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STING Contributes to Host Defense Against Staphylococcus Aureus Pneumonia Through Suppressing Necroptosis

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STING Contributes to Host Defense Against Staphylococcus Aureus Pneumonia Through Suppressing Necroptosis ORIGINAL RESEARCH published: 31 May 2021 doi: 10.3389/fimmu.2021.636861 STING Contributes to Host Defense Against Staphylococcus aureus Pneumonia Through Suppressing Necroptosis † † Zhen-Zhen Liu , Yong-Jun Yang , Cheng-Kai Zhou, Shi-Qing Yan, Ke Ma, Yu Gao and Wei Chen* Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China Edited by: Gee W. Lau, STING (Stimulator of interferon genes) is known as an important adaptor protein or direct University of Illinois at sensor in the detection of nucleotide originating from pathogens or the host. The Urbana-Champaign, United States implication of STING during pulmonary microbial infection remains unknown to date. Reviewed by: Jingjun Lin, Herein, we showed that STING protected against pulmonary S.aureus infection by University of California, Davis, suppressing necroptosis. STING deficiency resulted in increased mortality, more United States bacteria burden in BALF and lungs, severe destruction of lung architecture, and Lei Huang, Newcastle University, United Kingdom elevated inflammatory cells infiltration and inflammatory cytokines secretion. STING *Correspondence: deficiency also had a defect in bacterial clearance, but did not exacerbate pulmonary Wei Chen inflammation during the early stage of infection. Interestingly, TUNEL staining and LDH [email protected] release assays showed that STING-/- mice had increased cell death than WT mice. We † These authors have contributed -/- equally to this work further demonstrated that STING mice had decreased number of macrophages accompanied by increased dead macrophages. Our in vivo and in vitro findings further Specialty section: demonstrated this cell death as necroptosis. The critical role of necroptosis was detected This article was submitted to by the fact that MLKL-/- mice exhibited decreased macrophage death and enhanced host Microbial Immunology, a section of the journal defense to S.aureus infection. Importantly, blocking necroptosis activation rescued host Frontiers in Immunology defense defect against S.aureus pneumonia in STING-/- mice. Hence, these results reveal Received: 03 December 2020 an important role of STING in suppressing necroptosis activation to facilitate early Accepted: 14 May 2021 Published: 31 May 2021 pathogen control during pulmonary S.aureus infection. Citation: Keywords: Staphylococcus aureus (MRSA), pneumonia, STING, innate immune, necroptosis Liu Z-Z, Yang Y-J, Zhou C-K, Yan S-Q, Ma K, Gao Y and Chen W (2021) STING Contributes to Host Defense Against Staphylococcus Abbreviations: S.aureus, Staphylococcus aureus; STING, stimulator of interferon genes; PRRs, pattern recognition receptors; aureus Pneumonia Through IFI204, interferon-inducible protein 204; cGAS, cyclic GMP-AMP synthase; ZBP1, Z-DNA binding protein 1; DDX41, DEAD- Suppressing Necroptosis. box helicase 41; RIPK3, receptor-interacting-serine-threonine kinase-3; MLKL, mixed lineage kinase-domain like protein; Front. Immunol. 12:636861. TBK1, TANK binding kinase 1; IRF3, interferon regulatory factor 3; MOI, multiplicity of infection; BMDM, bone marrow- doi: 10.3389/fimmu.2021.636861 derived macrophage; CFU, colony-forming unit; H&E, hematoxylin and eosin. Frontiers in Immunology | www.frontiersin.org 1 May 2021 | Volume 12 | Article 636861 Liu et al. STING Inhibits Staphylococcus Pneumonia INTRODUCTION In the current study, we show that STING plays a critical role in pulmonary defense against S.aureus infection. STING- Staphylococcus aureus (S.aureus) is a leading cause of pneumonia deficient mice exhibit higher mortality rates, more bacterial and particularly as a secondary infection of influenza (1, 2). The colonization, and more severe lung damage compared to methicillin-resistant S.aureus (MRSA) USA300 strain causes a control mice. STING promotes early pulmonary clearance of widespread infection of the skin, soft tissues, and lung, these S.aureus before developing excessive inflammation. STING infections are related to high morbidity and mortality (3, 4). deficiency results in increased necroptosis which facilitates Furthermore, S.aureus has its arsenal of virulence factors to bacterial pulmonary proliferation. Blocking necroptosis rescues develop antibiotic resistance. Therefore, S.aureus is a serious the defect of pathogen control in STING-/- mice. Collectively, our threat to human health and requires effective treatment strategies. results suggest that STING is essential for the host defense Innate immunity is the first line of defense against pathogens against pulmonary S.aureus infection through inhibiting invasion. Host cells have equipped with a majority of pattern necroptosis activation. recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors, cytosolic DNA sensors, and RIG-I-like receptors, recognizing MATERIALS AND METHODS invading microbes and initiating appropriate immune responses (5). Concerning S.aureus, TLR2 (6), TLR8 (7), TLR9 (8), NOD2 Mice (9), and IFI204 (10) were implicated in S.aureus recognition. C57BL/6J wild-type (WT) mice and STING-/- mice were purchased Moreover, growing evidence indicates that S.aureus has evolved from the Jackson Laboratory (Bar Harbor, ME, USA). MLKL-/- mice to utilize host innate immune molecules to evade eradication by were a gift from Dr. Jia-Huai Han, Xiamen University, China. They the host immune system, as mice deficient in NLRC4, NLRP6, were subsequently backcrossed onto the C57BL/6J background at NOD2, TNFR, and IFNAR expression exhibited significantly least eight generations. Age and gender matched WT controls were improved outcomes in S.aureus pneumonia (11–15), mainly used. The animal studies were conducted according to the reflected in reduced bacterial burden and attenuated pro- experimental practices and standards approved by the Animal inflammatory cytokine production which contributing to Welfare and Research Ethics Committee at Jilin University increased survival. Hence, investigating the innate immune (No. 20150601). mechanisms of host resistance to S.aureus is conducive to the development of novel strategies for control of this infection. Pneumonia Model STING also known as TMEM173, ERIS, MITA, or MPYS. This To induce pneumonia, mice were anesthetized with pentobarbital endoplasmic reticulum-associated protein recognizes cyclic sodium (50 mg/kg, i.p.) prior to intranasal inoculation of S.aureus dinucleotides (CDNs), more importantly, STING also as an (USA300 strain), twenty mL of bacterial suspension containing 1 × adaptor protein for diverse DNA sensors including IFI204, cGAS, 108 CFU of log-phase S.aureus in phosphate-buffered saline (PBS) ZBP1, and DDX41. While it is activated, STING serves as a scaffold was inoculated intranasally to each mouse, subsequently rinsed with for TBK1 and the transcription factor IRF3 (16, 17). IRF3 is ten mL of PBS. At 6 h and 24 h post-infection, mice were euthanized phosphorylated by TBK1, after which it translocates into the to collect bronchoalveolar lavage fluid (BALF) and lung for nucleus to stimulate the transcription of type I interferons (18). quantification of bacterial burden. BALF was collected by STING-mediated type I interferons signaling mainly participates in instilling inside the lung with 0.8 mL PBS containing 100 µg/mL effective immune responses against viral infections. Its role during soybean trypsin inhibitor, which process repeated three times. Cell bacterial diseases is controversial, ranging from protective to counts were performed on BALF using light microscopy utilizing detrimental effects for the host (19). Particularly, IFNAR-deficient Quik-Dip Stain. A part of the lung was homogenized mechanically mice were sufficiently protected against S.aureus pneumonia in cold PBS (at a ratio of 4 mL per gram tissue). BALF and compared with WT mice, consistent with our previous study that homogenized lung were serially diluted and plated onto TSB agar administration of recombinant IFN-b promotes S.aureus plates for bacterial enumeration. For survival experiments, we used proliferation in IFI204-/- mice (10, 20–22). STING is involved in 2×108 CFUs/mouse of S.aureus andobservedsurvivalfor80h diverse bacterial infections and exerts different immune responses post-infection. In other experiments, 100 mL of 100 mMof depending on pathogens and different infectious models. Studies GW806742X (MLKL inhibitor) (SYN-1215, Synkinase, San Diego, have demonstrated that STING played a protective role in response CA, USA) was administered intraperitoneally 12 h and 1 h prior to to bacterial infections such as Pseudomonas aeruginosa (23), Listeria infection. Control mice received equal DMSO. monocytogenes (24), Brucella (25), and Mycobacterium tuberculosis (26, 27). Especially, in the model of S.aureus cutaneous infection, MPO Assay activation of STING antagonized innate immunity and resulted in Lungs collected from WT and KO mice after S.aureus infection infection spread through decreased neutrophil recruitment and IL- were homogenized in 0.5% cetyltrimethylammonium chloride 1b secretion (28). However, much less is known about the biological (4 µL/mg lung). The supernatants were obtained for MPO implication of STING in host defense specifically during pulmonary activity assay. Briefly, samples were transferred to a 96-well microbial infection. After all, the route of administration of bacteria plate mixing with equal volumes (75 µL) of the substrate (3,3’, also determines host diverse responses. 5,5’ tetramethyl-benzidine dihydrochloride,
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