A or B: a retrospective analysis of hospitalised patients in South East Queensland during 2015. Intern Med J. 2016;46(11):1328–32.PubMedCrossRef
58.
Durani U, Dioverti Prono MV, Tosh PK, Patnaik M, Barreto JN, Tande AJ. Influenza infection in neutropenic adults. Infect Dis (Lond). 2017;49(2):141–6.PubMedCrossRef
59.
Matsushita H, Kurihara N, Wakayama K, Fujimoto S, Kanazawa H, Fujiwara H, et al. Dyspnea and ventilatory muscle function during exercise on air and oxygen breathing in patients with chronic obstructive pulmonary disease (COPD). Nihon Kyobu Shikkan Gakkai Zasshi. 1992;30(6):1116–24.PubMed
60.
61.
Pokatayev V, Yang K, Tu X, Dobbs N, Wu J, Kalb RG, et al. Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP. Nat Immunol. 2020;21(2):158–67.PubMedPubMedCentralCrossRef
62.
Moriyama M, Koshiba T, Ichinohe T. Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses. Nat Commun. 2019;10(1):4624.PubMedPubMedCentralCrossRef
63.
Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45–65.PubMedCrossRef
64.
Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity. 1995;2(6):561–72.PubMedCrossRef
65.
Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993;73(3):457–67.PubMedCrossRef
66.
Lyons-Cohen MR, Thomas SY, Cook DN, Nakano H. Precision-cut mouse lung slices to visualize live pulmonary dendritic cells. J Vis Exp. 2017;122:55465.
67.
Metadata
Title
Cooperation of immune regulators Tollip and surfactant protein A inhibits influenza A virus infection in mice
Authors
Niccolette Schaunaman
Diana Cervantes
Taylor Nichols
Mari Numata
Julie G. Ledford
Monica Kraft
Hong Wei Chu
Publication date
01-12-2024
Publisher
BioMed Central
Keyword
Influenza
Published in
Respiratory Research / Issue 1/2024
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-024-02820-3

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